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COG ANBL00B1 - Neuroblastoma Biology Studies

This research trial studies biomarkers in tumor tissue samples from patients with newly diagnosed neuroblastoma or ganglio-neuroblastoma. Studying samples of tumor tissue from patients with cancer in the laboratory may help doctors identify and learn more about biomarkers related to cancer.

Emily Greengard
All
up to 30 Years old
N/A
This study is NOT accepting healthy volunteers
NCT00904241
0807M39682
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Inclusion Criteria:

• All newly diagnosed patients with suspected neuroblastoma, suspected ganglioneuroblastoma, or suspected ganglioneuroma/maturing subtype seen at Children's Oncology Group (COG) institutions are eligible for this study
• There will be no penalty under any circumstances for enrollment of a patient whose definitive institutional diagnosis, or central review diagnosis, is found to be a tumor other than neuroblastoma, ganglioneuroblastoma, or ganglioneuroma/ maturing subtype
• Patients may not have received chemotherapy prior to enrollment on ANBL00B1 and procurement of study-related tissues with the following exception:
• Patients that in the opinion of the treating physician are too ill to undergo pre-treatment tissue biopsy and require EMERGENT chemotherapy may be enrolled on ANBL00B1; documentation of the emergent nature of therapy initiation is required
• It is required that a good faith effort (documented by specimen tracking) be made to submit a neuroblastoma sample (tumor, metastasis, and/or tumor-involved bone marrow) of sufficient quality for MYCN analysis in the Neuroblastoma Reference Laboratory in order for any newly diagnosed patient to be enrolled on ANBL00B1; this should be obtained prior to initiation of therapy
• Exceptions
• In rare cases, patients may be deemed too ill to undergo pre-treatment tissue biopsy and require EMERGENT therapy; the following eligibility guidelines apply to these cases:
• For presumed INSS stage 4S patients: Efforts to submit tumor tissue (e.g., primary tumor, skin nodule, or metastatic site) within 96 hours of EMERGENT therapy initiation should be made; however, if the child is deemed too unstable for such a procedure they may still be enrolled as long as pre-treatment peripheral blood and serum have been submitted
• For all other INSS stages: tumor tissue should be obtained as soon as possible within 96 hours of EMERGENT therapy initiation; patients without tumor tissues submitted within this time-frame are not eligible for enrollment
• Note: it may not be possible to obtain all necessary tumor biomarkers for therapy stratification in such cases; if a patient enrolled on ANBL00B1 undergoes an additional diagnostic procedure within 96 hours of initiating therapy, additional tumor specimens may be submitted to obtain biomarkers used for risk classification; the decision to perform such procedures, and/or submit these specimens, is to be made by the managing clinicians and should reflect the clinical need to know the status of such biomarkers
• Patients enrolled on ANBL1232 in Group A (either A1 or A2) will not have a tumor biopsy or resection upfront; tumor tissue submission is therefore not required for these patients to enroll on ANBL00B1; a peripheral blood and serum sample is the only specimen required to be submitted for this group of patients; should they undergo a biopsy or resection at a later date tumor can be submitted for biomarker testing at this time
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:

• Patients with relapsed neuroblastoma who were not enrolled on ANBL00B1 at original diagnosis are NOT eligible; samples should be submitted as part of the ABTR04B1 protocol
Other: Cytology Specimen Collection Procedure, Other: Laboratory Biomarker Analysis
Ganglioneuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma
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MT2011-11C: High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell (PBSC) Rescue for Neuroblastoma

This therapy involves the use of consolidation chemotherapy, autologous stem cell rescue, post-transplant radiation therapy and a maintenance phase with Isotretinoin (Accutane, 13-cis-retinoic acid) therapy. If available, patients should also consider post-transplant therapy with cytokines and monoclonal antibody (ch14.18) on a COG or NANT trial. Ideally, patients should begin consolidation chemotherapy no later than 8 weeks after the start of Induction Cycle #6. (It is strongly recommended to begin consolidation within 4-6 weeks after starting Induction Cycle #6).

Ashish Gupta
All
up to 30 Years old
N/A
This study is NOT accepting healthy volunteers
NCT01526603
1112M07741
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Inclusion Criteria:

• Less than 30 years of age at diagnosis of neuroblastoma
• No evidence of disease progression: defined as increase in tumor size of >25% or new lesions
• Recovery from last induction course of chemotherapy (absolute neutrophil count > 500 and platelet > 20,000)
• No uncontrolled infection
• Minimum frozen peripheral blood stem cells (PBSCs) of 2 x 10^6 CD34 cells/kg for transplant are mandatory and 2 x 10^6 CD34 cells/kg for back-up are strongly recommended (thus, PBSC of 4 x 106 CD34 cells/kg is encouraged)
• Adequate organ function defined as:
• Hepatic: aspartate aminotransferase (AST) < 3 x upper limit of institutional normal 8 Cardiac: shortening fraction ≥ 27% or ejection fraction ≥ 50%, no clinical congestive heart failure 8 Renal: Creatinine clearance or glomerular filtration rate (GFR) > 60 mL/min/1.73m^2 If a creatinine clearance is performed at end induction and the result is < 100 ml/min/1.73m^2, a GFR must then be performed using a nuclear blood sampling method or iothalamate clearance method. Camera method is NOT allowed as measure of GFR prior to or during Consolidation therapy for patients with GFR or creatinine clearance of < 100 ml/min/1.73m^2 Exclusion Criteria
• Patients with progressive disease should consider participating in phase I studies since consolidation therapy using the regimen outlined in this document have not been determined to be useful.
• Patients who are delayed in consolidation chemotherapy beyond 8 weeks, and don't meet organ function criteria.
Drug: Carboplatin, Biological: Autologous stem cell infusion, Biological: Granulocyte colony stimulating factor, Radiation: Radiation therapy, Drug: Isotretinoin (13-cis-retinoic acid), Drug: Melphalan, Drug: Etoposide
Neuroblastoma
peripheral blood stem cell transplantation, autologous stem cell transplant
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MT2011-09C Alkylator-Intense Conditioning Followed By Autologous Transplantation for Patients with High Risk or Relapsed Solid or CNS Tumors

Treatment guidelines for high risk or relapsed solid tumors consisting of a busulfan, melphalan, thiotepa conditioning followed by an autologous peripheral blood stem cell transplant and, if appropriate, disease specific radiation therapy at day 60+

Ashish Gupta
All
up to 70 Years old
N/A
This study is NOT accepting healthy volunteers
NCT01505569
1107M02641
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Inclusion Criteria:
All patients must have histological verification of malignancy at original diagnosis.
• Eligible Diseases
• Arm A: Solid Tumor
• Ewing's Family Tumors (ES/PNET/DSRCT) - metastatic at time of diagnosis and/or relapsed after therapy
• Renal Tumors - relapsed (all histology - Wilm's tumor) or at diagnosis (clear cell sarcoma and Rhabdoid tumor)
• Hepatoblastoma - metastatic at time of diagnosis and/or relapsed after therapy
• Rhabdomyosarcoma - metastatic at time of diagnosis and/or relapsed after therapy
• Soft Tissue Sarcoma - chemotherapy responsive metastatic disease or chemotherapy responsive relapsed disease
• Primary Malignant Brain Neoplasms <18 years of age - at diagnosis and/or relapse
• Retinoblastoma - disseminated at diagnosis and/or relapsed
• CNS Lymphoma - primary or secondary CNS lymphoma.
• Other High Risk Metastatic or Relapsed Solid Tumors - to be approved by 2 or more pediatric hematology/oncology and bone marrow transplant (BMT) physicians
• Arm B: Certain CNS tumors
• Medulloblastoma: Children less than 36 months (3 years) of age at time of definitive surgery (for histopathologic diagnosis) who have high risk Medulloblastoma, defined as any one of the following:
• > 1.5 cm2 residual disease following resection for any Medulloblastoma histology
• lumbar CSF cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or at least 10 days after definitive surgery
• MRI evidence of (a) gross nodular seeding in the intracranial subarachnoid space or ventricular system distant from primary tumor site, M2; or (b) gross nodular seeding in the spinal subarachnoid space +/- evidence of intracranial seeding, M3; or (c) extraneural metastases, M4,
• Anaplastic Histologic Variant Medulloblastoma: less than 70 years of age, any metastatic stage, with total or sub-total resection.
• Infant Medulloblastoma: Children less than 8 months of age at the time of definitive surgery (for histopathologic diagnosis), any histology, any metastatic state, with total or sub-total resection.
• Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET): Children less than 36 months (3 years) of age at time of definitive surgery (for histopathologic diagnosis) with or without metastatic disease
• Atypical Teratoid/Rhabdoid Tumor (AT/RT): less than 70 years of age with CNS AT/RT (with or without metastatic disease).
• Other High Risk CNS Tumors - to be approved by 2 or more physicians (at least one oncologist and one BMT physician).
• Arm C: Germ Cell Tumors
• Confirmation of germ cell tumor (GCT) histology (both seminoma and nonseminoma). Tumor may have originated in any primary site. NOTE: In rare circumstances, patients will be allowed to enroll even if a pathologic diagnosis may not have been established. This would require a clinical situation consistent with the diagnosis of GCT (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor marker levels {HCG ≥ 500; AFP ≥ 500} and typical pattern of metastases).
• One or more unfavorable prognostic features for achieving a CR with conventional-dose chemotherapy. Unfavorable prognostic features include:
• extragonadal primary site
• PD following an incomplete response (IR) to first-line therapy,
• PD after a conventional-dose salvage (cisplatin + ifosfamide -based) regimen
• Arm D: Certain CNS Tumor patients who can only undergo one transplant
• Medulloblastoma: Children less than 36 months (3 years) of age at time of definitive surgery (for histopathologic diagnosis) who have high risk Medulloblastoma, defined as any one of the following:
• > 1.5 cm2 residual disease following resection for any Medulloblastoma histology
• lumbar CSF cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or at least 10 days after definitive surgery
• MRI evidence of (a) gross nodular seeding in the intracranial subarachnoid space or ventricular system distant from primary tumor site, M2; or (b) gross nodular seeding in the spinal subarachnoid space +/- evidence of intracranial seeding, M3; or (c) extraneural metastases, M4,
• Anaplastic Histologic Variant Medulloblastoma: less than 70 years of age, any metastatic stage, with total or sub-total resection.
• Infant Medulloblastoma: Children less than 8 months of age at the time of definitive surgery (for histopathologic diagnosis), any histology, any metastatic state, with total or sub-total resection.
• Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET): Children less than 36 months (3 years) of age at time of definitive surgery (for histopathologic diagnosis) with or without metastatic disease
• Atypical Teratoid/Rhabdoid Tumor (AT/RT): less than 70 years of age with CNS AT/RT (with or without metastatic disease).
• Other High Risk CNS Tumors including choroid plexus carcinoma in children- to be approved by 2 or more physicians (at least one oncologist and one BMT physician).
• Arm E: Neuroblastoma ** Neuroblastoma (ICD-O morphology 9500/3) or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites.
• Disease Status at Enrollment
• Arm A, Arm B and Arm D must have fit one of the following:
• no evidence of disease or
• stable, non-progressive disease (defined as non-progressive abnormalities on physical exam or CT and/or MRI) within 4 weeks of study entry
• Arm C: Evidence of progressive or recurrent GCT (measurable or non-measurable) following one or more cisplatin-based chemotherapy, defined as meeting at least one of the following criteria:
• Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT. Patients with incomplete gross resection where viable GCT is found are considered eligible.
• Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease.
• Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase.
• Arm E: Patients with the following disease stages at diagnosis are eligible, if they meet the other specified criteria.
• Patients with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following:
• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or
• Age > 18 months (> 547 days) regardless of biologic features or
• Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown.
• Patients with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following:
• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or
• Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.
• Patients with newly diagnosed neuroblastoma with INSS Stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.
• Patients with newly diagnosed neuroblastoma with INSS Stage 4S with MYCN amplification (> 4-fold increase in MYCN expression signals as compared to reference signals), regardless of additional biologic features.
• Patients ≥ 365 days initially diagnosed with neuroblastoma INSS Stage 1, 2, 4S who progressed to aStage 4 without interval chemotherapy.
• Age and Performance Status
• Age and Performance Status, Arm A
• Age: 0 - 70 years
• Performance status: Karnofsky Performance Status ≥ 50% for patients > 16 years of age or Lansky Play Score ≥ 50 for patients ≤ 16 years of age (Note: Neurologic deficits in patients with CNS tumors must be stable for a minimum of 1 week prior to study entry)
• Age and Performance Status, Arm B
• Age: see Eligible diseases, section 3.1, for age criteria
• Performance status: Karnofsky Performance Status ≥ 50% for patients > 16 years of age or Lansky Play Score ≥ 50 for patients ≤ 16 years of age (Note: Neurologic deficits in patients with CNS tumors must be stable for a minimum of 1 week prior to study entry)
• Age and Performance Status, Arm C
• Age: 0-70 years of age
• Performance status: Karnofsky Performance Status ≥ 70% for patients > 16 years of age or Lansky Play Score ≥ 70 for patients ≤ 16 years of age
• Age and Performance Status, Arm D
• Age: see Eligible diseases, section 3.1, for age criteria
• Performance status: Karnofsky Performance Status ≥ 50% for patients > 16 years of age or Lansky Play Score ≥ 50 for patients ≤ 16 years of age (Neurologic deficits in patients with CNS tumors must be stable for a minimum of 1 week prior to study entry)
• Age and Performance Status, Arm E
• Age: Patients must be ≤ 30 years of age at the time of initial diagnosis.
• Performance status: Karnofsky Performance Status ≥ 50% for patients > 16 years of age or Lansky Play Score ≥ 50 for patients ≤ 16 years of age
• Organ Function
• Organ Function, Arm A
• Hematologic: hemoglobin of >9 gm/dl and platelet count > 20,000/μl. Patients may receive transfusions as necessary.
• Renal: GFR ≥ 50 ml/min/1.73m2 or serum creatinine ≤ 2.5 x ULN for age
• Hepatic: AST or ALT ≤ 5 x ULN and bilirubin ≤ 5 x ULN
• Cardiac: ejection fraction ≥ 45% or no clinical evidence of heart failure
• Pulmonary: oxygen saturation > 92% at rest (on room air)
• Organ Function, Arm B (to begin first consolidation cycle)
• Timing: patients must be fully recovered from radiation, induction chemotherapy or surgery prior to receiving consolidation, with minimum elapsed time of 2 weeks.
• Hematologic: ANC > 750/μl, hemoglobin of >8 gm/dl (may receive PRBC transfusions) and platelet count > 75,000/μl (transfusion independent).
• Renal: GFR ≥ 50 ml/min/1.73m2
• Hepatic: AST or ALT ≤ 2.5 x ULN and bilirubin ≤ 1.5 x ULN
• Cardiac: ejection fraction ≥ 45% or no clinical evidence of heart failure
• Pulmonary: oxygen saturation > 94% at rest (on room air)
• Central Nervous System: patients with seizure history are allowed if on anti-convulsants and well controlled; patients must not be in status epilepticus, coma or require assisted ventilation
• Organ Function, Arm C (to begin TI chemotherapy)
• Hematologic: ANC ≥ 750/mm3, platelets ≥ 75,000/mm3
• Renal: GFR ≥ 50 ml/min/1.73m2 or serum creatinine ≤ 2.5 x ULN for age
• Hepatic: AST or ALT ≤ 2.5 x upper limits of normal (ULN), if hepatic involvement < 5 x ULN; bilirubin ≤ 2.0 x upper limits of normal (ULN)
• Arms A and C: Patients with a history of CNS tumor involvement are eligible if they have completed treatment for CNS disease (radiotherapy or surgery or chemotherapy), have recovered from or stabilization of the side effects associated with the therapy and have no evidence of progressive CNS disease at the time of enrollment
• Organ Function, Arm D
• Timing: patients must be fully recovered from radiation, induction chemotherapy or surgery prior to receiving consolidation, with minimum elapsed time of 2 weeks.
• Hematologic: ANC > 750/μl, hemoglobin of >8 gm/dl (may receive PRBC transfusions) and platelet count > 75,000/μl (transfusion independent).
• Renal: GFR ≥ 50 ml/min/1.73m2
• Hepatic: AST or ALT ≤ 2.5 x ULN and bilirubin ≤ 1.5 x ULN
• Cardiac: ejection fraction ≥ 45% or no clinical evidence of heart failure
• Pulmonary: oxygen saturation > 92% at rest (on room air)
• Central Nervous System: patients with seizure history are allowed if on anti-convulsants and well controlled; patients must not be in status epilepticus, coma or require assisted ventilation
• Organ Function, Arm E
• No evidence of disease progression: defined as increase in tumor size of >25% or new lesions.
• Timing: Recovery from last induction course of chemotherapy.
• Minimum frozen PBSC of 4 x 106 CD34 cells/kg as 2 aliquots; i.e. 2 x 106 CD34 cells/kg for each transplant are mandatory. A third aliquot of 2 x 106 CD34 cells/kg is strongly recommended for back-up.
• Hepatic: AST < 3 x upper normal
• Cardiac: Shortening fraction ≥ 27%, or ejection fraction ≥ 50%, no clinical congestive heart failure.
• Renal: Creatinine clearance or GFR > 60 ml/min/1.73m2 (If a creatinine clearance is performed at end of induction and the result is < 100 ml/min/1.73m2, a GFR must be performed using a nuclear blood sampling method or iothalamate clearance method. Camera method is NOT allowed as measure of GFR prior to or during Consolidation therapy for patients with GFR or creatinine clearance of < 100 ml/min/1.73m2.)
Exclusion Criteria:

• Arm A, B, C, and D:
• Pregnant or breastfeeding
• Active, uncontrolled infection and/or human immunodeficiency virus (HIV) positive constitute progressive disease.
• Concomitant enrollment on clinical study (such as COG study) that does not allow co-enrollment on this standard of care protocol (Arm B only)
• Arm E: Pregnant or breastfeeding
• Active, uncontrolled infection and/or HIV positive
• Known contraindication to PBSC collection. Examples of contraindications might be a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.
• Patients that are 12-18 months of age with INSS Stage 4 and all 3 favorable biologic features (ie, non- amplified MYCN, favorable pathology, and DNA index > 1).
Drug: Ifosfamide, Drug: Etoposide, Drug: Mesna, Biological: G-CSF, Drug: Busulfan, Drug: Melphalan, Drug: Thiotepa, Biological: Autologous stem cell infusion, Radiation: Radiation, Drug: Carboplatin, Drug: Paclitaxel, Procedure: Leukapheresis, Drug: Anti-seizure prophylaxis, Drug: Ursodiol
Ewing's Family Tumors, Renal Tumors, Hepatoblastoma, Rhabdomyosarcoma, Soft Tissue Sarcoma, Primary Malignant Brain Neoplasms, Retinoblastoma, Medulloblastoma, Supra-tentorial Primative Neuro-Ectodermal Tumor (PNET), Atypical Teratoid/Rhabdoid Tumor (AT/RT), CNS Tumors, Germ Cell Tumors
autologous transplantation, high risk solid tumor, relapsed solid tumor, Clinics and Surgery Center (CSC)
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COG ANBL1232 - Utilizing Response- and Biology-Based Risk Factors to Guide Therapy in Patients with Non-High- Risk Neuroblastoma

This phase III trial studies how well response and biology-based risk factor-guided therapy works in treating younger patients with non-high risk neuroblastoma. Sometimes a tumor may not need treatment until it progresses. In this case, observation may be sufficient. Measuring biomarkers in tumor cells may help plan when effective treatment is necessary and what the best treatment is. Response and biology-based risk factor-guided therapy may be effective in treating patients with non-high risk neuroblastoma and may help to avoid some of the risks and side effects related to standard treatment.

Emily Greengard
All
up to 18 Months old
Phase 3
This study is NOT accepting healthy volunteers
NCT02176967
1410M54605
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Inclusion Criteria:

• Patients must be:
• < 12 months (< 365 days) of age at diagnosis with INRG stage L1; or
• < 18 months (< 547 days) of age at diagnosis with INRG stage L2 or stage Ms neuroblastoma/ganglioneuroblastoma
• Enrollment on ANBL00B1 or APEC14B1 is required for all newly diagnosed patients
• Patients must have newly diagnosed v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) non-amplified neuroblastoma (International Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or MYCN non-amplified ganglioneuroblastoma verified by histology
• Patients must meet the specified criteria for one of the treatment groups defined below; genomic features include MYCN gene amplification, segmental chromosome aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p, or 17q) and deoxyribonucleic acid (DNA) index
• "Favorable" genomic features are defined by one or more whole-chromosome gains or hyperdiploid tumor (DNA index > 1) in the absence of segmental chromosome aberrations as defined above
• "Unfavorable" genomic features are defined by the presence of any segmental chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p, or 17q) or diploid tumor (DNA index = 1); this includes copy neutral loss of heterozygosity (LOH)
• Only patients with MYCN non-amplified tumors are eligible for this study
• Group A: patients < 12 months (< 365 days) of age with newly diagnosed INRG stage L1 neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• Greatest tumor diameter < 5 cm of adrenal or non-adrenal origin
• Patients with non-adrenal primaries are eligible, but must have positive uptake on metaiodobenzylguanidine (MIBG) scan or elevated catecholamine metabolites (urine or serum) to support the diagnosis of neuroblastoma
• No prior tumor resection or biopsy
• Group A will be further split into two subsets, which are mutually exclusive, for statistical purposes
• Group A1:
• > 6 months and < 12 months of age with an adrenal primary tumor < 5 cm in greatest diameter OR
• Patients less than 6 months of age with an adrenal primary tumor > 3.1 and < 5 cm in greatest diameter OR
• < 12 months of age with a non-adrenal primary site < 5 cm in greatest diameter
• Group A2: =< 6 months of age with an adrenal primary site and tumor =< 3.1 cm in greatest diameter.
• Group B: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage L2 neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• No life threatening symptoms or no impending neurologic or other organ function compromise (e.g. epidural or intraspinal tumors with existing or impending neurologic impairment, periorbital or calvarial-based lesions with existing or impending cranial nerve impairment, anatomic or mechanical compromise of critical organ function by tumor [abdominal compartment syndrome, urinary obstruction, etc.]); horner syndrome is not considered neurologic compromise
• No prior tumor resection, tumor biopsy ONLY
• Only patients with both favorable histology and favorable genomic features will remain on study as part of Group B; the institution will be notified of histologic and genomic results within 3 weeks of specimen submission on ANBL00B1 or APEC14B1
• Group C: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage Ms neuroblastoma/ganglioneuroblastoma
• No prior radiotherapy or chemotherapy, with the exception of dexamethasone, which is allowed
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:

• Patients with MYCN amplified tumors are not eligible
• Group B and C patients who do not enroll on ANBL1232 within 4 weeks of definitive diagnostic procedure
• Group A and C patients, not required to undergo tumor biopsy, who do not enroll on ANBL1232 within 4 weeks of confirmatory imaging study
Drug: Carboplatin, Other: Clinical Observation, Drug: Cyclophosphamide, Drug: Doxorubicin Hydrochloride, Drug: Etoposide, Other: Laboratory Biomarker Analysis, Other: Pharmacological Study
Ganglioneuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Neuroblastoma
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Treatment of Chronic Itch in Atopic Dermatitis with oral Clonidine and oral Nalfurafine

To assess the safety and efficacy of two novel oral agents (clonidine, naltrexone) in the management of atopic dermatitis

Maria Hordinsky
All
18 Years to 70 Years old
Phase 1
This study is NOT accepting healthy volunteers
NCT02268448
1412M57481
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Inclusion Criteria:

• Age range 18-70 years old and ability to give informed consent and HIPAA authorization.
• Female subjects of childbearing potential must have a negative pregnancy test, and must agree to practice two methods of effective birth control during the study period as clonidine is an FDA pregnancy category C drug (including abstinence, oral or implant contraceptives or condoms).
• Diagnosis of AD via simplified UK Working Group Criteria and a baseline PSGA score of 2 or greater
• Willingness to adhere to study protocol
• Subjects taking hormone-containing medications must be on a stable dose for 6 months prior to study start to avoid any confounding influence on sensory and pain perception
Exclusion Criteria:

• Use of topical or oral anti-inflammatory medications for 2 weeks prior to the study start.
• Use of topical or oral anti-histamines for 2 weeks prior to the study start.
• Use of topical or oral anti-pruritic agents for 2 weeks prior to the study start.
• Use of oral neuromodulatory agents for 2 months prior to study start.
• Current use of chronic pain medications (including opioids, antidepressants and anti-epileptic drugs).
• Use of nicotine-containing products for the past 6 months prior to study start.
• History of radiation or chemotherapy.
• History of traumatic injury on prospective test sites.
• Unstable thyroid function within the past 6 months prior to study start to exclude thyroid-related neuropathy (Duyff et al, 2000).
• Known history of central or peripheral nervous system dysfunction.
• History of acute hepatitis, chronic liver disease or end stage liver disease.
• History of human immunodeficiency virus (HIV) or acquired immune deficiency syndrome.
• History of neuropathy associated with chronic obstructive pulmonary disease, diabetes mellitus, documented exposure to organophosphates or heavy metals or polychlorinated biphenyls.
• Known nutritional deficiency (vitamin B12, vitamin D, iron or zinc) within 3 months prior to the study start.
• Use of illicit drugs within the past 6 months prior to study start.
• History of daily use of power tools.
• Lyme disease, porphyria, rheumatoid arthritis, Hansen's disease (leprosy) or use of antineoplastic chemotherapeutic agents.
• Subject has any medical condition that, in the judgment of the Investigator, would jeopardize the subject's safety following exposure to the administered medications.
• Adults lacking capacity to consent
Drug: Clonidine, Drug: Naltrexone
Cutaneous Nerves CNS Itch
itch atopic dermatitis
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Longitudinal Study of Urea Cycle Disorders

This study is seeking individuals with urea cycle disorders. The study aims to perform a long-term analysis of individuals with a UCD.

All
Not specified
N/A
This study is NOT accepting healthy volunteers
NCT00237315
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Inclusion Criteria:

• Diagnosis of NAGS deficiency, defined as the detection of a pathogenic mutation, and/or decreased (less than 20 % of control) NAGS enzyme activity in liver ,and/or hyperammonemia and first degree relative meets at least one of the criteria for NAGS deficiency
• Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver, and/or an identified pathogenic mutation, and/or hyperammonemia and first degree relative meets at least one of the criteria for CPS I deficiency
• Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, and/or less than 20% of control of OTC activity in the liver, and/or elevated urinary orotate (greater than 20 uM/mM) in a random urine sample or after allopurinol challenge test, and/or hyperammonemia and first degree relative meets at least one of the criteria for OTC deficiency
• Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, and/or decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AS gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AS Deficiency
• Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, and/or decreased AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AL gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AL Deficiency
• Diagnosis of ARG deficiency (Hyperargininemia), defined as a greater than or equal to 5-fold elevated arginine levels in the blood, and/or decreased arginase enzyme levels in red blood cells or other appropriate tissue, and/or identification of a pathogenic mutation in the ARG gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for ARG Deficiency
• Diagnosis of HHH Syndrome or ORNT deficiency, defined as a greater than or equal to 5-fold elevated plasma ornithine and homocitrulline levels in the urine, and/or a pathogenic mutation, and/or less than 20% residual labeled ornithine incorporation into protein in cultured fibroblasts, and/or hyperammonemia and first degree relative meets at least one of the criteria for HHH Syndrome or ORNT Deficiency
• Diagnosis of CITR deficiency (Citrullinemia Type II), defined as elevated citrulline levels in the blood and a pathogenic mutation and/or hyperammonemia and first degree relative meets criteria for CITR Deficiency
• Pending diagnosis of a UCD (UCD highly likely), defined as laboratory values highly suggestive of a UCD with symptomatic hyperammonemic episodes but without a verifiable diagnosis
Exclusion Criteria:

• Hyperammonemia caused by an organic academia, lysinuric protein intolerance, mitochondrial disorder, congenital lactic academia, fatty acid oxidation defects, or primary liver disease
• Rare and unrelated comorbidities (e.g., Down's syndrome, intraventricular hemorrhage in the newborn period, and extreme prematurity)
Brain Diseases, Metabolic, Inborn, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders
Urea, Inherited metabolic disorders
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MT2015-25: Tandem Myeloablative Consolidation Therapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma

Ashish Gupta
All
up to 30 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT02605421
1601M82901
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• Less than 30 years of age at diagnosis of neuroblastoma
• End of Induction disease evaluation demonstrating CR, PR, MR or SD
• Hematopoietic Recovery from last induction course of chemotherapy
• No uncontrolled infection
• Minimum frozen PBSCs of 2 x 10^6 CD34 cells/kg for each transplant are mandatory and a PBSC of 2 x 10^6 CD34 cells/kg for back-up are strongly recommended (thus, PBSC of no less than 6 x 10^6 CD34 cells/kg is encouraged). These must all be collected prior to the initiation of consolidation.
• Adequate organ function defined as:
• Hepatic: AST and ALT < 3 x upper limit of institutional normal; ALT ≤ 3 x ULN for age; total bilirubin ≤ 1.5 x ULN for age, if baseline was normal, > 1.0 1.5 x baseline if baseline was abnormal
• Cardiac: shortening fraction ≥ 27% or ejection fraction ≥ 45%, no clinical congestive heart failure
• Pulmonary: no evidence of dyspnea at rest and norequirement for supplemental oxygen
• Renal: Creatinine clearance or GFR > 60 mL/min/1.73m^2. If a creatinine clearance is performed at end induction and the result is < 100 ml/min/1.73m^2, a GFR must then be performed using a nuclear blood sampling method or iothalamate clearance method. Camera method is NOT allowed as measure of GFR prior to or during Consolidation therapy for patients with GFR or creatinine clearance of < 100 ml/min/1.73m^2
• Recovery from acute toxicities of last cycle of induction chemotherapy
• Appropriate written consent - adult or parent/guardian if patient is < 18 years of age and minor information sheet if patient is > 8 years of age
Drug: Thiotepa, Drug: Cyclophosphamide, Drug: Melphalan, Drug: Etoposide, Drug: Carboplatin, Biological: Autologous Stem Cell Infusion, Biological: Granulocyte colony stimulating factor
Neuroblastoma
High-risk neuroblastoma, Neuroblastoma, Myeloablative chemotherapy, Myeloablative consolidation chemotherapy, Autologous peripheral blood stem cell rescue, PBSC, Autologous stem cell rescue
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Circuit-Based Deep Brain Stimulation for Parkinson's disease; Udall Clinical Core

The goal of this study is to provide comprehensive longitudinal assessments of a cohort of PD patients before, during, and after DBS surgery, including neurological, neurophysiological, and neuropsychological data.

Scott Cooper
All
22 Years to 85 Years old
N/A
This study is NOT accepting healthy volunteers
NCT03021031
1611M00822
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Inclusion Criteria:

• Age 22-85 years
• Diagnosis of Parkinson's disease
• Candidate for DBS
Exclusion Criteria:

• Other significant neurological disorder
• Diagnosis of dementia
• Prior history of stereotactic neurosurgery for treatment of Parkinson's disease, tremor, or dystonia.
• Pregnant women
Other: Observational
Parkinson Disease
Parkinson's Disease, Clinics and Surgery Center (CSC)
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Circuit-Based Deep Brain Stimulation for Parkinsons disease; Udall Project 1 Aim 2 and 3

Study objectives: -To characterize spontaneous and movement-related LFP changes in STN and GP in externalized patients under conditions that modulates the severity of tremor, bradykinesia and rigidity (off meds/off stim; on meds/off stim; off meds/on stim, on meds/on stim). -To characterize and compare the relative effect of different forms of closed loop stimulation (e.g., triggered at specific thresholds of low beta/HFO PAC or beta band activity) to standard isochronal high frequency DBS on motor signs and performance during movement.

Michael Park
All
22 Years to 85 Years old
N/A
This study is NOT accepting healthy volunteers
NCT03079037
1701M04144
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Inclusion Criteria:

• Diagnosis of idiopathic PD
• A history of a good response to levodopa (carbidopa/levodopa) defined as at least a 30% improvement in motor UPDRS score
• DBS surgery or IPG battery replacement at UMN is planned as part of routine clinical care.
Exclusion Criteria:

• Other significant neurological disorder
• History of dementia
• Prior history of stereotactic neurosurgery
• Patients with post-operative complications or adverse effects (e.g. ON stimulation dystonias) that affect patient safety or confound the experiment will be excluded from further study
• Pregnant women
Device: Stimulation
Parkinson Disease
Clinics and Surgery Center (CSC)
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Efficacy and Mechanisms of Combined Aerobic Exercise and Cognitive Training in MCI (The ACT Trial)

This study will be a multi-site, single-blinded, randomized controlled trial (RCT) that will screen older adults with mild cognitive impairment (MCI) using 4 steps (over the phone, in-person interview including informed consent, medical verification, exercise stress test/magnetic resonance imaging [MRI]). We will enroll 128 participants (target 96 completers, assuming 25% attrition rate at 6 months). After baseline assessment, participants will be enrolled and randomized within age (65-74 years of age or ≥75 years of age) and study site (Minnesota or Rochester) strata centrally at the University of Minnesota (UMN) to one of four groups: ACT, cycling only, SOP only, or control with equal allocation and using a randomization scheme generated by our UMN biostatistician (CI: Vock). Group allocations will be concealed to all investigators and data collectors. The interventions will last for 6 months with 12-month follow-up. Outcomes include: 1) cognition: composite measures of executive function and episodic memory, 2) AD signature cortical thickness: composite using structural magnetic resonance imaging (MRI), 3) functional connectivity in DMN: resting-state using functional MRI (fMRI), 4) aerobic fitness, and 5) clinical and pathological AD conversion. Cognition and aerobic fitness will be assessed at baseline, 3, 6, 12, and 18 months; AD conversion at 6, 12, and 18 months; and AD signature cortical thickness and DMN at baseline, 6, 12, and 18 months. PIs Yu and Lin have developed and tested strategies in their preliminary studies to successfully ensure the protection of human participants.

Dereck Salisbury
All
18 Years and over
N/A
This study is NOT accepting healthy volunteers
NCT03313895
STUDY00001135
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Inclusion Criteria:
-65 years and older
Behavioral: ACT, Behavioral: Cycling Only, Behavioral: Cognitive Training Only, Behavioral: Stretching and Mental Stimulating Activities
Mild Cognitive Impairment
cognitive impairment, Alzheimer's disease, exercise, cognitive training, imaging, cognitive decline, memory complaint, mild cognitive impairment
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Development of the upper limb motor scale Awareness of Functional tasks with Arm and hand in Stroke (AFAS) (AFAS)

There are 3 objectives in this study: • Reliability of AFAS • Impact of relaxation breathing and patient perception on spasticity and movement of the upper limb • Validity of AFAS

Ann Van de Winckel
All
18 Years to 99 Years old
N/A
This study is NOT accepting healthy volunteers
NCT03328468
STUDY00000821
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Inclusion Criteria:

• Females and males ages 18-99 years of age
• People with stroke who are medically stable with one or more ischemic or
• hemorrhagic stroke(s)
• left or right hemiplegia
• willing and able to attend a one-time behavioral testing session
• willing and able to sign consent to participate
• able to hear, read and comprehend instructions given during the study
• English speaking (or willing to work with a (student) translator)
Exclusion Criteria:

• cognitive impairment (Mini-mental State Exam-brief version, <13/16)
• contractures in the tested arm that would hinder testing arm movements
• adults lacking capacity to consent
• severe neglect, aphasia, apraxia
• other medical conditions that preclude participation
Other: Breathing Exercise
Stroke
Stroke
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COG APEC1621F - NCI-COG PEDIATRIC MATCH (MOLECULAR ANALYSIS FOR THERAPY CHOICE)- PHASE 2 SUBPROTOCOL OF ENSARTINIB IN PATIENTS WITH TUMORS HARBORING ALK OR ROS1 GENOMIC ALTERATIONS

The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) study, referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using genomic sequencing technologies in refractory/recurrent tumors from children and adolescents with cancer. The NCI-COG Pediatric MATCH study (APEC1621) is considered one study under one IND consisting of a Master Version Control protocol, screening protocol component and multiple subprotocol components, with each component being contained in its own separate document. Each “component” consists of the protocol document and its associated informed consent document. The Master Version Control Protocol is the overarching administrative protocol that will keep an up-to-date record of the current version of the screening protocol component and each subprotocol component of Pediatric MATCH. Since each subprotocol component operates independently from the other subprotocol components contained in Pediatric MATCH, each has its own version date. Likewise, the screening protocol component has its own version date since changes in any of the subprotocols may not require changes in the screening protocol.

Emily Greengard
All
12 Months to 21 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT03213652
STUDY00001752
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Inclusion Criteria:

• Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621F based on the presence of an actionable mutation
• Patients must have a body surface area >= 0.5 m^2 at enrollment
• Patients must have radiographically measurable disease at the time of study enrollment. Patients with neuroblastoma who do not have measurable disease but have iobenguane (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on a standard magnetic resonance imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age
• Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil counts [ANC] counts): >= 7 days after the last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell Infusions (with or without total body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial none marrow (BM) radiation
• Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have received prior exposure to ensartinib; prior treatment with other ALK inhibitors is permitted given that at least 5 half-lives or 21 days have elapsed since therapy discontinuation, whichever is greater
• For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (within 7 days prior to enrollment) or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for female
• Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for female
• Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for female
• Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for male and 1.2 mg/dL for female
• Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for male and 1.4 mg/dL for female
• Age >= 16 years: maximum serum creatinine 1.7 mg/dL for male and 1.4 mg/dL for female
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment) (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
• Patients must be able to swallow intact capsules
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study because there is currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment and for one week after the last dose of ensartinib
• Concomitant medications
• Corticosteroids: patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients who are currently receiving another investigational drug are not eligible
• Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• CYP3A4 agents: patients who are currently receiving drugs that are strong inducers or strong inhibitors of CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study
• Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Drug: Ensartinib, Other: Laboratory Biomarker Analysis, Other: Pharmacological Study
Malignant Solid Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Wilms Tumor
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Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)

The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) study, referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using genomic sequencing technologies in refractory/recurrent tumors from children and adolescents with cancer. The NCI-COG Pediatric MATCH study (APEC1621) is considered one study under one IND consisting of a Master Version Control protocol, screening protocol component and multiple subprotocol components, with each component being contained in its own separate document. Each “component” consists of the protocol document and its associated informed consent document. The Master Version Control Protocol is the overarching administrative protocol that will keep an up-to-date record of the current version of the screening protocol component and each subprotocol component of Pediatric MATCH. Since each subprotocol component operates independently from the other subprotocol components contained in Pediatric MATCH, each has its own version date. Likewise, the screening protocol component has its own version date since changes in any of the subprotocols may not require changes in the screening protocol.

Emily Greengard
All
12 Months to 21 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT03213704
STUDY00001752
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Inclusion Criteria:

• APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621A based on the presence of an actionable mutation as defined in APEC1621SC
• Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have iobenguane (MIBG)+ evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT); Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required time frame, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last dose of agent; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell Infusions (with or without total body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.)
• Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial brain metastases (BM) radiation; Note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have received prior exposure to other NTRK inhibitors including but not limited to LOXO-101 (larotrectinib), entrectinib (RXDX-101), DS6051, PLX7486
• For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL); male: 0.6 female: 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL); male: 0.8 female: 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL); male: 1 female: 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL); male: 1.2 female: 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL); male: 1.5 female: 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL); male: 1.7 female: 1.4
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL
• Patients with seizure disorder may be enrolled if on anti-convulsants and well controlled
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflect (DTR); any grade of DTR is eligible
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study treatment
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease (GVHD) post bone marrow transplant are not eligible for this trial
• Patients who are currently receiving drugs that are strong inducers or inhibitors of CYP3A4 are not eligible; strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study; Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed
• Patients who have received prior therapy with a specific inhibitor of TRK (including but not limited to entrectinib [RXDX-101], DS-6051b, and PLX7486) are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Drug: Larotrectinib Sulfate
Advanced Malignant Solid Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Wilms Tumor
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COG APEC1621SC - NCI-COG PEDIATRIC MATCH (MOLECULAR ANALYSIS FOR THERAPY CHOICE) SCREENING PROTOCOL

The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) study, referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using genomic sequencing technologies in refractory/recurrent tumors from children and adolescents with cancer. The NCI-COG Pediatric MATCH study (APEC1621) is considered one study under one IND consisting of a Master Version Control protocol, screening protocol component and multiple subprotocol components, with each component being contained in its own separate document. Each “component” consists of the protocol document and its associated informed consent document. The Master Version Control Protocol is the overarching administrative protocol that will keep an up-to-date record of the current version of the screening protocol component and each subprotocol component of Pediatric MATCH. Since each subprotocol component operates independently from the other subprotocol components contained in Pediatric MATCH, each has its own version date. Likewise, the screening protocol component has its own version date since changes in any of the subprotocols may not require changes in the screening protocol.

Emily Greengard
All
12 Months to 21 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT03155620
STUDY00001752
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Inclusion Criteria:

• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must be >= 12 months and =< 21 years of age at the time of study enrollment
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g. langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where patient enrolls prior to histologic confirmation of recurrent disease, patient is ineligible and should be withdrawn from study if histology fails to confirm recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor Testing Requirement: Tumor sample availability requirement for stage 1 of Pediatric MATCH (patients enrolled from start of study in July 2017 through 12/31/21); Patients must have an formalin-fixed paraffin-embedded (FFPE) tumor sample available for MATCH study testing from a biopsy or surgery that was performed at any point after initial tumor recurrence/progression, or be planned to have a procedure to obtain such a sample that is considered to be of potential benefit by the treating clinicians; a tumor sample from a clinically performed diagnostic (pre-treatment) biopsy will be acceptable for enrollment onto Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized acid-based decalcification methods are not generally suitable for MATCH study testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor molecular profiling report availability requirement for Stage 2 of Pediatric MATCH (patients enrolled starting 2022): In stage 2 of the study, no tumor samples will be submitted for centralized clinical tumor profiling; instead, a tumor molecular profiling report from a College of American Pathologists (CAP)/ Clinical Laboratory Improvements Amendments (CLIA)-approved testing laboratory must be submitted for review by the Molecular Review Committee (MRC)
• This molecular profiling must have been performed on a tumor sample that was obtained at any point after initial tumor recurrence/progression and must be accompanied by a pathology report for the same tumor specimen; a molecular profiling report for a diagnostic (pre-treatment) tumor sample will be acceptable for enrollment onto Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse intrinsic pontine gliomas) or thalamus. In the event that molecular profiling reports are available from multiple timepoints, the most recent report should be prioritized for study submission
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic deficits in patients with central nervous system (CNS) tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have radiographically measurable disease; measurable disease based on imaging obtained less than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but will need to meet all criteria prior to enrollment on any assigned treatment subprotocol. Patients must be enrolled onto a subprotocol within 2 weeks (14 days) of treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); Note: neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol specified therapy, the patients must have radiographically measurable disease; patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard MRI or CT
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a subprotocol, the following general criteria for initiation of therapy will be required:
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer directed therapy prior to enrollment to the subprotocol; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anticancer agents known to be myelosuppressive: for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the last dose of agent; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells, etc.)
• X-ray therapy (XRT)/External Beam Irradiation including Protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation; note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase (SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact capsules/tablets, unless otherwise specified in the subprotocol to which they are assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior therapy will be included with specific treatment subprotocols
Exclusion Criteria:

• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, or because there is currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in females who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific subprotocols, patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment to the subprotocol will not be eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time of consent and enrollment to a subprotocol; other investigational agents may not be administered to patients while they are receiving study drug as part of a subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of consent and enrollment to a subprotocol; other investigational agents may not be administered to patients while they are receiving study drug as part of a subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will be included with specific treatment subprotocols
Procedure: Biopsy, Procedure: Biospecimen Collection, Drug: Ensartinib, Drug: Erdafitinib, Other: Laboratory Biomarker Analysis, Drug: Larotrectinib Sulfate, Procedure: Mutation Carrier Screening, Drug: Olaparib, Drug: Palbociclib, Other: Pharmacological Study, Drug: Samotolisib, Drug: Selpercatinib, Drug: Selumetinib Sulfate, Drug: Tazemetostat, Drug: Tipifarnib, Drug: Ulixertinib, Drug: Vemurafenib
Advanced Malignant Solid Neoplasm, Ann Arbor Stage III Non-Hodgkin Lymphoma, Ann Arbor Stage IV Non-Hodgkin Lymphoma, Histiocytic Sarcoma, Juvenile Xanthogranuloma, Langerhans Cell Histiocytosis, Malignant Glioma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Recurrent Soft Tissue Sarcoma, Refractory Ewing Sarcoma, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Rhabdoid Tumor, Stage III Osteosarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Wilms Tumor
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Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)

The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) study, referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using genomic sequencing technologies in refractory/recurrent tumors from children and adolescents with cancer. The NCI-COG Pediatric MATCH study (APEC1621) is considered one study under one IND consisting of a Master Version Control protocol, screening protocol component and multiple subprotocol components, with each component being contained in its own separate document. Each “component” consists of the protocol document and its associated informed consent document. The Master Version Control Protocol is the overarching administrative protocol that will keep an up-to-date record of the current version of the screening protocol component and each subprotocol component of Pediatric MATCH. Since each subprotocol component operates independently from the other subprotocol components contained in Pediatric MATCH, each has its own version date. Likewise, the screening protocol component has its own version date since changes in any of the subprotocols may not require changes in the screening protocol.

Emily Greengard
All
12 Months to 21 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT03213678
STUDY00001752
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Inclusion Criteria:

• Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621D based on the presence of an actionable mutation as defined in APEC1621SC; note that treatment assignment may be to primary cohort A for patients with TSC1 or TSC2 loss of function mutations or primary cohort B for patients with other PI3K/MTOR pathway mutations
• Patients accruing to dose level 1 must have a body surface area >= 0.52 m^2 at the time of study enrollment; patients accruing to dose level 2 must have a body surface area >= 0.37 m^2 at the time of study enrollment; patients accruing to dose level -1 must have a body surface area >= 0.75 m^2 at the time of study enrollment
• Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Bone lesions without an associated soft tissue mass >= 10 mm in greatest diameter; bone lesions with an associated soft tissue mass >= 10 mm in greatest diameter imaged by CT or MRI are considered measurable
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell Infusions (with or without total body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
• Note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, iobenguane I-131 [131I-MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have received prior exposure to LY3023414
• Patients must not have received prior exposure to an agent specifically directed at the PI3K/MTOR pathway (a PI3K inhibitor, an AKT inhibitor, an MTOR inhibitor, including rapalogs, or a combined PI3K/MTOR inhibitor)
• For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL
• Patients must have a normal blood sugar level for age; if an initial random draw (i.e. non-fasting) blood glucose value is out of range, it is acceptable to repeat this test as a fasting draw
• Patients must have a serum triglyceride level =< 300 mg/dL and serum cholesterol level =< 300 mg/dL; if an initial random draw (i.e. non-fasting) is out of range, it is acceptable to repeat this test as a fasting draw
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Nervous system disorders (by Common Terminology Criteria for Adverse Events version
• 0 [CTCAE V 5.0]) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible
• Corrected QT (QTc) interval =< 480 milliseconds
• Patients must be able to swallow intact tablets
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while receiving study treatment and for 3 months after the last dose of LY3023414
• Concomitant medications
• Corticosteroids: patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients who are currently receiving another investigational drug are not eligible
• Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who have an uncontrolled infection are not eligible
• Patients who have insulin dependent diabetes are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients with subependymal giant cell astrocytomas (SEGAs) are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Other: Laboratory Biomarker Analysis, Other: Pharmacological Study, Drug: Samotolisib
Advanced Malignant Solid Neoplasm, Ann Arbor Stage III Non-Hodgkin Lymphoma, Ann Arbor Stage IV Non-Hodgkin Lymphoma, Malignant Glioma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Solid Neoplasm, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Primary Central Nervous System Neoplasm, Rhabdoid Tumor, Stage III Osteosarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Wilms Tumor
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Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia

This phase II trial studies how well trametinib works in treating patients (≥ 2 years and < 22 years of age) with juvenile myelomonocytic leukemia that has come back or does not respond to treatment. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Emily Greengard
All
1 Month to 21 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT03190915
STUDY00003883
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Inclusion Criteria:

• Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease; the diagnosis is made based on the following criteria
• JMML category 1 (all of the following): the diagnostic criteria must include all features in category 1 and EITHER (i) one of the features in category 2 OR (ii) two features from category 3 to make the diagnosis
• Splenomegaly
• > 1000 (1 x 10^9/uL) circulating monocytes
• < 20% blasts in the bone marrow or peripheral blood
• Absence of the t(9;22) or BCR/ABL fusion gene
• JMML category 2 (at least one of the following if at least two category 3 criteria are not present):
• Somatic mutation in RAS or PTPN11
• Clinical diagnosis of NF1 or NF1 gene mutation
• Homozygous mutation in CBL
• Monosomy 7
• JMML category 3 (at least two of the following if no category 2 criteria are met):
• Circulating myeloid precursors
• White blood cell count, > 10 000 (10 x 10^9/ uL)
• Increased hemoglobin F for age
• Clonal cytogenetic abnormality
• GM-CSF hypersensitivity
• Patients with refractory or relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (DNA) demethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality; frontline therapy is defined as one cycle of intravenous chemotherapy that includes of any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine; frontline therapy will also include any conditioning regimen as part of a stem cell transplant; patients who transform to AML at any point with more than 20% blasts are not eligible for this trial
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment
• Myelosuppressive chemotherapy: patients must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea
• Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy
• Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• Biologic (anti-neoplastic agent): at least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
• Monoclonal antibodies:
• At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines
• At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody
• Radiotherapy:
• >= 2 weeks must have elapsed since local palliative external radiation therapy (XRT) (small port)
• >= 6 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if traumatic brain injury (TBI) was received
• >= 4 weeks must have elapsed if other substantial bone marrow irradiation was given
• Stem cell transplant or rescue without TBI: no evidence of active graft versus (vs.) host disease and >= 3 months must have elapsed since transplant; >= 4 weeks must have elapsed since any donor lymphocyte infusion
• Patients must not be known to be refractory to red blood cell or platelet transfusions
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: Maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male) 0.4 (female)
• 6 months to < 1 year: 0.5 (male) 0.5 (female)
• 1 to < 2 years: 0.6 (male) 0.6 (female)
• 2 to < 6 years: 0.8 (male) 0.8 (female)
• 6 to < 10 years: 1 (male) 1 (female)
• 10 to < 13 years: 1.2 (male) 1.2 (female)
• 13 to < 16 years: 1.5 (male) 1.4 (female)
• >= 16 years: 1.7 (male) 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (=< 135 U/L) (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL
• Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA)
• Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs
• Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed
Exclusion Criteria:

• Patients who are pregnant or breast-feeding are not eligible for this study as there is yet no available information regarding human fetal or teratogenic toxicities; negative pregnancy tests must be obtained in girls who are post-menarchal; patients of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; women of childbearing potential should be advised to use effective contraception for 4 months after the last dose of trametinib; trametinib may also potentially be secreted in milk and therefore breastfeeding women are excluded; female patients should not breastfeed during treatment with trametinib, and for 4 months following the last dose; male patients must use a condom during intercourse and agree not to father a child during therapy and for 4 months following discontinuation of trametinib to avoid unnecessary exposure of trametinib to the fetus
• Concomitant Medications
• Corticosteroids: patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Note: hydrocortisone used as a pre-medication to prevent transfusion related reactions is not considered a concomitant corticosteroid
• Investigational drugs: patients who are currently receiving another investigational drug are not eligible
• Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible (except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
• Anti-graft versus host disease (GVHD) or agents to prevent organ rejection post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
• Cardiac medications: any medications for treatment of left ventricular systolic dysfunction
• Patients who have an uncontrolled infection are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
• Patients with a history of hepatic sinusoid obstructive syndrome (veno-occlusive disease) within the prior 3 months are not eligible
• Patients with a history of or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible
• Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension
• Patients with uncontrolled systemic disease(s) such as hypertension or diabetes mellitus are not eligible; blood pressure must be =< the 95th percentile for age, height, and gender
• Patients with a history of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib are not eligible
• Patients with a clinical diagnosis of Noonan syndrome are not eligible; Note: patients with Casitas B-lineage lymphoma (CBL) syndrome, also known as Noonan-like syndrome, are eligible to enroll
Drug: Trametinib
Juvenile Myelomonocytic Leukemia, Neurofibromatosis Type 1
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MT2018-19: COG ANBL1531 - A Phase 3 Study of 131I-Metaiodobenzylguanidine (131I-MIBG) or ALK Inhibitor Therapy Added to Intensive Therapy for Children with Newly Diagnosed High-Risk Neuroblastoma (NBL) (IND# 134379)

This partially randomized phase III trial studies iobenguane I-131 or ALK Inhibitor Therapy and standard therapy in treating younger patients (365 days to 30 years of age) with newly-diagnosed high-risk neuroblastoma or ganglioneuroblastoma.

Emily Greengard
All
365 Days to 30 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT03126916
STUDY00003568
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Inclusion Criteria:

• Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to enrollment on ANBL1531 (NCT03126916)
• Patient must be >= 365 days and =< 30 years of age at diagnosis
• Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; the following disease groups are eligible:
• Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features:
• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR
• Age > 547 days regardless of biologic features
• Patients with INRG stage MS disease with MYCN amplification
• Patients with INRG stage L2 disease with MYCN amplification
• Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS disease who progressed to stage M without prior chemotherapy may enroll within 4 weeks of progression to stage M
• Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1 disease who progress to stage M without systemic therapy may enroll within 4 weeks of progression to stage M
• Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing); patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease but subsequently found to meet the criteria will also be eligible; patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows:
• 1 to < 2 years: male = 0.6; female = 0.6
• 2 to < 6 years: male = 0.8; female = 0.8
• 6 to < 10 years: male = 1; female = 1
• 10 to < 13 years: male = 1.2; female = 1.2
• 13 to < 16 years: male = 1.5; female = 1.4
• >= 16 years: male = 1.7; female = 1.4
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN; for the purposes of this study, ULN for SGPT (ALT) is 45
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by echocardiogram or radionuclide angiogram
• No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure
Exclusion Criteria:

• Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for high risk classification but are not eligible for this trial)
• Patients with bone marrow failure syndromes
• Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to underlying medical disorders
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
Procedure: Autologous Hematopoietic Stem Cell Transplantation, Drug: Busulfan, Drug: Carboplatin, Drug: Cisplatin, Drug: Cyclophosphamide, Drug: Dexrazoxane Hydrochloride, Biological: Dinutuximab, Drug: Doxorubicin Hydrochloride, Drug: Etoposide Phosphate, Radiation: External Beam Radiation Therapy, Radiation: Iobenguane I-131, Drug: Isotretinoin, Drug: Lorlatinib, Drug: Melphalan Hydrochloride, Biological: Sargramostim, Procedure: Therapeutic Conventional Surgery, Drug: Thiotepa, Drug: Topotecan Hydrochloride, Drug: Vincristine Sulfate
Ganglioneuroblastoma, Neuroblastoma
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Sleep SMART: Sleep for Stroke Management And Recovery Trial (Sleep SMART)

Investigator-initiated, phase 3 multicenter, prospective randomized open-, blinded-endpoint (PROBE) controlled trial to test whether treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure is effective for secondary prevention and recovery after stroke.

Kamakshi Lakshminarayan
All
18 Years and over
N/A
This study is NOT accepting healthy volunteers
NCT03812653
STUDY00006842
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Inclusion Criteria:

• TIA with ABCD2 ≥4 or ischemic stroke, within the prior 14 days.
Exclusion Criteria:

• pre-event inability to perform all of own basic ADLs
• unable to obtain informed consent from subject or legally authorized representative
• incarcerated
• known pregnancy
• current mechanical ventilation (can enroll later if this resolves) or tracheostomy
• current use of positive airway pressure, or use within one month prior to stroke
• anatomical or dermatologic anomaly that makes use of CPAP interface unfeasible
• severe bullous lung disease
• history of prior spontaneous pneumothorax or current pneumothorax
• hypotension requiring current treatment with pressors (can enroll later if this resolves)
• other specific medical circumstances that conceivably, in the opinion of the site PI, could render the patient at risk of harm from use of CPAP
• massive epistaxis or previous history of massive epistaxis
• cranial surgery or head trauma within the past 6 months, with known or possible CSF leak or pneumocephalus
• recent hemicraniectomy or suboccipital craniectomy (i.e. those whose bone has not yet been replaced), or any other recent bone removal procedure for relief of intracranial pressure
• current receipt of oxygen supplementation >4 liters per minute
• current contact, droplet, respiratory/airborne precautions
Device: CPAP
Ischemic Stroke, Sleep Apnea, Sleep Apnea, Obstructive, TIA, Stroke, CPAP, Telemedicine, Home Sleep Apnea Test, Randomized Clinical Trial, Multicenter Trial
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Maximizing the Impact of Neuroplasticity Using Transcranial Electrical Stimulation Study 1 (MINUTES)

All
18 Years to 60 Years old
N/A
This study is also accepting healthy volunteers
NCT03896425
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Inclusion Criteria:

• Ability to provide consent and comply with study procedures.
• Age 18 - 60 years old.
• Estimated IQ range within the range: 70 ≤ IQ ≤ 115.
• No Serious and Persistent Mental Illness (SPMI) or addictive disorder diagnosis as measured by the MINI (Mini International Neuropsychiatric Interview), or sleep disorder;
• Ability to participate in three weekly 45' training sessions over 12 weeks and participate in four assessments.
Exclusion Criteria:

• Any medical condition or treatment with neurological sequelae (e.g. stroke, tumor, loss of consciousness > 30 min, HIV).
• Contraindications for tDCS or MRI scanning (tDCS contraindication: history of seizures; MRI contraindications: The research team will utilize the CMRR Center's screening tools and adhere to the screening SOP during enrollment of all research participants in this protocol. The CMRR Center's screening tools and SOP are IRB approved under the CMRR Center Grant (HSC# 1406M51205) and information regarding screening procedures is publicly available on the CMRR website (CMRR Policies / Procedures).
Device: Transcranial direct current stimulation (tDCS)
Transcranial Direct Current Stimulation, Healthy
tDCS, cognitive training, functional connectivity, non-invasive brain stimulation
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Increased thalamocortical connectivity in tdcs-potentiated generalization of cognitive training (MINUTES)

The overarching goals of this proposal are to deploy neuroimaging and cognitive testing to understand how tDCS with cognitive training affect thalamocortical circuitry in individuals with and without psychosis and to examine variability in response within both groups.

Kelvin Lim
All
18 Years to 60 Years old
N/A
This study is NOT accepting healthy volunteers
NCT03896438
STUDY00003506
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Inclusion Criteria:

• Ability to provide consent and comply with study procedures.
• Age 18 - 60 years old.
• Estimated IQ range within the range: 70 ≤ IQ ≤ 115.
• Schizophrenia or schizoaffective disorder as assessed by the MINI (Mini International Neuropsychiatric Interview)(Sheehan et al., 1998).
• Not having a current addictive disorder as measured by MINI (Mini International Neuropsychiatric Interview), or a sleep disorder.
• Ability to participate in three weekly 45' training sessions over 12 weeks and participate in four assessments.
• Clinically stable and on stable medications for at least one month before start of study.
Exclusion Criteria:

• Any medical condition or treatment with neurological sequelae (e.g. stroke, tumor, loss of consciousness > 30 min, HIV).
• Contraindications for tDCS or MRI scanning (tDCS contraindication: history of seizures; MRI contraindications: The research team will utilize the CMRR Center's screening tools and adhere to the screening SOP during enrollment of all research participants in this protocol. The CMRR Center's screening tools and SOP are IRB approved under the CMRR Center Grant (HSC# 1406M51205) and information regarding screening procedures is publicly available on the CMRR website (CMRR Policies / Procedures).
Device: Transcranial Direct Current Stimulation (tDCS)
Transcranial Direct Current Stimulation, Schizophrenia, Schizoaffective Disorder
tDCS, cognitive training, functional connectivity
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Phase 1/2 Study to Evaluate Palbociclib (IBRANCE?) in Combination With Irinotecan and Temozolomide or in Combination with Topotecan and Cyclophosphamide in Pediatric Patients With Recurrent or Refractory Solid Tumors Protocol No.: ADVL1921/A5481092

This is a Phase 1/2 multicenter, open-label study to evaluate palbociclib in combination with either irinotecan (IRN) and temozolomide (TMZ) or topotecan (TOPO) and cyclophosphamide (CTX) chemotherapy in children, adolescents and young adults with recurrent or refractory solid tumors. The study consists of a non- randomized Phase 1 portion for recurrent or refractory solid tumors followed by potential non- randomized tumor specific cohort(s) and a randomized, Phase 2 portion for recurrent or refractory EWS.

Emily Greengard
All
2 Years to 20 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT03709680
STUDY00007068
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Inclusion:
• Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma. Histopathology confirmation of EWSR1-ETS or FUS-ETS rearrangement is required or availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or refractory disease with no known bone marrow metastases and at least evaluable disease.
• Age ≥2 and <21 years at the time of study entry.
• Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
• Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed).
• Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits.
• Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome.
• Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component).
• Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia.
• Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit.
• Evidence of a personally signed and dated informed consent document indicating that the patient or a legally acceptable representative/parent(s)/legal guardian of minors, has been informed of all pertinent aspects of the study. Minor study patients also must provide age appropriate assent according to the local guidelines, where applicable.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures. Exclusion:
• Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 :prior treatment with a CDK4/6 inhibitor or prior treatment with an IRN and/or TMZ-containing regimen.
• Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination.
• Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.)
• Prior growth factors (including filgrastim) within 7 days before study entry or PEG-filgrastim within 14 days before study entry.
• Radiation therapy within 14 days before study entry.
• Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
• Previous high dose chemotherapy requiring stem cell rescue within 90 days or persistent AE >Grade 1.
• Prior irradiation to >50% of the bone marrow (see Appendix 9).
• Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry.
• Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
• For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
• Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days.
• Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable.
• Hereditary bone marrow failure disorder.Phase 2 portion patients with bone marrow involvement are excluded.
• QTc >470 msec.
• History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%.
• Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
• Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
• Other severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
• Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
• Fertile male patients and female patients of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 after the last dose of investigational product.
Drug: Palbociclib, Drug: Temozolomide, Drug: Irinotecan, Drug: Topotecan, Drug: Cyclophosphamide
Ewing Sarcoma, Solid Tumors, Rhabdoid Tumor, Rhabdomyosarcoma, Neuroblastoma, Medulloblastoma, Diffuse Intrinsic Pontine Glioma
Ewing sarcoma (EWS), rhabdomyosarcoma (RMS), neuroblastoma (NBL), Brain tumor
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A Safety and Pharmacokinetic Study of Single Agent REGN2810 in Pediatric Patients with Relapsed or Refractory Solid or Central Nervous System (CNS) Tumors and a Safety and Efficacy Trial of REGN2810 in Combination with Radiotherapy in Pediatric Patients with Newly Diagnosed Diffuse Intrinsic Pontine Glioma, Newly Diagnosed High-Grade Glioma, or Recurrent High-Grade Glioma (PNOC013)

Phase I will include children 0 years of age to <18 years of age with recurrent or refractory solid or CNS tumors. Efficacy Phase will include children and young adults ≥3 years of age and <25 years of age with newly diagnosed diffuse intrinsic pontine glioma (DIPG), newly diagnosed high-grade glioma (HGG), or recurrent HGG.

Christopher Moertel, MD
All
up to 25 Years old
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT03690869
STUDY00004561
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Key
Inclusion Criteria:

• Age 0 to <18 years of age (Phase 1)
• Age ≥3 and ≤25 years of age (Efficacy Phase)
• Karnofsky performance status ≥50 (patients >16 years) or Lansky performance status ≥50 (patients ≤ 16 years)
• Life expectancy >8 weeks
• Adequate Bone Marrow Function
• Adequate Renal Function
• Adequate Liver Function
• Adequate Neurologic Function Key
Exclusion Criteria:

• Patients with bulky metastatic disease of the CNS causing Uncal herniation or symptomatic midline shift, significant, symptomatic mass effect, or uncontrolled neurological symptoms such as seizures or altered mental status
• Patients with metastatic spine disease and gliomatosis as documented by diffuse involvement of >2 lobes
• Patients who are receiving any other investigational anticancer agent(s)
• Patients on greater than dexamethasone 0.1 mg/kg/day (maximum 4 mg/day) or equivalent dose in alternate corticosteroid, or actively undergoing corticosteroid dose escalation in the last 7 days
• Patients with a history of allogeneic stem cell transplant
• Prior treatment with an agent that blocks the PD-1/PD-L1/PD-L2 pathway Note: Other protocol-defined Inclusion/Exclusion criteria apply
Drug: cemiplimab (monotherapy), Drug: cemiplimab (maintenance), Radiation: Conventional or hypofractionated, Radiation: Re-irradiation
Relapsed Solid Tumor, Refractory Solid Tumor, Relapsed Central Nervous System Tumor, Refractory Central Nervous System Tumor, Diffuse Intrinsic Pontine Glioma, High Grade Glioma
Newly Diagnosed, Recurrent, Refractory
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Multi-arm Optimization of Stroke Thrombolysis (MOST)

This study is designed to find out whether adding one of two blood-thinning medications, argatroban or eptifibatide, to the standard treatment after a stroke helps to decrease the impact of strokes and is safe. Both are FDA-approved blood thinners, but are not approved for treating strokes.

Oladi Bentho
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT03735979
STUDY00006255
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Inclusion Criteria:

• Acute ischemic stroke patients
• Treated with 0.9mg/kg IV rt-PA or 0.25mg/kg IV TNK within 3 hours of stroke onset or time last known well
• Age ≥ 18
• NIHSS score ≥ 6 prior to IV thrombolysis
• Able to receive assigned study drug within 60 minutes but no later than 75 minutes of initiation of IV thrombolysis
Exclusion Criteria:

• Known allergy or hypersensitivity to argatroban or eptifibatide
• Previous stroke in the past 90 days
• Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation
• Clinical presentation suggested a subarachnoid hemorrhage, even if initial CT scan was normal
• Any surgery, or biopsy of parenchymal organ in the past 30 days
• Trauma with internal injuries or ulcerative wounds in the past 30 days
• Severe head trauma in the past 90 days
• Systolic blood pressure persistently >180mmHg post-IV thrombolysis despite antihypertensive intervention
• Diastolic blood pressure persistently >105mmHg post-IV thrombolysis despite antihypertensive intervention
• Serious systemic hemorrhage in the past 30 days
• Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR >1.5
• Positive urine or serum pregnancy test for women of child bearing potential
• Glucose <50 or >400 mg/dl
• Platelets <100,000/mm3
• Hematocrit <25 %
• Elevated pre-thrombolysis PTT above laboratory upper limit of normal
• Creatinine > 4 mg/dl
• Ongoing renal dialysis, regardless of creatinine
• Received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) in full dose within the previous 24 hours
• Abnormal PTT within 48 hours prior to randomization after receiving heparin or a direct thrombin inhibitor (such as bivalirudin, argatroban, dabigatran or lepirudin)
• Received Factor Xa inhibitors (such as Fondaparinaux, apixaban or rivaroxaban) within the past 48 hours
• Received glycoprotein IIb/IIIa inhibitors within the past 14 days
• Pre-existing neurological or psychiatric disease which confounded the neurological or functional evaluations e.g., baseline modified Rankin score >3
• Other serious, advanced, or terminal illness or any other condition that the investigator felt would pose a significant hazard to the patient if rt-PA, TNK, eptifibatide or argatroban therapy was initiated a. Example: known cirrhosis or clinically significant hepatic disease
• Current participation in another research drug treatment or interventional device trial - Subjects could not start another experimental agent until after 90 days
• Informed consent from the patient or the legally authorized representative was not or could not be obtained
• High density lesion consistent with hemorrhage of any degree
• Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT Scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for treatment
Drug: Argatroban, Drug: Eptifibatide, Drug: Placebo
Acute Ischemic Stroke
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COG ANBL1821 - A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab with or without Eflornithine (DFMO) (IND# 141913) in Children with Relapsed, Refractory or Progressive Neuroblastoma

The purpose of this prospective, randomized Phase 2 study is to find out if giving eflornithine (DFMO) along with dinutuximab, irinotecan, and temozolomide is tolerated in patients ≥ 1 year of age. It will also investigate how effective the drug combination is against relapsed or refractory neuroblastoma (NBL).

Emily Greengard
All
1 Year and over
Phase 2
This study is NOT accepting healthy volunteers
NCT03794349
STUDY00006850
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Inclusion Criteria:

• Patients must have had histologic verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the time of initial diagnosis.
• For the purposes of this study, aggressive multidrug chemotherapy is defined as chemotherapy including 2 or more agents that must include an alkylating agent and a platinum-containing compound as intended to treat high-risk disease. The doses of chemotherapy must be comparable to those used in frontline high-risk neuroblastoma therapies (examples include A3973, ANBL0532, ANBL09P1, ANBL12P1, and ANBL1531). Patients must have ONE of the following:
• First episode of recurrent high-risk disease following completion of aggressive multi-drug frontline high-risk therapy.
• First episode of progressive high-risk disease during aggressive multi-drug frontline therapy.
• Primary resistant/refractory disease (less than partial response by International Neuroblastoma Response Criteria [INRC]) detected at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1, ANBL12P1, ANBL1531, etc.).
• Patients must have at least ONE of the following at the time of enrollment:
• Measurable tumor on magnetic resonance imaging (MRI) or computed tomography (CT) scan. Measurable is defined as >= 10 mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates increased fludeoxyglucose F-18 (FDG) uptake on positron emission tomography (PET) scan.
• MIBG-avid lesion detected on MIBG scan with positive uptake at a minimum of one site. This site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction.
• Patients with resistant/refractory soft tissue disease that is not MIBG avid or does not demonstrate increased FDG uptake on PET scan must undergo biopsy to document the presence of viable neuroblastoma. Biopsy is not required for patients who have a new site of soft tissue disease (radiographic evidence of disease progression) regardless of whether progression occurs while receiving therapy or after completion of therapy.
• Patients with bone marrow disease only will be eligible if they have more than 5% disease involvement (documented neuroblastoma cells) in at least one sample from bilateral bone marrow biopsies.
• Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT eligible for this study.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age.
• Primary refractory/resistant patients must have received at least 4 cycles of frontline high-risk chemotherapy. Frontline therapy may also have included surgery, chemotherapy, autologous stem cell transplantation (SCT) +/- MIBG, immunotherapy, radiotherapy, and retinoids but must NOT have received second line therapy for resistant/refractory, relapsed, or progressive disease. Patients who received intensified therapy for poor induction response or refractory disease (e.g. MIBG) will be considered to have received second line therapy and will not be eligible.
• At least 14 days must have elapsed since completion of myelosuppressive therapy.
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent.
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1.
• No interim time prior to study entry is required following prior radiation therapy (RT) for non-target lesions. However, patients must not have received radiation for a minimum of 4 weeks prior to study entry at the site of any lesion that will be identified as a target lesion to measure tumor response. Lesions that have been previously radiated cannot be used as target lesions unless there is radiographic evidence of progression at the site following radiation or a biopsy done following radiation shows viable neuroblastoma. Palliative radiation while on study is not permitted.
• Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell infusions (including stem cell infusions given as supportive care following 131 I-MIBG therapy) as long as hematologic and other eligibility criteria have been met.
• Patients are eligible >= 6 weeks after therapeutic 131 I-MIBG provided that all other eligibility criteria are met.
• Subjects who have previously received anti-GD2 monoclonal antibodies with or without retinoids for biologic therapy are eligible unless they have had progressive disease while receiving prior anti-GD2 therapy or progressed/relapsed within 3 months of receiving anti-GD2 therapy. However, eligible patients may NOT have received anti-GD2 monoclonal antibodies in combination with chemotherapy.
• Subjects who have received autologous marrow infusions or autologous stem cell infusions that were purged using monoclonal antibody linked to beads are eligible.
• Subjects who have previously received DFMO are eligible for this study provided they have not had progressive disease while receiving DFMO or progressed/relapsed within 3 months of completing DFMO.
• Patients must not have received long-acting myeloid growth factors (e.g. pegfilgrastim) within 14 days of entry on this study. Seven days must have elapsed since administration of a short-acting myeloid growth factor.
• For patients with solid tumors (without marrow involvement) including status post SCT: peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to enrollment).
• For patients with solid tumors (without marrow involvement) including status post SCT: platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to enrollment).
• Patients known to have bone marrow involvement with neuroblastoma are eligible provided that minimum ANC and transfusion independent platelet count criteria are met (as above). However, these patients are not evaluable for hematological toxicity.
• Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
• 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
• 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
• 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
• 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)
• >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to enrollment).
• Total bilirubin =< 1.5 x ULN for age (within 7 days prior to enrollment).
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L). For the purpose of this study, the ULN for SGPT is 45 U/L (within 7 days prior to enrollment).
• Shortening fraction of >= 27% by echocardiography (ECHO) (within 7 days prior to enrollment).
• Ejection fraction of >= 50% by ECHO or gated radionuclide study (within 7 days prior to enrollment).
• No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry > 94% if there is a clinical indication for pulse oximetry. Normal pulmonary function tests in patients who are capable of cooperating with testing (including diffusion capacity of the lung for carbon monoxide [DLCO)] are required if there is a clinical indication for determination. For patients who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT required.
• Patients with a history of central nervous system (CNS) disease must have no clinical or radiological evidence of active CNS disease at the time of study enrollment.
• Patients with seizure disorders may be enrolled if seizures are well controlled on anti-convulsants.
• CNS toxicity =< grade 2.
Exclusion Criteria:

• Men and women of childbearing potential and their partners must agree to use adequate contraception while enrolled on this study. Based on the established teratogenic potential of alkylating agents, pregnant women will be excluded from this study. Because of potential risks to breastfed infants due to drug metabolites that could be excreted in breast milk, female patients who are lactating must agree to stop breastfeeding or will otherwise be excluded from this study. Females of childbearing potential must have a negative pregnancy test to be eligible for this study.
• Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT eligible for this study.
• Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment. Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible. The only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions. The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency. Patients on any other immunosuppressive medications (e.g. cyclosporine, tacrolimus) are not eligible.
• Patients must not have received prior treatment with irinotecan and temozolomide.
• Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, or carbamazepine for at least 7 days prior to study enrollment. Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic acid, or levetiracetam will be eligible.
• Patients who have received drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment are not eligible.
• Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma.
• Patients with symptoms of congestive heart failure are not eligible.
• Patients must not have >= grade 2 diarrhea.
• Patients who are unable to tolerate oral/nasogastric/gastrostomy medications will not be eligible for this trial. Additionally, patients with significant malabsorption will not be eligible for this trial.
• Patients must not have uncontrolled infection.
• Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required permanent discontinuation of the anti-GD2 therapy are not eligible.
• Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of study agents or to significantly increase the severity of the toxicities experienced from study treatment are not eligible.
Biological: Dinutuximab, Drug: Eflornithine Hydrochloride, Drug: Irinotecan Hydrochloride, Biological: Sargramostim, Drug: Temozolomide
High Risk Neuroblastoma, Recurrent Neuroblastoma, Refractory Neuroblastoma
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A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma

This study is a randomized phase 3 study comparing selumetinib to Carboplatin and Vincristine (CV) in previously untreated NF1-associated LGG. This study will compare both the event-free survival (EFS) and visual functional outcomes between the 2 randomized arms.

Christopher Moertel, MD
All
2 Years to 21 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT03871257
STUDY00008583
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Inclusion Criteria:

• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or germline genetic testing
• Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that has not been treated with any modality other than surgery
• For patients with optic pathway gliomas (OPGs):
• Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findings associated with the tumor
• Previously-diagnosed patients with OPG are eligible if they have new or worsening neurologic symptoms (including visual dysfunction, as defined below) or have tumor growth
• For both newly-diagnosed and previously-diagnosed OPG, the patient may be eligible, irrespective of whether there has been tumor growth or other neurological symptoms or worsening, if they meet at least one of the following visual criteria:
• Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR
• Significant visual dysfunction (defined as VA worse than normal for age by
• 6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
• For patients with LGG in other locations (i.e., not OPGs):
• Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms or other exam findings associated with the tumor
• NOTE: Newly-diagnosed patients with LGG without associated neurologic symptoms or exam findings are not eligible
• Previously-diagnosed patients with LGG are eligible if they have new or worsening neurologic symptoms or have tumor growth
• Although not required, if a biopsy/tumor resection is performed, eligible histologies will include all tumors considered LGG or low-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
• Patients must have two-dimensional measurable tumor >= 1 cm^2
• Patients with metastatic disease or multiple independent primary LGGs are allowed on study
• Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender within 7 days prior to enrollment as follows:
• Age; maximum serum creatinine (mg/dL)
• 2 to < 6 years; 0.8 (male) and 0.8 (female)
• 6 to < 10 years; 1 (male) and 1 (female)
• 10 to < 13 years; 1.2 (male) and 1.2 (female)
• 13 to < 16 years; 1.5 (male) and 1.4 (female)
• >= 16 years; 1.7 (male) and 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age within 7 days prior to enrollment (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect [unconjugated] bilirubin levels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) = 135 U/L within 7 days prior to enrollment. For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL within 7 days prior to enrollment
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram within 7 days prior to enrollment
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) within 7 days prior to enrollment
• Absolute neutrophil count >= 1,000/uL (unsupported) within 7 days prior to enrollment
• Platelets >= 100,000/uL (unsupported) within 7 days prior to enrollment
• Hemoglobin >= 8 g/dL (may be supported) within 7 days prior to enrollment
• Patients with a known seizure disorder should be stable and should have not experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of enrollment. Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of antihypertensive medications).
• Note: Adequate blood pressure can be achieved using medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
• For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site(s) of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
• For patients who undergo a surgery on the target tumor (not required), a pre- and post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine (depending on the site(s) of primary disease) with and without contrast must also be performed within 4 weeks prior to enrollment
• The post-operative MRIs should be performed ideally within 48 hours after surgery if possible
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Patients must have the ability to swallow whole capsules
• Patients must have receptive and expressive language skills in English or Spanish to complete the quality of life (QOL) and neurocognitive assessments
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
Exclusion Criteria:

• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/ condition, including substance use disorders likely in the judgement of the investigator to interfere or limit compliance with study requirements/treatment are not eligible
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible
• Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
• Cardiac conditions:
• Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Ophthalmologic conditions:
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN, such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
• Treatments and/or medications patient is receiving that would make her/him ineligible, such as:
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical placement for vascular access or cerebrospinal fluid (CSF) diverting procedures such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP) shunt.
• Note: Patients must have healed from any prior surgery prior to enrollment
• Patients who have an uncontrolled infection are not eligible
Drug: Carboplatin, Other: Quality-of-Life Assessment, Other: Questionnaire Administration, Drug: Selumetinib Sulfate, Drug: Vincristine Sulfate
Low Grade Glioma, Neurofibromatosis Type 1, Visual Pathway Glioma
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Study in Parkinson Disease of Exercise Phase 3 Clinical Trial: SPARX3 (SPARX3)

This study is a Phase 3 multi-site, randomized, evaluator-masked, study of endurance treadmill exercise on changes in the motor severity of Parkinson's disease after 12 months of exercise.

Colum MacKinnon
All
40 Years to 80 Years old
N/A
This study is NOT accepting healthy volunteers
NCT04284436
STUDY00012549
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Inclusion Criteria:

• A diagnosis of idiopathic Parkinson Disease based on the modified * United Kingdom (UK) PD brain bank criteria and which are consistent with recent criteria proposed for clinically established early established Parkinson's disease that no longer exclude individuals with a family history of Parkinson's disease.
• Hoehn and Yahr stages less than 3
• Disease duration: less than 3 years since disease diagnosis
• Age 40-80 years
• Positive DaTscan™ SPECT by quantitative readout for idiopathic Parkinson disease.
Exclusion Criteria:

• Currently being treated with PD medications such as levodopa or dopamine receptor agonists, monoamine oxidase-B (MAO-B) inhibitors, amantadine, or anticholinergics.
• Expected to require treatment with medication for PD in the first 6 months of the study.
• Use of any PD medication 60 days prior to the baseline visit including but not limited to levodopa, direct dopamine agonists, amantadine, Rasagiline (Azilect), Selegiline (Eldepryl), Artane (trihexyphenidyl).
• Duration of previous use of medications for PD exceeds 60 days.
• Use of neuroleptics/dopamine receptor blockers for more than 30 days in the year prior to baseline visit, or any use within 30 days of baseline visit
• Presence of known cardiovascular, metabolic, or renal disease or individuals with major signs or symptoms suggestive of cardiovascular, metabolic, or renal disease without medical clearance to participate in the exercise program.
• Uncontrolled hypertension (resting blood pressure >150/90 mmHg)
• Individuals with orthostatic hypotension and standing systolic BP below 100 will be excluded. Orthostatic hypotension (OH) is a reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.
• Hypo- or hyperthyroidism (TSH <0.5 or >5.0 mU/L), abnormal liver function (AST or ALT more than 2 times the upper limit of normal), abnormal renal function (estimated glomerular filtration rate (eGFR) using the MDRD4 equation or the CKD-EPI equation <45mL/min/1.73m2 ).
• Complete Blood Count (CBC) out of range and physician's judgment that abnormal value is clinically significant.
• Recent use of psychotropic medications (e.g., anxiolytics, hypnotics, benzodiazepines, antidepressants) where dosage has not been stable for 28 days prior to screening.
• Serious illness (requiring systemic treatment and/or hospitalization) within the last 4 weeks.
• Any other clinically significant medical condition, psychiatric condition, drug or alcohol abuse, assessment or laboratory abnormality that would, in the judgment of the investigator, interfere with the subject's ability to participate in the study.
• Montreal Cognitive Assessment (MoCA) score of <24.
• Beck Depression Inventory II (BDI) score > 28, indicating severe depression that precludes ability to exercise. Any subject with such a score will be referred to a PCP or physician for further evaluation and management of depression. Individuals with a BDI-II score of 17-28 will be excluded if any of the following conditions are met: (1) individual is suicidal, (2) is in need of depression treatment modification currently or (3) depressive symptoms likely to interfere with adherence to study protocol. Any subject with such a score will be referred to a PCP or physician for further evaluation and management of depression.
• Individuals who have been exercising at greater than moderate intensity for 120 minutes or more per week consistently over the last 6 months will be excluded. Greater than moderate intensity is defined as a range greater than 60-65% HRmax. These individuals are excluded since their exercise activities are greater than the activities they would experience if they were assigned to the 60-65% treatment group. As such, they would be expected to lose fitness.
• Use of the following within 90 days prior to the DAT neuroimaging screening evaluation: modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, any amphetamine or amphetamine derivative, or use of buproprion within 8 days prior to the DAT neuroimaging screening evaluation. These can compromise DaTscan™ SPECT.
• Known allergy to iodinated products.
• Known hypersensitivity to DaTscan™ SPECT (either to the active substance of 123I-ioflupane or any of the excipients.
• (For women only) Actively breast-feeding an infant, and/or pregnant, or plan to become pregnant in the next 12 months.
• Other disorders, injuries, diseases, or conditions that might interfere with ability to perform endurance exercises (e.g. history of stroke, respiratory problems, traumatic brain injury, orthopedic injury, or neuromuscular disease).
Behavioral: Treadmill walking
Parkinson Disease
Clinics and Surgery Center (CSC)
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Determining the Effectiveness of early Intensive Versus Escalation approaches for the treatment of Relapsing-Remitting Multiple Sclerosis (DELIVER-MS) (DELIVER-MS)

The DELIVER-MS study seeks to answer the important question: Does early treatment with highly effective DMT improve the prognosis for people with MS? This is an area of significant controversy and no data currently exist to guide treatment choices for patients and clinicians. The study results will help guide overall treatment philosophy and will be applicable not only to a wide range of existing therapies but also to new therapies, meeting a significant unmet need in patient decision making and aiding the decision for medication approval by third parties.

William Schmalstieg
All
18 Years to 60 Years old
Phase 4
This study is NOT accepting healthy volunteers
NCT03535298
STUDY00004712
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Inclusion Criteria:

• Men and women aged 18 to 60 years.
• Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria (99).
• RRMS disease course as defined by the 2013 revisions of the MS clinical course definition (4).
• Participants must have evidence of active disease based on: one or more MS relapses within the last 18 months prior to screening visit or radiological evidence of MS activity (≥2 new T2 lesions within the last 12 months from screening [compared to a previous recent MRI within 18 months of screening] or ≥1 GdE demonstrated on brain or spinal cord MRI performed within the last 12 months of screening).
• Participants must be ambulatory with disease onset ≤ 5 years and treatment-naïve (i.e., no MS DMT at any time in the past).
• Participants must be eligible to receive at least one form of DMT within each treatment arm.
• EDSS at Baseline visit ≤ 6.5
Exclusion Criteria:

• Participants with contraindications to all forms of DMT in either of the treatment arms.
• Participants must never have received any of the following medications: natalizumab, alemtuzumab, ocrelizumab, rituximab, ofatumumab, cladribine, siponimod, interferon beta-1a, interferon beta-1b, pegylated interferon beta-1a, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, daclizumab, mitoxantrone, diroximel fumarate, ozanimod, monomethyl fumarate, ponesimod.
• Participants must have not received any of the following medications, for reasons other than MS, in the last 12 months: cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, leflunomide, laquinimod, atacicept, other monoclonal antibodies.
• Participants with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study
• Participants unable to provide informed consent.
• Contraindication or inability to undergo MRI with Gd due to metal or metal implants, allergy to Gd contrast, claustrophobia, pain, spasticity, or excessive movement related to tremor.
• Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, mental, or social) that, in the opinion of the PI, is likely to affect the participant's ability to comply with the study protocol.
Drug: Early Highly Effective Therapies Group, Drug: Escalation Therapies Group
Multiple Sclerosis, Relapsing-Remitting
Clinics and Surgery Center (CSC)
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Concurrent Aerobic Exercise and Cognitive Training to Prevent Alzheimer's in At-risk Older Adults (Exergames)

The purpose of this study is to examine the efficacy of a new low-cost Virtual Reality Cognitive Training (VRCT) combined with concurrent cycling intervention called exergame on improving cognition in at-risk community-dwelling older adults at risk for Alzheimer's disease and dementia. We will conduct this study in two phases: Phase I (Feasiblity Testing)aims: Aim1. Develop a prototype exergame that supports integrated, concurrent cycling and VRCT. Aim 2. Examine the feasibility of the exergame in older adults at risk for AD. Phase II (Effect Testing) aims: Aim 1. Develop a fully-featured version of the VRCT aspect of the exergame. Aim 2. Determine the efficacy of the exergame in older adults at risk for AD using an RCT. We hypothesize that cognitive improvement will be greatest for exergame subjects followed by cycling subjects, and least in control subjects. Aim 3. Assess the distraction effect of the concurrent VRCT in exergame on gains in aerobic fitness. We hpothesize that exergame subjects will achieve similar gains in aerobic fitness to cycling only subjects (difference is < 1 standard deviation).

All
65 Years and over
N/A
This study is also accepting healthy volunteers
NCT04311736
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Inclusion Criteria:

• Cognitive complaint (defines as answering yes to the question "Do you feel that your memory or thinking skills have gotten worse recently within the last 2 years?");
• Not engaging in aerobic exercise or cognitive training >2 days/week, 30 minutes a session in the past 3 months;
• Age 65 years and older;
• Written consent.
• Medical clearance to participate in a supervised exercise program
Exclusion Criteria:

• Resting heart rate > 100 or <50 beats/min with symptoms;
• Dementia or mild cognitive impairment (self-report, diagnosis, or scoring <26 on the Telephone Interview for Cognitive Status;
• Evidence that cognitive decline or memory complaints were caused by underlying neurological or psychiatric disorder or chemical dependency as determined by primary health care provider;
• Current enrollment in another intervention study;
• ACSM contraindications to exercise or other factors that make exercise impossible or unsafe.
Behavioral: Exergame, Behavioral: Cycling, Behavioral: Stretching
Mild Cognitive Impairment, Exercise Training
mild cognitive impairment, cognitive decline, aerobic exercise, physical exercise, exercise training, cognitive exercise, cognitive games, virtual reality
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A natural history study to TRACK brain and spinal changes in individuals with Friedreich Ataxia (TRACK-FA) ((TRACK-FA))

TRACK-FA is a multi-site, international, prospective, observational neuroimaging study in Friedreich’s Ataxia. The objective is to obtain natural history MRI and MRS data over time in the brain and spinal cord in a large cohort of FRDA patients and healthy control. This will permit validation of neuroimaging biomarkers in FRDA for future clinical trials. In addition to neuroimaging data, the study will collect data from clinical, cognitive and mood assessments as well as blood samples to measure blood markers (frataxin and neurofilament light chain). The present IRB protocol covers only subjects enrolled at the University of Minnesota.

Pierre-Gilles Henry
All
5 Years and over
NA
This study is NOT accepting healthy volunteers
NCT04349514
STUDY00009047
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Inclusion Criteria:

• Age ≥ 5 years
• Written informed consent provided
• Individuals with FA must have a genetic confirmation of diagnosis and be biallelic for a GAA repeat length > 55 in intron 1 of FXN and/or have a GAA repeat length > 55 in intron 1 of FXN in one allele and another type of mutation that is inferred to cause loss of function in the second FXN allele
• Individuals with FA must have an age of disease onset ≤ 25 years
• Individuals with FA must have a disease duration ≤ 25 years
• Individuals with FA must have a Friedreich Ataxia Rating Scale (FARS) Functional staging score of ≤ 5 and total modified FARS (mFARS) score of ≤ 65 on enrolment
Exclusion Criteria:

• Age < 5 years
• Unable to provide written informed consent
• Magnetic resonance contraindications (e.g. pacemaker or other metallic surgical implants)
• Presence of metallic dental braces
• Pregnancy (ascertained via a question or test as mandated at particular sites)
• Individuals with FA must not have acute or ongoing medical or other conditions that, after discussion between the Site Investigator and steering committee, is deemed to interfere with the conduct and assessments of the study
• Individuals with FA must not have another neurological condition apart from FA
• Individuals with FA must not have other neurologic conditions that, in the opinion of the Site Investigator, would interfere with the conduct and assessments of the study
• Controls must not have a diagnosed psychiatric or neurological condition
• Controls must not have acute or ongoing medical or other conditions that would interfere with the conduct and assessments of the study
Other: Natural history
Friedreich Ataxia
Neuroimaging, Longitudinal, Biomarkers, Natural history
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Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)

The NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) study, referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using genomic sequencing technologies in refractory/recurrent tumors from children and adolescents with cancer. The NCI-COG Pediatric MATCH study (APEC1621) is considered one study under one IND consisting of a Master Version Control protocol, screening protocol component and multiple subprotocol components, with each component being contained in its own separate document. Each “component” consists of the protocol document and its associated informed consent document. The Master Version Control Protocol is the overarching administrative protocol that will keep an up-to-date record of the current version of the screening protocol component and each subprotocol component of Pediatric MATCH. Since each subprotocol component operates independently from the other subprotocol components contained in Pediatric MATCH, each has its own version date. Likewise, the screening protocol component has its own version date since changes in any of the subprotocols may not require changes in the screening protocol.

Emily Greengard
All
12 Months to 21 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT04195555
STUDY00001752
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Inclusion Criteria:

• Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621K based on the presence of an actionable mutation as defined in APEC1621SC
• Patients must be >= than 12 months and =< 21 years of age at the time of study enrollment
• Patients must have a body surface area >= 0.78 m^2 at enrollment
• Patients must be able to swallow intact tablets
• Patients must have radiographically measurable disease at the time of study enrollment. Patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG)+ evaluable disease are eligible. Measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular Therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• Radiation therapy (XRT)/external beam Irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
• Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have received prior exposure to AG-120 (ivosidenib) or other IDH1 inhibitors
• For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement: Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood count (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (within 7 days prior to enrollment), or
• A serum creatinine based on age/gender (within 7 days prior to enrollment)
• Age 1 to < 2 years, maximum serum creatinine (mg/dL) male 0.6, female 0.6
• Age 2 to < 6 years, maximum serum creatinine (mg/dL) male 0.8, female 0.8
• Age 6 to < 10 years, maximum serum creatinine (mg/dL) male 1, female 1
• Age 10 to < 13 years, maximum serum creatinine (mg/dL) male 1.2, female 1.2
• Age 13 to < 16 years, maximum serum creatinine (mg/dL) male 1.5, female 1.4
• Age >= 16 years, maximum serum creatinine (mg/dL) male 1.7, female 1.4
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• Serum glutamate-pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. (For the purpose of this study, the ULN for SGPT is 45 U/L) (within 7 days prior to enrollment)
• Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
• Corrected QT (QTc )interval =< 450 milliseconds (within 7 days prior to enrollment)
• Note: Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades de Pointes. Patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective non-hormonal contraceptive method for the duration of study treatment and for at least 1 month after last dose of AG-120 (ivosidenib). Since AG-120 (ivosidenib) may decrease concentrations of hormonal contraceptives, hormonal contraceptives are not considered effective contraception when co-administered with AG-120 (ivosidenib)
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who are currently receiving drugs that are strong inducers or moderate to strong inhibitors of CYP3A4 are not eligible. Strong inducers or moderate to strong inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed. In addition, patients receiving sensitive or narrow therapeutic range substrates of CYP3A4 are not eligible
• Patients with a history of progressive multifocal leukoencephalopathy are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Drug: Ivosidenib
Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory WHO Grade 2 Glioma, Wilms Tumor
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