A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont (NBI-74788) in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia, Followed by Open-Label Treatment
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont (NBI-74788) in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia, Followed by Open-Label Treatment Participants will be randomized to placebo or Crinecerfont for 28 weeks followed by an open-label period where all participants will receive Crinecerfont for 24 weeks. The purpose of this research study in children (ages 2 to 17 years) with CAH are: • To study whether crinecerfont can lower high levels of adrenal androgens (male hormones) and high doses of glucocorticoid medication • To study whether improving high androgen levels and high glucocorticoid doses can lead to improvements in CAH • To learn about what happens to crinecerfont in the body by measuring levels in your child’s body after starting the study drug. • To study the safety and tolerability of crinecerfont The study will last for about 60 weeks with 14 study visits. The main activities in this study are: physical exams, height and weight measurements, vital signs, study drug dosing, glucocorticoid dose adjustments, blood draws, saliva and urine tests, electrocardiogram (ECG) testing, x-ray for bone age, ultrasound of testes (boys), and questionnaires.
KIN-1902-2001: A Randomized, Double-blind, Placebo-controlled Phase 2 Study with Open-label Extension to Assess the Efficacy and Safety of Namilumab in Subjects with Chronic Pulmonary Sarcoidosis
Primary Objective: The primary objective of this study is: • To evaluate the efficacy of namilumab in subjects with chronic pulmonary sarcoidosis (CPS). Key Secondary Objective: • To evaluate the effect of namilumab on proportion of subjects on OCS taper without rescue. Other Secondary Objectives: The other secondary objectives of this study are: • To assess the safety and tolerability of namilumab; • To assess the effect of namilumab on measures of pulmonary function; • To assess the effect of namilumab on Patient Reported Outcomes (PROs): o St. George’s Respiratory Questionnaire (SGRQ); o Modified King’s Sarcoidosis Questionnaire (mKSQ); o Fatigue Assessment Scale (FAS); o Subject Global Assessment (SGA); o Leicester Cough Questionnaire (LCQ); o Pain Visual Analog Scale (VAS); o General Sleep Disturbance Scale (GSDS); o Bothersomeness and Subject Global Impression of Change (BSGIC). • To assess the effect of namilumab on dyspnea; • To assess the effect of namilumab on cumulative OCS use and toxicity; • To assess the effect of namilumab on the rate of clinical benefit; • To evaluate the effect of namilumab on clinical worsening. • To assess the effect of namilumab on sarcoid associated skin lesions (when present); • To assess the effect of namilumab on the severity of extrapulmonary organ involvement; • To assess the effect of namilumab on use of rescue therapy; • To assess the population pharmacokinetics (PPK) and exposure-response (E-R) relationships for efficacy and safety of namilumab; • To assess the effect of namilumab on laboratory parameters; • To assess the efficacy of namilumab on the radiologic features of CPS; • To assess the effect of namilumab on 6-Minute Walking Distance (6MWD).
MT2019-06: A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with the LentiGlobin BB305 Lentiviral Vector in Subjects with Sickle Cell Disease.
Evaluate the efficacy of treatment with bb1111 (also known as LentiGlobin BB305 Drug Product for Sickle Cell Disease) in subjects with sickle cell disease (SCD).
• Have a diagnosis of SCD, with either βS/βS, βS/β0, or βS/β+ genotype.
• Be ≥2 and ≤50 years of age at time of consent.
• Weigh a minimum of 6 kg.
• Have a Karnofsky performance status of ≥60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age).
• Be treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on sickle cell disease history.
• In the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 protocol-defined VOEs in the 24 months prior to informed consent.
• Have either experienced HU failure at any point in the past or must have intolerance to HU (intolerance is defined as the patient being unable to continue to take HU per PI judgment).
• Female and male subjects of childbearing potential agree to use 1 method of highly effective contraception from Screening to at least 6 months after drug product infusion.
• Provision of written informed consent for this study by subject, or as applicable, subject's parent(s)/legal guardian(s).
• Subjects for whom allogeneic hematopoietic stem cell transplantation (allo-HSCT) is medically appropriate per PI judgment and a willing, human leukocyte antigen (HLA)-matched related hematopoietic stem cell donor is available.
• Severe cerebral vasculopathy, defined by any history of overt ischemic or hemorrhagic stroke, a history of abnormal transcranial Doppler (TCD) or TCD imaging (TCDI) for subjects ≤ 16 years of age (e.g. TCD velocity >200 cm/sec) requiring ongoing chronic transfusions, a Screening TCD or TCDI velocity > 200 cm/sec (central read), a Screening MRA showing > 50% stenosis or occlusion in the circle of Willis (central read), or a Screening MRA showing the presence of Moyamoya (central read).
• Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotropic virus-1 (HTLV-1), active syphilis.
• Clinically significant, active bacterial, viral, fungal, or parasitic infection
• Advanced liver disease, such as
• clear evidence of liver cirrhosis, active hepatitis or significant fibrosis (based on MRI or liver biopsy)
• liver iron concentration ≥15 mg/g unless liver biopsy shows no evidence of cirrhosis, active hepatitis or significant fibrosis
• Inadequate bone marrow function, as defined by an absolute neutrophil count of <1×10^9/L (<0.5×10^9/L for subjects on hydroxyurea treatment) or a platelet count <100×10^9/L.
• Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients.
• Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment
• Unable to receive pRBC transfusion.
• Prior receipt of an allogeneic transplant.
• Prior receipt of gene therapy.
• Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
• Immediate family member with a known or suspected Familial Cancer Syndrome.
• Female subject is breastfeeding, pregnant or will attempt to become pregnant from Screening to at least 6 months after drug product infusion.
• Any other condition that would render the subject ineligible for HSCT.
• Participation in another clinical study with an investigational drug within 30 days of screening.
• Presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) per Investigator's judgment.
• Presence of genetic mutations that result in the inactivation of 2 or more α-globin genes
MT2020-06: A PHASE 1/2 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND EFFICACY OF JSP191 FOR HEMATOPOIETIC CELL TRANSPLANTATION CONDITIONING TO ACHIEVE ENGRAFTMENT AND IMMUNE RECONSTITUTION IN SUBJECTS WITH SCID
Phase 1: To evaluate the safety and tolerability of JSP191 and to determine Phase 2 doses of JSP191 as a conditioning agent prior to allogeneic hematopoietic cell transplantation (HCT) in two populations of subjects with severe combined immunodeficiency (SCID): • SCID subjects with history of prior allogeneic HCT but with poor graft function • SCID subjects who are HCT-naïve Phase 2: • To evaluate the efficacy of JSP191 conditioning to enable engraftment of allogeneic CD34+ hematopoietic cells, as determined by CD15+ donor myeloid chimerism • To evaluate the efficacy of JSP191 conditioning to enable immune reconstitution determined by the production of naïve T cells
• Typical SCID as defined by Primary Immune Deficiency Treatment Consortia including but not limited to the following subtypes:
• T-, B+, NK-: IL-2Rcγ deficient, JAK3-deficient
• T-, B-, NK+: RAG1/2 deficient, Artemis-deficient
• T-, B+, NK+: IL7Rα deficient, CD3 subunit deficient, CD45 deficient OR Variant SCID with absent or low T cell function, Omenn syndrome, Leaky SCID, Reticular dysgenesis, Adenosine deaminase deficiency, and Purine nucleoside phosphorylase deficiency may be included after consultation with the medical monitor.
• Patients with human leukocyte antigen (HLA) matched related or unrelated donors
• Adequate end organ function as defined in study protocol Key
• Patients with any acute or uncontrolled infections
• Patients receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
• Patients with active malignancies
• Active GVHD within 6 months prior to enrollment, or on immunosuppressive therapy for GVHD
A Phase 1, Open-label Study of ASP9801, an Oncolytic Virus, Administered by Intratumoral Injection as a Single Agent and in Combination with Pembrolizumab in Patients with Advanced/Metastatic Solid Tumors
The purpose of this study is to assess the safety and tolerability of ASP9801 in participants with cancer who have tumors that cannot be removed or have spread to a different part of the body, as well as to determine the maximum tolerated dose and/or recommended phase 2 dose of ASP9801.
• Subject must have histologically- or cytologically-confirmed diagnosis of advanced or metastatic solid tumor(s).
• Subject has measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. At least 1 lesion must be suitable for intratumoral (IT) injection. Lesions for injection must be ≥ 10 mm and ≤ 60 mm in longest diameter.
• Subject has had disease progression after, been intolerant to, or has refused all available therapies that are known to confer clinical benefit. Note: There is no limit to the number of prior treatment regimens.
• Subject has a predicted life expectancy ≥ 12 weeks.
• Subject has at least 2 sites of disease suitable for biopsy and is willing and able to undergo required tumor biopsies according to the treating institution's guidelines at screening and during study treatment.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• A female subject is eligible to participate if she is not pregnant as documented by negative pregnancy test within 72 hours prior to treatment and at least 1 of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) OR
• WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study investigational product (IP) administration.
• Female subject must agree not to breastfeed starting at screening, and throughout the study period and 180 days after the final study IP administration.
• Female subject must not donate ova starting at screening, and throughout the study period and for 180 days after the final study IP administration.
• Male subject must agree to remain abstinent or use a condom throughout the study period and for 180 days after the final study IP administration.
• Male subject with female partner(s) of childbearing potential must agree to use contraception during the treatment period and for at least 180 days after the final study IP administration.
• Male subject must not donate sperm during the treatment period and for at least 180 days after the final study IP administration.
• Subject must be willing and able to comply with the study requirements including prohibited concomitant medication restrictions.
• Subject agrees not to participate in another interventional study while receiving study IP.
• Subject has the ability to understand and the willingness to sign a written informed consent document.
• Subject has ongoing toxicity ≥ National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 2 attributable to prior antineoplastic therapies considered clinically significant.
• Subject who has had major surgery ≤ 4 weeks of screening. Subjects must have recovered from prior procedures and/or any complications from surgery prior to starting study treatment.
• Subject is concurrently participating in another interventional study or has received an investigational product ≤ 30 days or 5 half-lives whichever is shorter, prior to first IP administration.
• Subject with symptomatic or untreated central nervous system (CNS) metastases or leptomeningeal disease. Subjects with treated symptomatic brain metastases should be neurologically stable (without evidence of progression by imaging for at least 4 weeks prior to screening and any neurologic symptoms have returned to baseline) and off steroids for at least 2 weeks prior to first IP administration. Subjects with carcinomatous meningitis are excluded regardless of clinical stability.
• Subject with active or prior autoimmune or inflammatory disorders requiring systemic therapy within past 2 years (including inflammatory skin conditions or severe eczema, inflammatory bowel disease (e.g., colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc. The following are exceptions to this criterion:
• Subject with vitiligo or alopecia
• Subject with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Subject with another malignancy that currently requires treatment.
• Subject with only tumors encasing major vascular structures such as the carotid artery, tumors adjacent to vital neurovascular structures or tumors in locations that are at high risk for adverse events (AEs) or otherwise not considered appropriate for IT injection. Subjects with such tumors that have other injectable tumors would be eligible.
• Subject with inadequate organ and marrow functions meeting any of the below criteria:
• Leukocytes < 3000/μL
• Absolute neutrophil count < 1500/μL
• Platelets < 100,000/μL
• Hemoglobin (Hgb) < 9 g/dL (Criteria must be met without packed red blood cell transfusion within the prior 2 weeks. Subjects can be on stable dose of erythropoietin [≥ approximately 3 months])
• International normalized ratio (INR) > 1.5 × ULN and/or activated partial thromboplastin time (aPTT) > 1.5 × institutional normal limits, except for subjects in Group B (Visceral Lesions) escalation and expansion groups where INR and aPTT must be normal
• Total Bilirubin (TBL) > 1.5 × institutional normal limits (subjects with known Gilbert syndrome who are excluded if TBL > 3.0 × institutional normal limits or direct bilirubin > 1.5 × institutional normal limits)
• Aspartate aminotransferase (AST) and Alanine transaminase (ALT) > 2.5 × institutional normal limits. Subjects with tumors in the liver AST and ALT > 5 × institutional normal limits.
• Albumin < 3.0 g/dL
• Creatinine > 1.5 × institutional normal limits
• Subject with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of first administration of study IP. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Subject has an uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, any form of substance abuse or psychiatric illness/social situations that would limit compliance with study visits or requirements or a condition that could invalidate communication with the investigator.
• Subject is positive for human immunodeficiency virus, hepatitis B surface antigen, hepatitis B core immunoglobulin or immunoglobulin G (IgG) antibody or hepatitis C (IgG or ribonucleic acid (RNA) test) indicating acute or chronic infection.
• Subject has a history of moderate to severe ascites, clinically significant and/or rapidly accumulating ascites, bleeding esophageal varices, hepatic encephalopathy or pericardial and/or pleural effusions related to liver insufficiency within 6 months of screening. Mild ascites that does not preclude safe IT injection of ASP9801 is allowed.
• Subject has a clinically significant abnormal electrocardiogram (ECG) at screening.
• Subject has symptomatic cardiovascular disease within the preceding 12 months unless cardiology consultation and clearance has been obtained for study participation, including but not limited to the following: significant coronary artery disease (e.g., requiring angioplasty or stenting), acute myocardial infarction or unstable angina pectoris < 3 months prior to screening, uncontrolled hypertension, clinically significant arrhythmia or congestive heart failure (New York Heart Association grade ≥ 2).
• Subject has medical conditions that predispose the subject to untoward medical risk in the event of volume loading (e.g., intravenous fluid bolus infusion), tachycardia or hypotension during or following treatment with ASP9801.
• Subject has a known or suspected hypersensitivity to ASP9801 or any components of the formulation used, including prior adverse reaction to vaccinia (e.g., as smallpox vaccine).
• Subject has had previous exposure with ASP9801.
• Subject has an active infection requiring systemic therapy.
• Subject with known history of active Bacillus Tuberculosis.
• Subject has received prior therapy with an anti-PD-1, anti-programmed cell death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4, OX 40, CD137) and was discontinued from that treatment due to an immune-related adverse event.
• Subject has received prior radiation therapy within 2 weeks of start of study treatment. Subject must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• Subject has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus Calmette-Guérin and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Subject has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients, or history of ≥ grade 2 infusion reactions that were not prevented by adequate premedication.
• Subject has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Subject has had an allogeneic tissue/solid organ transplant.
A randomized, participant and investigator blinded, sponsor open-label, placebo-controlled, single dose study to investigate the safety and tolerability of XXB750 in heart failure participants with reduced ejection fraction (HFrEF)
This is a multi-center, randomized, sponsor open-label, participant and investigator blinded, placebo-controlled, single dose study to investigate the safety and tolerability of a single subcutaneous dose of XXB750 in HFrEF.
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.
• 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
• 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
Phase II Randomized, Intervention Versus Non-Intervention, Multi-Center Study of the Effects of Thyroid Hormone (T3) on Extravascular Lung Water (EVLW) in Subjects with Acute Respiratory Distress Syndrome (ARDS) (ARDS+T3)
Study objective: To determine the safety and tolerability of Thyroid Hormone (T3) delivery into the lungs of Acute Respiratory Distress Syndrome (ARDS) patients, and to measure the effect of T3 on extravascular lung water in ARDS patients.
• Chest x-ray: bilateral pulmonary infiltrates
• Hypoxemia: PaO2:FIO2 ratio <200
• Volume status: wedge and CVP<18 Main inclusion criteria:
• Adults (≥18 years of age), non-pregnant
• On mechanical ventilatory support
• Inadequate medical history for determining inclusion/exclusion criteria, as determined by the Principal Investigator and/or Sub-Investigators.
• Unlikely to complete the protocol with clinic follow-up after discharge, as determined by the Principal Investigator and/or Sub-Investigators or hospice status.
• Active drug/alcohol use with positive drug screen or alcohol level on admission.
• Prior history of thyroid cancer or hyperthyroidism, per thorough patient/family interviews, review of past medical history, medication list, laboratory test.
• Prior history of cardiovascular disease including:
• Hypertensive crisis in the past 3 months (systolic >200, or diastolic >120 mmHg),
• Sustained ventricular arrhythmia in the past 3 months (duration > 30 seconds)
• Coronary artery disease (documented >50% occlusion in any coronary vessel)
• Cardiac-related angina pectoris (> 2 episodes in the past 3 months)
• Myocardial infarction with ischemia on ECG (i.e., new ST-elevation/depression of >1mm in contiguous leads), or positive cardiac enzymes (Ratio of CK-MB: Total CK > 3.5).
• Peripheral vascular disease (documented >50% occlusion in any peripheral vessel).
• Moderate or severe ischemic/non-ischemic cardiomyopathy (documented ejection fraction < 40%).
• Decompensated or symptomatic heart failure (i.e., hospitalized for CHF exacerbation, or a change in CHF medications within two weeks prior)
• Currently pregnant or breastfeeding.
• Currently taking tricyclic antidepressants, glycosides, ketamine, or vasopressors with ongoing evidence of myocardial ischemia.
• Known allergy to study drug.
A Study Evaluating the Efficacy and Safety of Adjuvant Giredestrant Compared With Physician's Choice of Adjuvant Endocrine Monotherapy in Participants With Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer (lidERA Breast Cancer)
SPR001-205 A Phase 2 Study to Evaluate the Safety, Pharmacokinetics, and Exploratory Pharmacodynamics of SPR001 (Tildacerfont) in Children Aged 6 to 17 Years with Congenital Adrenal Hyperplasia
This is a Phase 2, open-label, multiple-dose study designed to provide safety, PK, and exploratory PD data for tildacerfont in male and female children aged 6 to 17 years with CAH. The study will last approximately 10 weeks including Screening. After the 14-day Treatment Period, there will be a Safety Follow-up Visit 30 days after the last dose.
MT2019-40: A Phase I, Open-Label, Multicenter Study of FT596 as a Monotherapy and in Combination with Rituximab or Obinutuzumab in Subjects with Relapsed/Refractory B-cell Lymphoma and Chronic Lymphocytic Leukemia
This study is designed to determine the recommended Phase II dose (RP2D), as well as evaluate the safety and efficacy for FT596 as monotherapy and in combination with rituximab or obinutuzumab in patients with relapsed/refractory B-cell Lymphoma and Chronic Lymphocytic Leukemia.
• Histologically documented lymphomas expected to express CD19 and CD20
• Relapsed/refractory disease following prior systemic immunochemotherapy regimen Chronic Lymphocytic Leukemia (CLL):
• Diagnosis of CLL per iwCLL guidelines
• Relapsed/refractory disease following at least two prior systemic treatment regimens ALL SUBJECTS:
• Capable of giving signed informed consent
• Age ≥ 18 years old
• Stated willingness to comply with study procedures and duration
• Contraceptive use for women and men as defined in the protocol Key
• Females who are pregnant or breastfeeding
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≥2
• Body weight <50 kg
• Evidence of insufficient organ function
• Receipt therapy within 2 weeks prior to Day 1 or five half-lives, whichever is shorter; or any investigational therapy within 28 days prior to Day 1
• Currently receiving or likely to require systemic immunosuppressive therapy
• Prior allogeneic hematopoietic stem cell transplant (HSCT) or allogeneic CAR-T within 6 months of Day 1, or ongoing requirement for systemic GvHD therapy
• Receipt of an allograft organ transplant
• Known active central nervous system (CNS) involvement by malignancy
• Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
• Clinically significant cardiovascular disease
• Known HIV infection
• Known active Hepatitis B (HBV) or Hepatitis C (HCV) infection
• Live vaccine <6 weeks prior to start of lympho-conditioning
• Known allergy to albumin (human) or DMSO
A Phase 3, Open-label, Randomized Study of Nivolumab Combined with Ipilimumab, or with Standard of Care Chemotherapy, versus Standard of Care Chemotherapy in participants with Previously Untreated Unresectable or Metastatic Urothelial Cancer
This is a randomized, open-label, Phase 3 study comparing combination therapy of nivolumab plus ipilimumab administered every 3 weeks for up to 4 doses, followed by nivolumab monotherapy administered every 4 weeks, versus the standard of care in participants with previously untreated unresectable or metastatic urothelial cancer. In addition, a substudy of treatment with nivolumab 360mg in combination with SoC every 3 weeks for up to 6 cycles followed by nivolumab monotherapy versus SoC alone will be evaluated in cisplatin-eligible participants with previously untreated unresectable or metastatic urothelial cancer.
A Phase 3, Randomized, Placebo-controlled, Double-blind, Adaptive Study to Evaluate the Safety and Efficacy of Inhaled Treprostinil in Patients With Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (PH-COPD) (PERFECT)
The primary objective of this study is to demonstrate the efficacy of inhaled treprostinil compared to placebo in improving exercise ability as measured by change from baseline in 6MWD following 12 weeks of active treatment in subjects with PH-COPD.
• Participant voluntarily gives informed consent to participate in the study.
• Males and females 18 years of age and above at the time of informed consent.
• Women of childbearing potential (defined as less than 1 year post-menopausal and not surgically sterile) must agree to practice abstinence or use 2 highly effective methods of contraception (defined as a method of birth control that results in a low failure rate, [<1% per year], such as approved hormonal contraceptives, barrier methods [such as condom or diaphragm] used with a spermicide, or an intrauterine device) for the duration of study treatment and for 48 hours after discontinuing study drug. Participants must have a negative pregnancy test at the Screening Visit 1 (urine [prior to the first dose of study medication] and serum) and Baseline Visit (Study Week 1) (urine).
• Males with a partner of childbearing potential must agree to use a barrier method (condom) with a spermicide for the duration of treatment and for at least 48 hours after discontinuing study drug.
• Diagnosis of PH-COPD (World Heath Organization [WHO] Group 3).
• Clinical diagnosis of COPD will be made using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria (GOLD Criteria 2020) and spirometry with the following documented parameters measured during Screening Visit 1 (prior to start of low-dose inhaled treprostinil):
• Forced expiratory volume in 1 second (FEV1) <80% predicted
• FEV1/Forced vital capacity (FVC) <70
• The participant has a resting saturation peripheral capillary oxygenation (SpO2) greater than or equal to 90%, with or without supplemental oxygen, but not to exceed 10 liters (L)/min oxygen supplementation by any mode of delivery during Screening Visit 1.
• During Screening Visit 1 prior to start of low-dose inhaled treprostinil, a 6MWD greater than or equal to 100 meters.
• Have a right heart catheterization (RHC) performed during Screening Visit 1. (A previous RHC obtained within 12 months prior to the start of Screening Visit 1 is acceptable for determining eligibility, even if done without oxygen or vasodilator challenge, and a repeat RHC is not required.) The following parameters must be documented for eligibility:
• Pulmonary vascular resistance (PVR) greater than or equal to 4 Wood units
• A pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) of less than or equal to 15 millimeters of mercury (mmHg)
• A Pulmonary artery pressure mean (PAPm) of greater than or equal to 30 mmHg
• Participants must be on a stable and optimized dose of chronic COPD medications for greater than or equal to 30 days prior to start of Screening Visit 1 and remain on the same dose throughout the Screening Period.
• In the opinion of the Investigator, the participant can communicate effectively with study personnel and is considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.
• The participant has a diagnosis of either pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) due to reasons other than COPD. This would include, but is not limited to, chronic thromboembolic PH or acute/recent deep vein thrombosis or pulmonary embolism, untreated or inadequately treated obstructive sleep apnea, connective tissue disease (including but not limited to systemic sclerosis/scleroderma or systemic lupus erythematosus), sarcoidosis, human immunodeficiency virus-1 infection, and other conditions under WHO Group 1, 2, 4, and 5 classifications.
• Based on chest computed tomography (CT) imaging during Screening Visit 1, the participant has a confirmed diagnosis of WHO Group 3 PH, other than COPD, such as idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, diffuse parenchymal lung disease or interstitial lung disease. A previous chest CT scan performed within the 6 months prior to the start of Screening Visit 1 is also acceptable, and a repeat assessment is not required. A redacted CT scan report (from Screening Visit 1 or dated within prior 6 months) should be provided to the Medical Monitor with the Pre-Baseline Review Form to confirm eligibility.
• The participant has received any Food and Drug Administration (FDA)-approved medication for the treatment of PAH (that is, prostacyclin, prostacyclin receptor agonist, endothelin receptor antagonist [ERA], phosphodiesterase type 5 inhibitor [PDE5-I], or soluble guanylate cyclase [sGC] stimulator) at Screening Visit 1 and thereafter, except if received for acute vasoreactivity testing.
• The participant has a previous diagnosis of homozygous alpha-1 antitrypsin deficiency.
• The participant has any prior intolerance to inhaled prostanoid therapy.
• Inability to tolerate low-dose (3 breaths, 18 mcg) study drug and/or inability to follow dosing regimen during the Screening Period (pre-randomization).
• Unwilling or unable to use Sponsor-provided devices (actigraph, spirometer, or smart device).
• The participant has evidence of clinically significant left-sided heart disease (including but not limited to left ventricular ejection fraction <40%, left ventricular hypertrophy,) or clinically significant cardiologic conditions, such as congestive heart failure, coronary artery disease, or valvular heart disease. Note: Participants with abnormal left ventricular function attributable to the effects of right ventricular overload will not be excluded, but a discussion with and approval by the Sponsor Medical Monitor is needed.
• Any exacerbation of COPD (including hospitalization or outpatient therapy) or active pulmonary or upper respiratory infection 60 days prior to start of Screening Visit 1 through the Baseline Visit. This is defined as worsening of respiratory symptoms that required treatment with corticosteroids and/or antibiotics.
• Initiation of pulmonary rehabilitation within 12 weeks prior to start of Screening Visit 1 or, in the opinion of the Investigator, pulmonary rehabilitation is likely to be needed during the study Treatment Period.
• The participant has any form of congenital heart disease (repaired or unrepaired; other than a patent foramen ovale).
• The participant has any musculoskeletal disorder (severe arthritis of the lower limbs which limits ambulation, recent hip or knee joint replacement, artificial leg) or any other condition that would likely be the primary limitation to ambulation.
• Use of any other investigational drug or device within 30 days prior to the start of Screening Visit 1.
• Any other clinically significant illness or abnormal laboratory value(s) measured during the Screening Period that, in the opinion of the Investigator, might adversely affect the interpretation of the study data or safety of the participant.
A Phase 3, Randomized, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1647 Cytomegalovirus (CMV) Vaccine in Healthy Females 16-40 Years of Age (mRNA-1647-P301)
This is a Phase 3, randomized, observer-blinded, placebo-controlled study in healthy participants 16 to 40 years of age. The primary efficacy objective is to demonstrate vaccine effect of mRNA-1647 against primary cytomegalovirus (CMV) infection in female participants who are CMV-seronegative at enrollment.
An Open-Label, Multicenter Phase 1/2 Study of Surufatinib in Combination with Gemcitabine in Pediatric, Adolescent, and Young Adult Patients with Recurrent or Refractory Solid Tumors Protocol Number: 2020-012-GLOB2/ADVL2121
This is an open-label, multicenter, phase 1/2 study of surufatinib in combination with gemcitabine in pediatric, adolescent, and young adult patients with recurrent or refractory solid tumors. The study will be conducted in 2 parts (part 1: ≥2 and ≤21 years of age; part 2: ≥2 and ≤21 years of age [patients with osteosarcoma up to <30 years old can enroll]).
MT2021-36: A Randomized, Open Label Phase 3 Study Evaluating Safety and Efficacy of Venetoclax in combination with Azacitidine after allogeneic Stem Cell Transplantation in Subjects with Acute Myeloid Leukemia (AML) (VIALE-T)
Part 1 Primary: To determine the recommended Phase 3 dose of venetoclax in combination with azacitidine in AML subjects when given as maintenance therapy following allogeneic SCT. Part 2 primary: 1. To determine the efficacy of venetoclax in combination with azacitidine to improve RFS in AML subjects compared to BSC when given as maintenance therapy following allogeneic SCT
A Phase 2 Study of the JAK1/JAK2 Inhibitor Ruxolitinib With Chemotherapy in Children With De Novo High-Risk CRLF2-Rearranged and/or JAK PathwayMutant Acute Lymphoblastic Leukemia Protocol Number: AALL1521/INCB 18424-269
This is a nonrandomized study of ruxolitinib in combination with a standard multi-agent chemotherapy regimen for the treatment of B-ALL. Subjects with de novo B-ALL, aged 1 to 21 years at the time of diagnosis, will be evaluated for genetic eligibility during the Induction phase of a 4-drug regimen (modified augmented Berlin-Frankfurt-Münster (aBFM) or equivalent).
• Eligible for study when participant is 1 year to 21 years at the time of diagnosis
• Eligible Ages in Australia and Canada; 2 years to 21 years
• De novo high-risk (HR) Ph-like B-ALL for which any of following criteria are present at diagnosis:
• Age ≥ 10 years
• White blood cell (WBC) ≥ 50 × 10^3/μL
• CNS3 leukemia at diagnosis
• Systemic steroid pretreatment without presteroid WBC documentation
• Diagnostic bone marrow or peripheral blood sample must have gene expression profiling and downstream genetic testing performed by submitting diagnostic specimens under the COG AALL08B1 or APEC14B1 biology studies, or AALL1131 or its successor study. Specimens must demonstrate a Ph-like expression profile (ie, LDA-positive) as tested by low density microarray testing at the COG ALL reference laboratory or TriCore laboratory at the University of New Mexico AND must contain 1 of the following genetic lesions: (determined at COG ALL reference laboratories, or equivalent CAP/CLIA-certified laboratories approved by the medical monitor:
• CRLF2 rearrangement* with confirmed JAK1 or JAK2 mutation (JAK+)
• CRLF2 rearrangement* without JAK mutation
• Other JAK pathway alterations (eg, JAK2 fusions, EPOR fusions, SH2B3 deletions, IL7RA mutations) with or without CRLF2-R, or CRLF2-R with unknown JAK status*† as determined by a COG ALL Reference Laboratory
• Completed a 4-drug Induction therapy regimen (modified aBFM regimen or equivalent) in Study AALL1131 or its successor study, or as per the institutional standard of care for HR B-ALL and have had end-Induction minimal residual disease (MRD) assessed
• Male and female subjects of reproductive non childbearing potential or willing to take appropriate precautions to avoid pregnancy or fathering a child for the duration of study participation
• Receipt of any other cytotoxic chemotherapy before Induction therapy, with exception of hydroxyurea or steroid pretreatment
• Trisomy 21 (Down syndrome)
• BCR-ABL1-rearranged (Ph+) ALL
• Calculated creatinine clearance or radioisotope glomerular filtration rate < 70 mL/min/1.73 m^2
• Alanine aminotransferase ≥ 5 × upper limit of normal (ULN) for age
• Direct bilirubin ≥ 1.5 × ULN (may be assumed if total bilirubin is below ULN)
• History or evidence of cirrhosis
• Platelet count < 75 × 10^3/μL
• Absolute neutrophil count (ANC) < 750/μL
• Positive screen for hepatitis B or C
• Known human immunodeficiency virus infection
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.
• 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 at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging.
• 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. 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 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible.
• 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.)
• Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
• 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.
• 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).
• 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.
A Phase I/II, Multicenter, Open-Label, Single-Dose, Dose-Ranging Study to Assess the Safety and Tolerability of ST-920, a rAAV2/6 Human Alpha Galactosidase A Gene Therapy, in Subjects with Fabry Disease
• ≥ 18 years of age
• Documented diagnosis of Fabry disease
• One or more of the following symptoms: i) cornea verticillata, ii) acroparesthesia, iii) anhidrosis, iv) angiokeratoma
• Subject must be fully vaccinated (as per the Centers for Disease Control and Prevention (CDC) definition in the US and as per local guidelines in other countries) for COVID-19 at least one month prior to dosing Additional
• Screening eGFR value between 40-90 mL/min/1.73 m²
• Linear negative eGFR slope (estimated from at least 3 serum creatinine values within 18 months, including the value obtained during screening visit) of ≥ 2 mL/min/1.73m²/year Cardiac Cohort: • Left ventricular hypertrophy (LVH) in 2D echocardiography or CMR defined as an end diastolic septum and posterior wall thickness ≥12 mm with no other explanation for LVH, OR presentation with cardiac changes indicative of disease progression such as decreased global longitudinal strain on 2D strain echocardiography or low native T1 mapping on CMR
• Neutralizing antibodies to AAV6
• eGFR < 40 ml/min/1.73m2
• New York Heart Association Class III or higher
• Active infection with hepatitis A, B or C, HIV or TB
• History of liver disease such as clinically significant steatosis, fibrosis, non-alcoholic steatohepatitis (NASH) and cirrhosis, biliary disease within 6 months of informed consent; except for Gilbert's syndrome
• Elevated circulating serum AFP
• Recent or recurrent hypersensitivity response to ERT within within 6 months prior to consent
• Current or history of systemic (IV or oral) immunomodulatory agents, or biologics or steroid use in the past 6 months prior to consent (topical treatment and inhaled allowed).
• Contraindication to use of corticosteroids
• History of malignancy except for non-melanoma skin cancer and localized prostate cancer treated with curative intent
• Recent history of alcohol or substance abuse
• Participation in investigational interventional drug or medical device study throughout the duration of this study and within previous 3 months prior to consent
• Prior treatment with a gene therapy product
• Known hypersensitivity to components of ST-920 formulation
• Any other reason that, in the opinion of the Site Investigator or Medical Monitor, would render the subject unsuitable for participation in the study including but not limited to risk of COVID-19 infection Additional exclusion criteria for: Renal cohort:
• History of renal dialysis or transplantation
• History of acute kidney insufficiency in the 6 months prior to screening
• Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated within 4 weeks prior to screening or changed ACE inhibitor or ARB dose in the 4 weeks prior to screening
• Urine protein to creatinine ratio (UPCR) > 0.5 g/g who are not being treated with an ACE inhibitor or ARB Cardiac cohort:
• Significant cardiac fibrosis defined by late gadolinium enhancement on CMR
• Any contraindications to CMR as per local hospital/institution guidelines
• Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy initiated within 4 weeks prior to screening or changed ACE inhibitor or ARB dose in the 4 weeks prior to screening
• NYHA Class IV
MT2020-24: A Phase 1 Dose Escalation and Cohort Expansion Study of the Safety and Efficacy of Anti-CD19 Allogeneic CRISPR-Cas9 Engineered T Cells (CTX110) in Subjects With Relapsed or Refractory B Cell Malignancies
Primary objective, Part A (dose escalation): To assess the safety of escalating doses of CTX110 in subjects with relapsed or refractory B cell malignancies to determine the recommended Part B dose Primary objective, Part B (cohort expansion): To assess the efficacy of CTX110 in subjects with relapsed or refractory B cell malignancies, as measured by objective response rate (ORR)
• For NHL patients: Age ≥18 years. For B cell ALL patients: age ≥18 years to ≤70 years
• Refractory or relapsed non-Hodgkin lymphoma, as evidenced by 2 or more lines of prior therapy, or histologically confirmed B cell ALL, refractory or relapsed.
• Eastern Cooperative Oncology Group performance status 0 or 1.
• Adequate renal, liver, cardiac and pulmonary organ function
• Female subjects of childbearing potential and male subjects must agree to use acceptable method(s) of contraception from enrollment through at least 12 months after CTX110 infusion.
• Agree to participate in an additional long-term follow-up study after completion of this study. Key
• Treatment with any gene therapy or genetically modified cell therapy, including CAR T cells.
• For NHL patients: prior allogeneic HSCT. For B cell ALL patients: prior allogeneic HSCT within 6 months, and/or any evidence of GvHD.
• History of central nervous system (CNS) involvement by malignancy
• History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
• Presence of bacterial, viral, or fungal infection that is uncontrolled or requires IV anti-infectives.
• Active HIV, hepatitis B virus or hepatitis C virus infection.
• Previous or concurrent malignancy, except basal cell or squamous cell skin carcinoma, adequately resected and in situ carcinoma of cervix, or a previous malignancy that was completely resected and has been in remission for ≥5 years.
• For NHL patients: Use of systemic anti-tumor therapy or investigational agent within 14 days or 5 half-lives, whichever is longer, of enrollment. For B cell ALL patients: Use of systemic antitumor therapy within 7 days of enrollment.
• Primary immunodeficiency disorder or active autoimmune disease requiring steroids and/or other immunosuppressive therapy.
• Women who are pregnant or breastfeeding.
A Phase 1/2 Study of the Oral RET Inhibitor LOXO-292 in Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors; Protocol Number: LOXO-RET-18036 (J2G-OX-JZJJ) (LIBRETTO-121)
This is an open-label, multi-center, Phase 1/2 study of oral LOXO-292 in pediatric patients with an activating RET alteration and an advanced solid or primary CNS tumor.
• Advanced or metastatic solid or primary CNS tumor which has failed standard of care therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16) performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically stable for 7 days prior and must not have required increasing doses of steroids within the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and effective birth control
• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant required a modification to current thyroid medication in the 7 days before start of LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s])
A Phase II, Open Label, Two Arm Study of Therapeutic Iobenguane (131I) as Single Agent or in Combination with Vorinostat for Recurrent or Progressive High-Risk Neuroblastoma Subjects (OPTIMUM Trial) Protocol Number: MIBG 2014-01 (OPTIMUM)
This will be a Phase II, two-arm, nonrandomized, non-comparative, open-label study in participants ≥ 1 year of age with iobenguane avid, recurrent or progressive high-risk neuroblastoma. Participants not eligible for vorinostat treatment may receive 131I-MIBG as monotherapy.
• Subjects with a diagnosis of iobenguane avid, high-risk neuroblastoma based on Revised INRC criteria at the time of study enrollment with recurrent or progressive disease at any time prior to enrollment, regardless of overall response to frontline therapy, where frontline therapy includes a minimum of 4 cycles of induction therapy at any time prior to enrollment.
• May have had prior 131I-MIBG therapy, provided:
• It has been at least 6 months from the date of last 131I-MIBG ;
• Response was other than progressive disease on first restaging after 131I-MIBG ;
• Prior 131I-MIBG was given as monotherapy and not in combination with systemic anticancer agents;
• Cumulative lifetime dose of 131I-MIBG at enrollment does not exceed 18 mCi/kg.
• All soft tissue lesions identified on CT/MRI scans must be iobenguane avid lesions on an (123I)-iobenguane scan, or
• any progressive non-iobenguane avid lesion is proven by biopsy to be a non-neuroblastoma lesion.
• any other non-avid lesion is comprised of a fibrotic or scarred mass as shown by routine imaging and confirmed by the investigator.
• Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least 2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment).
• If a male, must agree to use an adequate contraception method as deemed appropriate by the Investigator (e.g., vasectomy, condoms) or partner using effective contraception and to not donate sperm during the study and for 90 days after receiving the last dose of study drug.
• If a female of childbearing potential, have a negative serum pregnancy test result prior to each dosing and, if sexually active, be practicing an effective method of birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner sterilization throughout the study.
• Age at study entry ≥1 year.
• Previous platelet transfusions are permitted, as long as the subject has a platelet count ≥50,000/μL without transfusion support for at least 1 week.
• Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline.
• An absolute neutrophil count ≥750/μL without growth factor for 5 days.
• Liver function parameter results: total bilirubin ≤2 × upper limit of normal for age, and Serum alanine aminotransferase (glutamic-pyruvic transaminase) and serum aspartate aminotransferase (glutamic-oxaloacetic transaminase) ≤ 10 times the upper limit of normal (for all sites, the upper limit of normal for alanine aminotransferase is defined as 45 U/L).
• Normal thyroid function as measured by T4 or TSH or have abnormal results that are not considered clinically important by the Investigator or may be receiving levothyroxine.
• Cardiac Function: shortening fraction of ≥ 27% by echocardiogram or ejection fraction ≥ 50% documented by echocardiogram or radionuclide angiogram within 1 month prior to Visit 1 (Baseline).
• Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance Status Performance Status (for subjects 1 to 16 years of age) ≥50%.
• Full recovery from the toxic effects of any prior therapy.
• Coagulation Function:
• International Normalized Ratio (INR) < 1.5
• Partial thromboplastin time (PTT) < 1.5 times upper limit of normal.
• Subjects within 5 half-lives after any antibody-based immunotherapy, or have not recovered from effects of any biologic therapy.
• Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant.
• Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit 1 are excluded. Those who have received allogeneic stem cell treatment more than 4 months from Visit 1 must have recovered and have no active graft versus host disease (GVHD) to be eligible.
• Subjects must not have received radiation for a minimum of 2 weeks prior to study enrollment. Subjects whose only site(s) of disease have been radiated are eligible as long as the subject has MIBG avidity 2 weeks after completion of radiation. A minimum of 12 weeks prior to study enrollment is required following prior large field radiation therapy (ie, craniospinal, whole abdominal, total lung, > 50% marrow space)
• History of total body irradiation.
• Subjects do not have adequate renal function defined as GFR ≥ 70 mL/min/1.73 m2 either by creatinine clearance or radioisotope direct measurement or by calculation with the Schwartz formula
• Subjects who are on hemodialysis.
• Pregnancy or breastfeeding.
• Significant active infections including active hepatitis B, or hepatitis C infection, or known infection with human immunodeficiency virus (HIV) (testing for HIV is not required prior to study entry).
• Clinically important cardiac, pulmonary, and hepatic impairment.
• Vorinostat treatment exclusion criteria (subjects, who meet any one of these criteria and otherwise meet eligibility criteria, are still eligible for 131I-MIBG monotherapy)
• Since valproic acid has HDAC inhibitory activity, patients must not have received valproic acid within 30 days of study entry.
• Since vorinostat may prolong the QT interval, patients must not be receiving other medications known to prolong the QT interval at the time of study entry . Pentamidine must not have been received within 1 week of study enrollment.
• Patients with a history of deep venous thrombosis that was not associated with the presence of a central venous catheter.
• Patients who are receiving Coumadin.
EA5163/S1709 INSIGNA: A Randomized, Phase III Study of Firstline Immunotherapy alone or in Combination with Chemotherapy in Induction/Maintenance or Postprogression in Advanced Nonsquamous Non Small Cell Lung Cancer (NSCLC) with Immunobiomarker SIGNature driven Analysis
A randomized, controlled, multi-center, safety and efficacy study of FCR001 cell-based therapy relative to a tacrolimus and mycophenolate-based regimen in de novo living donor renal transplant recipients, and safety in FCR001 donors (FREEDOM-1)
The purpose of this study is to assess the safety, efficacy and overall benefit of FCR001 cell therapy in de novo living donor renal transplantation, relative to a standard-of-care control regimen including tacrolimus, mycophenolate, antibody induction, and corticosteroids. FCR001 is a novel, cryopreserved allogeneic somatic cell therapy, derived from mobilized peripheral blood mononuclear cells from the same donor as the allograft, and containing hematopoietic progenitor cells, facilitating cells and αβ T cells. The rationale is to establish durable chimerism and donor-specific tolerance in the recipient enabling freedom from chronic IS and its associated toxicities.
• Recipient age ≥18 years.
• Donor age ≥18 and ≤60 years at time of signing informed consent.
• Recipients of a first or second living donor kidney transplant
• Donor willing to undergo mobilization, apheresis and 12-month safety follow-up and meet all local standard eligibility criteria to donate stem cells for allogeneic transplantation.
• Recipient meets all local standard eligibility criteria for allogeneic stem cell transplant.
• Donors must be deemed eligible as per the requirements of 21CFR1271. Main Recipient and Donor
• Recipient and donor who are identical twins.
• Recipient or donor with history of malignancy or premalignant syndrome (e.g., myelodysplastic syndrome, monoclonal gammopathy of renal significance [MGRS], monoclonal gammopathy of unknown significance [MGUS]) of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
• Recipient or donor with known bone marrow aplasia. Main Recipient-only
• Multi-organ or stem cell transplant recipient.
• Calculated panel reactive antibodies >80%.
• Recipient is blood type ABO incompatible with donor.
• Presence of donor-specific antibodies (DSA) (positive result) at any time pre-transplant.
• Recipient who is human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) positive.
• Recipient with any baseline condition requiring or anticipated will require chronic or intermittent use of systemic steroids or other IS (eg, autoimmune disease, asthma) throughout the course of the study.
• Recipient with a BMI < 18 or > 35 kg/m2.
• Recipient requiring systemic anticoagulation, (eg, for hyper-coagulation disorders, deep vein thrombosis, atrial fibrillation) that cannot be temporarily interrupted which would preclude renal biopsy. Main Donor-only
• Biologically unrelated (i.e., no genetic relationship) female donor transplant to male recipient.
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular Symptoms in Patients with Myotonic Dystrophy Type 1, Followed by an Open-Label Extension
The study will be evaluating the safety and efficacy of Pitolisant drug in patients with Myotonic Dystrophy type I.
• Is able to provide voluntary, written informed consent.
• Has a diagnosis of DM1 confirmed by genetic testing (cytosine-thymine-guanine [CTG] repeat of ≥100) from the Screening Visit.
• Male or female patients ages 18 to 65 years at the time of enrollment.
• Has a Clinical Global Impression of Severity (CGI-S) assessment of moderate or severe for overall severity of EDS at Screening.
• If on a wake-promoting treatment that could affect EDS (including stimulants, modafinil, and armodafinil):
• Must be on a stable dose for at least 2 months prior to Screening and agree to continue the stable dose for the duration of the Double-Blind Treatment Phase of the study (dose adjustments will be permitted in the OLE Phase).
• If not on a stable dose for 2 months prior to Screening, washout for 5 half-lives prior to randomization and agree to remain off these treatments for the duration of the Double-Blind Treatment Phase of the study.
• Washout of cannabidiol and tetrahydrocannabinol for 28 days prior to randomization and agree to remain off for the duration of the Double-Blind Treatment Phase of the study.
• Able to walk independently with or without an assistive device (e.g., cane, walker, orthoses allowed).
• A patient who is a female of child-bearing potential (FCBP) must have a negative serum pregnancy test at the Screening Visit and negative urine pregnancy test at the Baseline Visit and agree to remain abstinent or use an effective method of non-hormonal contraception to prevent pregnancy for the duration of the study and for 21 days after final dose of study drug.
• In the opinion of the Investigator, the patient is capable of understanding and complying with the protocol and administration of oral study drug.
• Has a diagnosis of another genetic or chromosomal disorder that is distinct from DM1 and that is not being managed adequately in the opinion of the Investigator.
• Experiences <6 hours on average of sleep per night based on their sleep diary during Screening (patients need to record at least 7 of 10 consecutive nights including 2 nights that fall on a weekend in their sleep diary during Screening).
• Consistently consumes >600 mg of caffeine per day and is unable/unwilling to reduce caffeine intake to <600 mg per day for the duration of the Double-Blind Treatment Phase of the study; caffeine intake should remain consistent during Screening and throughout the Double-Blind Treatment Phase of the study.
• Does not agree to discontinue any prohibited medication or substances listed in the protocol.
• Is currently breastfeeding or planning to breastfeed over the course of the study. Lactating women must agree not to breastfeed for the duration of the study (Double-Blind Treatment Phase and OLE Phase) and for 21 days after final dose of study drug.
• Participation in an interventional research study involving another investigational medication or device in the 28 days prior to enrollment; patients who undergo a washout of an investigational medication of at least 5 half-lives can be enrolled in the Double-Blind Treatment Phase of the study. Patients considering participation in another interventional research study in the OLE Phase must consult with the Investigator who will consult with the Medical Monitor.
• Has a primary diagnosis of severe psychiatric illness.
• Patients taking antidepressants who have not been on a stable dose of their antidepressant for at least 12 weeks prior to Screening; for patients on a stable dose of their antidepressant for at least 12 weeks prior to Screening, must agree to continue their stable dose for the duration of the Double-Blind Treatment Phase of the study. Dose adjustments will be permitted in the OLE Phase. In the Double-Blind Treatment Phase of the study, antidepressants that are strong CYP2D6 inhibitors are exclusionary.
• Has a history of sleep-disordered breathing or another underlying sleep disorder that in the opinion of the Investigator is a main contributory factor to the patient's EDS.
• Has a diagnosis of end-stage renal disease (ESRD; estimated glomerular filtration rate [eGFR] of <15 mL/minute/1.73 m2) or severe hepatic impairment (Child-Pugh C).
• Has a diagnosis of moderate or severe renal impairment (eGFR ≥15 to ≤59 mL/minute/1.73 m2) or moderate hepatic impairment (Child-Pugh B) at Screening or during the Double-Blind Treatment Phase.
• Has a family history of sudden cardiac death, unexplained death, or death from a primary dysrhythmia potentially associated with QT prolongation in any family member (i.e., first degree relative such as parent, sibling, or offspring).
• Has a history of unexplained syncope.
• Has a history of long corrected QT interval (QTc) syndrome or corrected QT interval using Fridericia's formula (QTcF) >450 msec for males or >470 msec for females (QTcF = QT / 3√ RR) sustained atrial fibrillation (AF) or left ventricular ejection fraction <50%.
• Has a history of documented symptomatic arrhythmias (e.g., ECG, Holter monitor).
• Electrocardiogram abnormalities during a 10-second, 12-lead ECG at Screening of first degree atrioventricular block (AVB; PR interval >220 msec), QRS >120 msec, heart rate (HR) <50 beats per minute (bpm), marked T-wave abnormalities, more than single atrial premature complexes (APCs) or premature ventricular contractions (PVCs), left bundle branch block, or Brugada pattern type 1. Note: Patients with 1st degree AVB with a PR interval >220 msec, who are treated prophylactically with an allowable implanted device are not excluded from the study.
• Based on Holter monitor, any episode of 3rd degree AVB, any prolonged episode of second degree AVB (>2 episodes during waking hours, >6 episodes during sleep), any prolonged episode of 2nd degree AVB (>10 seconds), any asystole longer than 3.5 seconds, any run of ventricular tachycardia (VT) >6 beats, frequent runs of non-sustained VT (>5/24 hour), >400 PVCs/24 hours, AF or paroxysmal AF, or frequent or complex atrial arrhythmias.
• Has history of New York Heart Association (NYHA) class III or class IV heart failure.
• Has an implanted defibrillator or implanted biventricular pacemaker. Note: Patients with implanted univentricular pacemakers that are used prophylactically to prevent or treat bradycardia or heart block may be included.
• Is receiving a medication known to prolong the QT interval.
• Has a history of clinically significant hypokalemia or hypomagnesemia that cannot be adequately controlled by supplementation.
• Has serum potassium or magnesium levels that are outside of the normal reference ranges and considered clinically significant at Screening. Patients with mild hyperkalemia that, in the opinion of the Investigator, does not pose an arrhythmia threat may be included.
• Is receiving a concomitant medication that is known to be a strong cytochrome P450 (CYP) 2D6 inhibitor, a strong CYP3A4 inducer; or a centrally acting histamine 1 receptor (H1R) antagonist (sedating antihistamine). Note: Patients who undergo a washout of these medications of at least 5 half-lives may be enrolled in the Double-Blind Treatment Phase of the study. Note: Use of strong CYP2D6 inhibitors and strong CYP3A4 inducers is allowed during the OLE Phase; however, adjustment of pitolisant dose is required. Although not prohibited during the OLE Phase of the study, use of centrally acting or sedating H1R antagonists should be avoided.
• Is a known CYP2D6 poor metabolizer (PM).
• Regular use (more than twice per week) of any sleep-promoting treatments that could affect EDS and not willing to limit use to no more than twice per week during Screening and for the duration of the Double-Blind Treatment Phase of the study (use of sleep-promoting agents are not allowed within one day prior to study-related assessments).
• Has abnormal laboratory values at Screening that are clinically significant as determined by the Investigator.
• Has initiated any new or change in allied health therapies or interventions that can interfere with the study outcomes within 28 days prior to randomization and that are prohibited during the Double-Blind Treatment Phase of the study, based on the Investigator's judgment.
• Has a current or recent (within 1 year) history of a substance use disorder or dependence disorder, including alcohol and caffeine use disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V).
• Has planned surgery during the Double-Blind Treatment Phase of the study; planned surgery is permitted during the OLE Phase.
• Has a significant risk of committing suicide or suicidality based on history, routine psychiatric examination, Investigator's judgment, or who has an answer of "yes" on any question other than questions 1 to 3 on the Columbia-Suicide Severity Rating Scale.
• Based on the judgment of the Investigator, is unsuitable for the study for any reason, including but not limited to an unstable or uncontrolled medical condition or one that might interfere with the conduct of the study, confound interpretation of study results, pose a health risk to the patient, or compromise the integrity of the study.
A Phase II Multicenter, Randomized, Double-Blind, 12-Week Treatment, 3-Arm, Parallel-Group, Placebo-Controlled Study to Investigate the Efficacy, Safety and Tolerability of RO7017773 in Participants Aged 15 to 45 Years with Autism Spectrum Disorder (ASD)
• Male and female participants with Autism Spectrum Disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
• Wechsler Abbreviated Scale of Intelligence (WASI-II) >/= 50 at screening or within the last 12 months prior to screening
• ASD or Autism diagnosis confirmed by Autism Diagnostic Observation Schedule (ADOS-2)
• Body mass index within the range of 18.5 to 40 kg/m2
• Female Participants: is eligible if she is not pregnant, not breastfeeding, and women of childbearing potential (WOCBP), who agree to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 28 days after the last dose of study drug
• Language, hearing, and vision compatible with the study measurements as judged by the Investigator
• Allowed existing treatment regimens should be stable for 8 weeks prior to screening. Investigator expects stability of these treatments and behavioral interventions for the duration of the study
• In the Investigator's opinion, able to participate and deemed appropriate for participation in the study, capable of following the study SoA and able to comply with the study restrictions
• In the Investigator's opinion, participation in the study or discontinuation of prohibited medication will not pose undue risks Exclusion Criteria Neurologic/Psychiatric Conditions:
• Non-verbal individuals
• Presence of chromosome 15q11.2 q13.1 duplication syndrome (Dup15q syndrome), known "syndromic" forms of ASD (confirmed per genetic results available at screening): fragile X syndrome, Prader Willi syndrome, Rett's syndrome, tuberous sclerosis, and Angelman syndrome, as well as genetic alterations strongly associated with ASD per genetic results available at screening affecting the following genes: CHD8, ANDP, SHANK3
• Medical history of alcohol and/or substance abuse/dependence in the last 12 months or positive test for drugs of abuse at screening
• Initiation of a major change in psychosocial intervention within 6 weeks prior to screening. Minor changes in ongoing treatment are not considered major changes
• Clinically significant psychiatric and/or neurological disorder that may interfere with the safety or efficacy endpoints
• Risk of suicidal behavior in the opinion of a certified clinician or as evidenced by a "yes" to questions 4 and/or 5 of Columbia-Suicide-Severity Rating Scale (C-SSRS) taken at screening and baseline with respect to the last 12 months, or any suicide attempt in the past 5 years
• Unstable epilepsy/seizure disorder within the past 6 months or changes in anticonvulsive therapy within the last 6 months Other Conditions:
• Medical history of malignancy if not considered cured or if occurred within the last 3 years with the exception of fully excised non-melanoma skin cancers or in-situ carcinoma of the cervix that has been successfully treated
• Concomitant disease, condition or treatment which would either interfere with the conduct of the study or pose an unacceptable risk to the participant in the opinion of the Investigator Prior/Concomitant Therapy
• Use of prohibited medications or herbal remedies within 6 weeks or 5 half-lives (t1/2) prior to randomization Prior/Concurrent Clinical Study Experience:
• Donation or loss of blood over 500 mL in adults and 250 mL in adolescents within 3 months prior to randomization
• Participation in an investigational drug study within 1 month or 5 times the t1/2 of the investigational molecule prior to randomization or participation in a study testing an investigational medical device within 1 month prior to randomization or if the device is still active Diagnostic Assessments
• Confirmed clinically significant abnormality in hematological, chemistry or coagulation laboratory parameters
• Positive test result at screening for hepatitis B surface antigen, hepatitis C virus (HCV, untreated), or human immunodeficiency virus (HIV)-1 and -2. HCV participants who have been successfully treated and who test negative for HCV RNA, may be considered eligible for entry into the study Other Exculsions:
• Uncorrected hypokalemia or hypomagnesaemia
A Phase 2 Open-label, Dose Escalation Study of HST5040 in Subjects with Propionic or Methylmalonic Acidemia Followed by a 6-Month, Randomized, Double-blind, Placebo-controlled, 2-period Crossover and an Open-label, Long-term Extension (HERO)
Phase 2 Open-label, Dose Escalation Study Followed by a 6-Month, Randomized, Double-blind, Placebo-controlled, 2-period Crossover and an Open-label, Long-term Extension
• Confirmed diagnosis of symptomatic PA or MMA (Mutase)
• Ages ≥ 2 years old.
• History of Inadequate metabolic control while receiving standard of care (SoC).
• Plasma MCA concentration > 3x upper limit of normal of the reference range at screening.
• Stable supplementation dose of carnitine for at least 1 week prior to the entry in the study.
• Moderate-to-severely impaired cardiac function with LVEF < 45% by ECHO.
• Clinically significant arrhythmia by Holter monitor.
• QTcF > 450 msec
• Moderate to severe chronic kidney disease with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2.
• Exposure to any investigational therapy, apart for a COVID-19 vaccine, within the past 6 months prior to study entry.
• Exposure to gene therapy for PA or MMA at any time prior to study entry.
• History of organ transplantation (Part A and B only)
• History of severe allergic or anaphylactic reactions to any of the components of HST5040.
HM2021-31: A Phase 1b Open-Label Study to Evaluate the Safety and Anti-cancer Activity of Loncastuximab Tesirine in Combination with Other Anti-cancer Agents in Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (LOTIS-7)
This protocol aims to characterize the safety and tolerability of loncastuximab tesirine in combination with gemcitabine, lenalidomide, polatuzumab vedotin, or umbralisib, and to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) for any of the combinations in subjects with relapsed or refractory B-cell Non-Hodgkin Lymphoma. This project aims to address the resistance mechanisms to single agent therapies and enhance efficacy by engaging different targets, in synergistic or additive manner.
MT2020-08 A Phase 1/2a, Open-label, Dose-escalation, Dose-expansion, Parallel Assignment Study to Evaluate the Safety and Clinical Activity of PBCAR0191 in subjects with Relapsed/Refractory Non-Hodgkin Lymphoma and r/r B-cell Acute Lymphoblastic Leukemia
To evaluate the safety and tolerability of PBCAR0191 in subjects with r/r B-ALL and r/r NHL and find an appropriate dose to optimize safety and efficacy. To evaluate the clinical benefit of PBCAR0191 in subjects with r/r B-ALL and r/r NHL. To evaluate the clinical activity of PBCAR0191 in subjects with r/r B-ALL and r/r NHL.
• Subject has unequivocal r/r CD19+ B-ALL that has been confirmed by morphology, flow cytometry, or a validated minimal residual disease assay.
• Subjects with Philadelphia chromosome positive disease can be eligible if they are intolerant to tyrosine kinase inhibitor therapy or if they have r/r disease. Criteria for NHL:
• Subject has unequivocal aggressive CD19+ r/r B-cell NHL that is confirmed by archived tumor biopsy tissue from last relapse after CD19-directed therapy and corresponding pathology report. Alternatively, if at least 1 tumor involved site is accessible at time of Screening, the subject's diagnosis is confirmed by pretreatment biopsy (excisional when possible) or by flow cytometry of fine needle aspirate. If a subject never had a CR, a sample from the most recent biopsy is acceptable. NHL subtypes included but are not limited to:
• Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation
• FL including Grade 3 or transformed FL
• High-grade B-cell lymphoma
• Primary mediastinal lymphoma
• Subject has measurable or detectable (for example positron emission tomography-positive) disease according to the Lugano Classification.
• Subject must have received at least 2 prior chemotherapy-containing regimens, consistent with standard of care treatment guidance (e.g., NCCN), unless no second line therapy of known benefit exists for a given subject. Other than those specifically prohibited, other therapies are allowed until 7 days prior to initiation of LD. In that case, all Screening safety laboratories and disease assessments must be performed after the last dose of prior therapy. For Richter's transformation, only 1 prior line of therapy is required for the DLBCL component.
• Subject has received no more than 7 systemic lines of anti-cancer therapy for the disease under study.
• Subjects previously treated with CD19-directed autologous CAR T therapies have received no more than 2 lines of therapy after administration of their previous CAR T product.
• Expansion cohort only: Subjects must have received autologous CD19-directed CAR T therapy and demonstrated clinical response to the treatment at Day 28 or later, followed by relapse. Criteria for both B-ALL and NHL:
• Eastern Cooperative Oncology Group performance status score of 0 or 1.
• An estimated life expectancy of at least 12 weeks according to the investigator's judgment.
• Seronegative for human immunodeficiency virus antibody (i.e., intact immune function).
• Subject has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function defined as:
• Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 (calculated using the CKD-EPI equation [Levey et al, 2009]). If there is a concern that eGFR calculation is not an accurate reflection of renal function, a 24-hour urine collection for creatinine clearance may be used at the investigator's discretion.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both ≤3 times of upper limit of normal (ULN), unless there is suspected disease in the liver.
• Total bilirubin <2.0 mg/dL, except in subjects with Gilbert's syndrome.
• Platelet count ≥50,000/μL and absolute neutrophil count of ≥1000/ μL. Platelet transfusions within 14 days of screening are not allowed except for subjects in B-ALL disease cohort with extensive bone marrow disease burden, in which case adequate bone marrow recovery after prior treatment is required to be documented.
• C-reactive protein (CRP) <2x ULN; subjects with CRP elevation within 2x ULN, ruling out infectious cause will be required.
• Left ventricular ejection fraction >45% as assessed by echocardiogram (ECHO) or multiple gated acquisition scan performed within 1 month before starting lymphodepleting chemotherapy. ECHO results performed within 6 months before Screening and at least 28 days after the last cancer treatment may be acceptable if the subject has not received any treatment with cardiotoxicity risks.
• No clinically significant evidence of pericardial effusion or pleural effusion causing clinical symptoms and needing immediate intervention, based on the investigator's opinion. Any known effusion must be stable without need for drainage within 2 weeks of enrollment.
• No clinically significant renal/pulmonary comorbidities.
• Baseline oxygen saturation >92% on room air. Key Exclusion Criteria* Criteria for B-ALL:
• Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.
• No active central nervous system (CNS) disease. Subjects with a history of CNS involvement must have a documented CR on at least 2 imaging studies at least 3 months apart (with no masses in parenchyma and no ocular involvement) and a negative cerebrospinal fluid cytology on at least 2 evaluations (one evaluation may be during the Screening Period and the other must be at least 3 months prior). Criteria for NHL:
• No prior or active CNS disease.
• Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
• Active hemolytic anemia. Criteria for B-ALL and NHL:
• Subject has had a malignancy, besides the malignancies of inclusion (B-ALL or NHL), that in the investigator's opinion, has a high risk of relapse in the next 2 years. In the case of Richter's transformation, subjects may be enrolled with ongoing chronic lymphocytic leukemia/small lymphocytic lymphoma.
• Uncontrolled and serious fungal, bacterial, viral, protozoal, or other infection that has not resolved and does require therapeutic anti-microbial medications at least 7 days prior to LD. Subjects with elevated CRP must undergo infectious disease workup and the recommendations discussed with medical monitor to be considered on an individual basis. The CRP must be trending toward the normal range for the laboratory with the exception when it's deemed related to the underlying malignancy.
• Any form of primary immunodeficiency (e.g., severe combined immunodeficiency disease).
• Active hepatitis B or hepatitis C confirmed by PCR. Subject positive for inactive hepatitis B is allowed to enroll if on prophylactic treatment.
• Subject is seropositive for hepatitis B antigen with confirmation. If confirmatory tests are negative, the subject can be enrolled.
• Subject is seropositive for hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, the subject must be tested for the presence of RNA by reverse transcription PCR and be hepatitis C virus-RNA negative.
• Any known uncontrolled cardiovascular disease at the time of Screening that, in the investigator's opinion, renders the subject ineligible, including but not limited to:
• Active ventricular or atrial dysrhythmia ≥ Grade 2, bradycardia ≥ Grade 2.
• Myocardial infarction within 6 months before Screening.
• Pulmonary embolism, deep vein thrombosis, or any other significant coagulopathy including disseminated intravascular coagulation.
• History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening. In case of hypertensive crisis caused by omission of well-established treatment regimen, transient and promptly stabilized, enrollment must be discussed and agreed upon with sponsor and medical monitor.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• Presence of a CNS disorder that, in the opinion of the investigator, renders the subject ineligible for treatment.
• Abnormal findings during the Screening Period or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject's safety.
• History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome.
• Active uncontrolled autoimmune disease requiring active immunosuppression at the time of Screening (excluding subjects needing steroids for physiologic replacement).
• Subject has received stem cell transplant within 90 days before Screening.
• Subject has active GvHD symptoms.
• Subject has received systemic biologic agent for treatment of disease under study within 28 days of LD or other systemic anti-cancer therapy within 10 days of LD Note: this criterion does not apply if the subject has clear evidence of disease progression after such an agent has been administered and all AEs have resolved to a Grade 2 or less in severity. This should be discussed with the medical monitor for confirmation.
• Participation in noninterventional registries or epidemiological studies is not excluded.
• Radiotherapy within 4 weeks before Screening should be discussed with monitor and determined on a case-by-case basis.
• Presence of pleural/peritoneal/pericardial catheter, as well as biliary and ureteral stents (does not apply to intravenous lines).
• Subject has received live vaccine within 4 weeks before Screening. Non-live virus vaccines are not excluded.
• Subject has received CD19-directed therapy other than autologous CD19-directed CAR T therapy within 90 days of the anticipated start date of LD.
• Additional criteria apply
A multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of finerenone on morbidity and mortality in participants with heart failure (NYHA II-IV) and left ventricular ejection fraction ≥ 40% (LVEF ≥ 40%)
This study is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, event-driven Phase 3 study with independently adjudicated clinical outcome assessments.