A Phase 1, Multicenter, Open-Label Study of JCAR017, CD19-targeted Chimeric Antigen Receptor (CAR) T Cells, for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL)
Disease Group: Lymphoma
Treatment Agent: JCAR017
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Juno Therapeutics
Primary: To evaluate the safety of JCAR017 in adult subjects with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) To assess the antitumor activity of JCAR017 To characterize the pharmacokinetic (PK) profile of JCAR017 Secondary: To assess the rate of CR and durability of antitumor activity of JCAR017 To estimate the progression-free survival (PFS) and overall survival (OS) of subjects treated with JCAR017 To assess health-related quality of life (HRQoL) and health economics and outcomes research (HEOR) Exploratory: To assess the effect of JCAR017 on antitumor activity using Bayesian methods To assess immune responses to JCAR017 To assess the pharmacodynamic effects of JCAR017 To assess the effect of JCAR017 attributes on safety, PK, and antitumor activity To assess the effect of tumor and tumor microenvironment on JCAR017 PK and pharmacodynamics
IRB Review and Approval Date: 09/02/2016
Recruitment Status: Open
Projected Accrual: 274
1) Age >/= 18 years at the time of consent
2) Signed written informed consent obtained prior to any study procedures
3) Relapsed or refractory B-cell NHL of the following histologies: a. DLBCL cohort: DLBCL, not otherwise specified (NOS; includes transformed DLBCL from indolent histology [tDLBCL]), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology, primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma Grade 3B. Subjects must have been treated with an anthracycline and rituximab (or other CD20-targeted agent) and have relapsed or refractory disease after at least 2 lines of therapy or after autologous hematopoietic stem cell transplant (auto-HSCT).
4) Inclusion criteria #3 cont.: b. MCL cohort: MCL (diagnosis must be confirmed with cyclin D1 expression or evidence of t(11;14) by cytogenetics, fluorescent in situ hybridization [FISH], or polymerase chain reaction [PCR]) with relapsed or refractory disease after at least 1 prior line of MCL therapy
5) Positron emission tomography (PET)-positive disease according to the "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
6) Archived tumor biopsy tissue available from the last relapse and corresponding pathology report available or, if at least one tumor-involved site is deemed accessible at time of screening, willing to undergo pre-treatment biopsy (excisional when possible) for disease confirmation. If the subject has never had a CR, a sample from the most recent biopsy is acceptable.
7) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8) Adequate organ function, defined as: * Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy; * Serum creatinine </=1.5 x age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft and Gault) >30mL/min/1.73m^2; * Alanine aminotransferase (ALT) </=5 x ULN and total bilirubin <2.0 mg/dL (or <3.0 mg/dL for subjects with Gilbert’s syndrome or lymphomatous infiltration of the liver); * Adequate pulmonary function, defined as </= CTCAE Grade 1 dyspnea and oxygen saturation (SaO2) >/=92% on room air; * Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >/=40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) scan performed within 1 month of enrollment
9) Adequate vascular access for leukapheresis procedure (either peripheral line or surgically-placed line)
10) Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy
11) Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must agree to use highly effective methods of contraception for 1 year after the last dose of JCAR017
12) Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method for 1 year after the last dose of JCAR017
1) Subjects with central nervous system (CNS) only involvement by
malignancy. (note: subjects with secondary CNS involvement are allowed
2) History of another primary malignancy that has not been in remission for at least 2 years The following are exempt from the 2-year limit: nonmelanoma skin cancer, definitively treated stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear.
3) Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis
4) Active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at the time of screening
5) Subjects with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or JCAR017 administration
6) Presence of acute or chronic graft-versus-host disease (GVHD)
7) History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease
8) History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
9) Pregnant or nursing women. NOTE: Women of reproductive potential must have a negative serum pregnancy test performed within 48 hours of starting lymphodepleting chemotherapy
10) Use of the following: * Therapeutic doses of corticosteroids (defined as >20 mg/day prednisone or equivalent) within 7 days of leukapheresis or 72 hours prior to JCAR017 administration. Physiologic replacement, topical, and inhaled steroids are permitted. *Low dose chemotherapy (e.g. vincristine, rituximab, cyclophosphamide </= 300 mg/m^2) given after leukapheresis to maintain disease control must be stopped >/= 7 days prior to lymphodepleting chemotherapy. * Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1 week of leukapheresis. Oral chemotherapeutic agents, including lenalidomide and ibrutinib, are allowed if at least 3 half-lives have elapsed prior to leukapheresis. * Lymphotoxic chemotherapeutic agents (e.g., cyclophosphamide, ifosofamide, bendamustine) within 2 weeks of leukapheresis.
11) Exclusion Criteria #10 cont...* Experimental agents within 4 weeks of leukapheresis unless no response or disease progression is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis; * Immunosuppresive therapies within 4 weeks of leukapheresis and JCAR017 administration (e.g., calcineurin inhibitors, methotrexate or other chemotherapeutivs, mycophenolyate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-TNF, anti-IL6, or anti-IL6R) *Donor lymphocyte infusions (DLI) within 6 weeks of JCAR017 administration * Radiation within 6 weeks of leukapheresis. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated PET-positive lesions are present, is allowed up to 2 weeks prior to leukapheresis. * Allo-HSCT within 90 days of leukapheresis
12) Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or unwillingness or inability to follow the procedures required in the protocol
13) Prior CAR T-cell or other genetically-modified T-cell therapy, with the exception of prior JCAR017 treatment in this protocol for subjects receiving retreatment
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