Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Study Overview
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Brief Summary
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This is a Phase 1/2, open-label, multicenter study to determine the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory CLL or SLL. The study will include a Phase 1 part to determine the recommended dose of JCAR017 monotherapy in subjects with relapsed or refractory CLL or SLL, followed by a Phase 2 part to further assess the efficacy and safety of JCAR017 monotherapy treatment at the recommended dose. A separate Phase 1 cohort will assess the combination of JCAR017 and concurrent ibrutinib. Another separate Phase 1 cohort will assess the combination of JCAR017 and concurrent venetoclax. In all subjects, the safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.

Official Title
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An Open-Label, Phase 1/2 Study of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (017004)

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Small Lymphocytic

Intervention / Treatment
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* Biological: JCAR017 (lisocabtagene maraleucel)
* Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib
* Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of: CLL with an indication for treatment based on the Investigator's opinion and measurable disease, or SLL (lymphadenopathy and/or splenomegaly and < 5×10^9 CD19+ CD5+ clonal B lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable disease that is biopsy-proven SLL) Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received and failed Bruton tyrosine kinase inhibitor (BTKi) treatment or have been deemed ineligible for BTKi therapy. Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must have received previous treatment as follows: Subjects with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy. Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy. Subjects in the ibrutinib + JCAR017 combination therapy cohort must either: be receiving ibrutinib and progressing at the time of study enrollment be receiving ibrutinib for at least 6 months with a response less than complete response/remission (CR) and have high-risk features as defined in inclusion criterion 5a have BTK or PLCgamma2 mutations per local laboratory assessment, with or without progression on ibrutinib have previously received ibrutinib and have no contraindications to restarting ibrutinib Eastern Cooperative Oncology Group performance status of ≤ 1 Assessed by the Investigator to have adequate bone marrow function to receive lymphodepleting chemotherapy Adequate organ function, defined as: Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated creatinine clearance > 30 mL/min Alanine aminotransferase ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome or leukemic infiltration of the liver) Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% as assessed by echocardiogram or multiple uptake gated acquisition scan performed within 30 days prior to determination of eligibility Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure. If prior CD19-targeted therapy has been administered, subject must have CD19-positive disease confirmed by immunohistochemistry or flow cytometry since completing the prior CD19-targeted therapy. Subjects in ibrutinib + JCAR017 combination cohort must have progressed on a BTKi and have received prior therapy with venetoclax Subjects in venetoclax + JCAR017 combination cohort must: have failed at least 1 prior line of therapy, including failed BTKi therapy or have been deemed ineligible to receive BTKi be venetoclax naive (required for dose expansion) or if prior venetoclax (only for dose escalation) have no contraindictions to re-initiation of venetoclax based on prior intolerance and have had at least 6 months elapsed since the last dose of venetoclax, if either, best response was stable disease, or subject experienced disease progression on venetoclax, or within 6 months of venetoclax discontinuation subjects in the venetoclax + JCAR017 combination must have hemoglobin >=9 g/dL, absolute neutrophil count >=500mm3 and platelets>= 75,000/mm3, unless cytopenias are judged by investigator to be due to CLL infiltration of the bone marrow must have diagnosis of CLL or SLL with an indication for treatment based on the investigator's opinion and measurable disease (any of the following measurable lymph nodes ≥1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly) and demonstration of CLL cells in the peripheral blood by flow cytometry Exclusion Criteria: Subjects with known active central nervous system (CNS) involvement by malignancy. Those with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging. 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, completely resected stage 1 solid tumor with low risk for recurrence, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected.) Subjects with Richter's transformation Prior treatment with any gene therapy product Active hepatitis B, active hepatitis C, or active human immunodeficiency virus (HIV) infection Systemic fungal, bacterial, viral, or other infection that is not controlled Presence of acute or extensive chronic graft versus host disease (GVHD) 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 History or presence of clinically relevant CNS pathology such as epilepsy, generalized seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain injuries, dementia, Parkinson's disease, cerebellar disease,cerebral edema, or psychosis Pregnant or nursing (lactating) women Use of any of the following medications or treatments within the noted time prior to leukapheresis: Alemtuzumab within 6 months prior to leukapheresis Allogeneic hematopoietic stem cell transplant within 100 days prior to leukapheresis Cladribine within 3 months prior to leukapheresis Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis Radiation including large bone marrow fields such as sternum or pelvis within 6 weeks prior to leukapheresis Fludarabine within 4 weeks prior to leukapheresis GVHD therapies such as calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6 [IL-6], or anti-interleukin-6 receptor [IL 6R]) within 4 weeks prior to leukapheresis Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2 weeks prior to leukapheresis Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis Venetoclax within 4 days prior to leukapheresis Idelalisib or duvelisib within 2 days prior to leukapheresis Lenalidomide within 1 day prior to leukapheresis Experimental agents, including off-label use of approved drugs (with the exception of acalabrutinib which may be continued up to the day before leukapheresis), within 4 weeks prior to leukapheresis unless progression is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the Investigator; or subject unwillingness or inability to follow the procedures required in the protocol Progressive vascular tumor invasion, thrombosis, or embolism Deep vein thrombosis or embolism not managed on a stable regimen of anticoagulation Use of any of the following medications or treatments within the noted time prior to leukapheresis lenalidomide or acalabrutinib within 1 day prior to leukapheresis experimental agents, including off-label use of approved drugs, within 4 weeks prior to leukapheresis. Venous thrombosis or embolism requiring treatment but not managed on a stable regimen of anticoagulation For subjects in the venetoclax + JCAR017 combination cohorts only, concomitant treatment with CYP3A moderate/strong inducers or moderate/strong inhibitors which cannot be discontinued

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1: subjects will be assigned to receive JCAR017, or JCAR017 + ibrutinib Phase 2: subjects will be assigned to receive JCAR017 at the recommended dose
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 JCAR017 monotherapy<br>Subjects will be assigned to receive JCAR017 (lisocabtagene maraleucel) | Biological: JCAR017 (lisocabtagene maraleucel)<br>* Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging anticancer therapy for disease control. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.<br>|
| Experimental: Phase 1 JCAR017 + ibrutinib<br>Subjects receiving ibrutinib at baseline will be assigned to receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm + ibrutinib | Biological: JCAR017 (lisocabtagene maraleucel) + ibrutinib<br>* Participants eligible for this cohort should be receiving ibrutinib at the time of screening. For participants who previously discontinued ibrutinib, ibrutinib will be started as soon as possible after eligibility is confirmed. Ibrutinib treatment will continue for up to 90 days after JCAR017 infusion (or longer for participants who are receiving benefit from ibrutinib). Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging chemotherapy for disease control. Upon successful generation of JCAR017 product, participants will receive treatment with JCAR017 therapy. Each cycle will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.<br>|
| Experimental: Phase 2 JCAR017 monotherapy<br>Subjects will receive JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm | Biological: JCAR017 (lisocabtagene maraleucel)<br>* Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants may receive bridging anticancer therapy for disease control. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection.<br>|
| Experimental: Phase 1 JCAR017 + venetoclax<br>Subjects will receive venetoclax as bridging anticancer therapy until lymphodepletion chemotherapy/ JCAR017 (lisocabtagene maraleucel) at the recommended dose from the Phase 1 monotherapy arm. After JCAR017 infusion subjects will receive venetoclax until Day 90. | Biological: JCAR017 (lisocabtagene maraleucel) + venetoclax<br>* Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCAR017. During JCAR017 production, participants will receive venetoclax as bridging anticancer therapy on a weekly ramp up dosing schedule until stopping one day prior to lymphodepletion. Treatment will include lymphodepleting chemotherapy followed by one dose of JCAR017 administered by intravenous (IV) injection, and the day after infusion venetoclax will be re-initiated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 JCAR017 monotherapy arm: adverse events | Proportion of subjects experiencing adverse events | Up to 48 months post treatment | 
| Phase 1 JCAR017 monotherapy arm: laboratory abnormalities | Proportion of subjects experiencing laboratory abnormalities | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: adverse events | Proportion of subjects experiencing adverse events | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose escalation therapy arm: laboratory abnormalities | Proportion of subjects experiencing laboratory abnormalities | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm | Proportion of subjects who have CR after treatment with JCAR017 + ibrutinib using iwCLL 2018 guidelines | Through post treatment up to Month 48 | 
| Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: adverse events | Proportion of subjects experiencing adverse events | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: laboratory abnormalities | Proportion of subjects experiencing laboratory abnormalities | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm | Proportion of subjects who have CR after treatment with JCAR017 + venetoclax using iwCLL 2018 guidelines | Through post treatment up to Month 48 | 
| Phase 2 JCAR017 monotherapy expansion arm | Proportion of subjects who have CR after treatment with JCAR017 using iwCLL 2018 guidelines | Through post treatment up to Month 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: adverse events | Proportion of subjects experiencing adverse events | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: laboratory abnormalities | Proportion of subjects experiencing laboratory abnormalities | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: ORR | Defined as the rate of CR (including CRi) | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD negative response rate in peripheral blood | Proportion of subjects who achieve MRD CR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: MRD-negative CR rate in peripheral blood | Proportion of subjects who achieve MRD CR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of response (DOR) | Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Duration of complete response (DoCR) | Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to response (TTR) | Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: Time to complete response (TTCR) | Defined as the interval from JCAR017 infusion to the first documentation of CR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: PFS | Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and ibrutinib combination dose expansion therapy arm: OS | Defined as the time from JCAR017 infusion to the date of death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: adverse events | Proportion of subject experiencing adverse events | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: lab abnormalities | Proportion of subjects experiencing laboratory abnormalities | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: ORR | Defined as the rate of CR (including CRi) | Through post treatment Day 90 | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: MRD-negative response rate in peripheral blood | Proportion of subjects who achieve MRD CR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose escalation therapy arm: MRD-negative CR rate in peripheral blood | Proportion of subjects who achieve MRD CR | Through post treatment Day 90 | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of response (DOR) | Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Duration of complete response (DoCR) | Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to response (TTR) | Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: Time to complete response (TTCR) | Defined as the interval from JCAR017 infusion to the first documentation of CR | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: PFS | Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 1 JCAR017 and venetoclax combination dose expansion therapy arm: OS | Defined as the time from JCAR017 infusion to the date of death due to any cause | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: adverse events | Proportion of subjects experiencing adverse events | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: laboratory abnormalities | Proportion of subjects experiencing laboratory abnormalities | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: ORR | Defined as the rate of CR (including CRi) | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: MRD negative response rate in peripheral blood | Proportion of subjects who achieve MRD CR | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: MRD-negative CR rate in peripheral blood | Proportion of subjects who achieve MRD CR | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: Duration of response (DOR) | Defined as the time from first response (CR, CRi, nPR, or PR) to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: Duration of complete response (DoCR) | Defined as the time from first CR or CRi to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: Time to response (TTR) | Defined as the interval from JCAR017 infusion to the first documentation of CR, CRi, nPR, or PR | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: Time to complete response (TTCR) | Defined as the interval from JCAR017 infusion to the first documentation of CR | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: PFS | Defined as the time from JCAR017 infusion to the earlier date of PD or death due to any cause | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: OS | Defined as the time from JCAR017 infusion to the date of death due to any cause | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: Health-related quality of life (HRQoL) questionnaire | Change from baseline in HRQoL assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: HRQoL questionnaire | Change from baseline in HRQoL assessed using the EORTC chronic lymphocytic leukemia (CLL)-specific module QLQ-CLL-17 | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: Health economics and outcomes research (HEOR) questionnaire | Change from baseline in measurement of health utility values using EuroQol instrument EQ-5D-5L | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: HEOR questionnaire | Proportion of participants with intensive care unit (ICU) inpatient days | Up to 48 months post treatment | 
| Phase 2 JCAR017 Monotherapy Expansion Arm: HEOR questionnaire | Proportion of participants with non-ICU inpatient days | Up to 48 months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRANSCEND_CLL_004