A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies

Study Overview
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Brief Summary
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This is a global, open-label, multi-arm, parallel multi-cohort, multi-center, Phase 1/2 study to determine the safety, tolerability, PK, efficacy and patient-reported quality of life of JCAR017 in combination with various agents. This protocol is intended to evaluate various drug combinations with JCAR017, as separate arms, over the life of the protocol, using the same objectives. Each combination will be evaluated separately (ie, the intention is not to compare between combinations) for the purposes of the objectives, trial design, and statistical analysis. The following combinations will be tested: Arm A: JCAR017 in combination with durvalumab Arm B: JCAR017 in combination with CC-122 (avadomide) Arm C: JCAR017 in combination with CC-220 (iberdomide) Arm D: JCAR017 in combination with ibrutinib Arm E: JCAR017 in combination with relatlimab and/or nivolumab Arm F: JCAR017 in combination with CC-99282 Additional arms will be added by way of amendment once combination agents have been selected. The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.

Detailed Description
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During Phase 1, different arms may be opened to test JCAR017 in combination with combination agent(s) in adult subjects with R/R aggressive B-cell NHL. Within each arm, different doses and schedules of JCAR017 and the combination agent(s) may be tested in several cohorts and subcohorts per arm. During Phase 2 of the study, the expansion of any dose level and schedule for any arm that has been shown to be safe may occur. Arm A will test JCAR017 in combination with Durvalumab Arm B will test JCAR017 in combination with CC-122 Arm C will test JCAR017 in combination with CC-220 (iberdomide ) Arm D will test JCAR017 in combination with ibrutinib. Arm E will test JCAR017 in combination with relatlimab and/or nivolumab Arm F will test JCAR017 in combination with CC-99282 All subjects from Phase 1 and Phase 2 will be followed for 24 months following JCAR017 infusion. Post-study follow-up for survival, relapse, long-term toxicity (including new malignancies), and viral vector safety will continue under a separate long-term follow-up (LTFU) protocol for up to 15 years after the JCAR017 dose as per health authority regulatory guidelines.

Official Title
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An Exploratory Phase 1/2 Trial To Evaluate The Safety And Efficacy Of JCAR017 Combinations In Subjects With Relapsed/Refractory B-Cell Malignancies (PLATFORM)

Conditions
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Lymphoma, Non-Hodgkin, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular

Intervention / Treatment
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* Biological: JCAR017
* Drug: Durvalumab
* Drug: CC-122
* Drug: Ibrutinib
* Drug: CC-220
* Drug: Relatlimab
* Drug: Nivolumab
* Drug: CC-99282


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥ 18 years of age at the time of signing the informed consent form (). Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. Subject must have aggressive B-cell NHL according to the 2016 revision of the WHO classification of lymphoid neoplasms, histologically confirmed at last relapse by the treating institution, defined as: Diffuse large B-cell lymphoma (DLBCL) Not otherwise specified (NOS) including transformed indolent Non-Hodgkin lymphoma (NHL) Follicular lymphoma Grade 3B T cell/histiocyte-rich large B-cell lymphoma Epstein-Barr virus (EBV) positive DLBCL, NOS Primary mediastinal (thymic) large B-cell lymphoma High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma) Subjects disease must have relapsed or be refractory to at least 2 prior lines of therapy. Previous therapy must have included a CD20-targeted agent and an anthracycline. Subject must have Positron emission tomography (PET)-positive (Deauville score 4 or 5) and computed tomography (CT) measurable disease as per Lugano Classification Sum of product of perpendicular diameters (SPD) of up to 6 index lesions ≥ 25 cm2 by CT scan (not applicable to Arm A or B or subjects with Richter's transformation) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at screening Adequate organ function Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals Participants must agree to use effective contraception Exclusion Criteria: Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study based on investigator´s judgment. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study based on investigator´s judgment. Subject has any condition that confounds the ability to interpret data from the study based on investigator´s judgment. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following non-invasive malignancies: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative. Other completely resected stage 1 solid tumor with low risk for recurrence Prior treatment with any prior gene therap y product Prior treatment with any adoptive T cell therapy; prior hematopoietic stem cell transplant (HSCT) is allowed Allogeneic HSCT within 90 days of leukapheresis Prior treatment with the combination agent from the assigned arm: Anti PD-1 or PD-L1 (Arm A and E) CC-122 (Arm B) CC-220 (Arm C) Prior treatment with ibrutinib is not exclusionary for subjects on any study arm Anti LAG-3 targeted agent (Arm E) CC-99282 (Arm F) Presence of acute or chronic graft-versus-host disease (GVHD) Presence of the following: Active hepatitis B or active hepatitis C infection History of or active human immunodeficiency virus (HIV) infection Uncontrolled bacterial, viral or fungal infection at the time of leukapheresis, lymphodepleting chemotherapy or JCAR017 infusion Any history of myocarditis (Arm E); 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 (all arms) History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis Subjects with active CNS or cerebrospinal fluid (CSF) involvement by malignancy Pregnant or nursing (lactating) women. Subjects with active auto immune disorders/processes or active neurological or inflammatory disorders For subjects to receive oral combination therapy (Arms B, C, D or F): History of a gastrointestinal (GI) condition or procedure that in the opinion of the investigator may affect oral drug absorption. Progressive tumor invasion of venous or arterial vessels. Deep venous thrombosis (DVT)/pulmonary embolism (PE) not managed on a stable regimen of anticoagulation.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: JCAR017 in combination with Durvalumab<br>JCAR017 will be administered at a single flat dose of 50 x 10^6 CAR+T cells or 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/ or schedules | Biological: JCAR017<br>* Gene modified autologous T cells<br>Drug: Durvalumab<br>* Anti-PD-L1<br>* Other names: MEDI4736;|
| Experimental: Arm B: JCAR017 in combination with CC-122<br>This arm will test JCAR017 in combination with the CC-122. In adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses | Biological: JCAR017<br>* Gene modified autologous T cells<br>Drug: CC-122<br>* Pleiotropic Pathway Modifier<br>|
| Experimental: Arm C: JCAR017 in combination with CC-220<br>This arm will test JCAR017 in combination with CC-220. In adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses | Biological: JCAR017<br>* Gene modified autologous T cells<br>Drug: CC-220<br>* CC-220<br>|
| Experimental: Arm D: JCAR017 in combination with Ibrutinib<br>This arm will test JCAR017 in combination with ibrutinib. In adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at a fixed dose of 420 mg daily | Biological: JCAR017<br>* Gene modified autologous T cells<br>Drug: Ibrutinib<br>* Ibrutinib<br>|
| Experimental: Arm E: JCAR017 in combination with relatlimab and/or nivolumab<br>This arm will test JCAR017 in combination with relatlimab and/or nivolumab in adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/or schedules | Biological: JCAR017<br>* Gene modified autologous T cells<br>Drug: Relatlimab<br>* Relatlimab<br>Drug: Nivolumab<br>* Nivolumab<br>|
| Experimental: Arm F: JCAR017 in combination with CC-99282<br>This arm will test JCAR017 in combination with CC-99282 in adult subjects with R/R aggressive B-cell NHL. JCAR017 will be administered at a dose of 100 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/or schedules. | Biological: JCAR017<br>* Gene modified autologous T cells<br>Drug: CC-99282<br>* CC-99282<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) rates | Percentage of participants experiencing DLTs | From first dose of the combination agent until 1 month (28 days) after JCAR017 infusion or from JCAR017 infusion until 1 month (28 days) after the first dose of combination agent | 
| Complete Response Rate | Is defined as the proportion of subjects achieving a CR according to the Lugano Classification. | Up to approximately 6 months post-JCAR017 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Number of participants with adverse events, type of adverse events, severity of adverse events, and number of participants with laboratory abnormalities, type of laboratory abnormalities and severity of laboratory abnormalities. | Up to approximately 24 months | 
| Progression-free survival (PFS) | Time from start of JCAR017, or start of combination agent, whichever occurs first, disease progression or death from any cause | Up to approximately 24 months post-JCAR017 infusion | 
| Overall survival (OS) | Time from start of JCAR017, or start of combination agent, whichever occurs first, to death due to any cause | Up to approximately 3.5 years | 
| Overall response rate (ORR) | Percentage of subjects achieving an objective response of partial response (PR) or better according to the Lugano Classification | Up to approximately 24 months post-JCAR017 infusion | 
| Duration of response (DOR) | Time from first response to disease progression or death from any cause | Up to approximately 24 months post-JCAR017 infusion | 
| Event-free survival (EFS) | Time from start of JCAR017 to disease progression, or starting a new antilymphoma therapy, or death from any cause, whichever occurs first | Up to approximately 24 months post-JCAR017 infusion | 
| Pharmacokinetic (PK)- Cmax | Maximum observed concentration in plasma | Up to approximately 24 months post-JCAR017 infusion | 
| Pharmacokinetic (PK)- Tmax | Time to maximum concentration | Up to approximately 24 months post-JCAR017 infusion | 
| Pharmacokinetic (PK)- AUC | Area under the plasma concentration vs time curve | Up to approximately 24 months post-JCAR017 infusion | 
| Health-related quality of life (HRQoL) | Is described as parameters assessed by European Organization for Research and Treatment of Cancer | Up to approximately 24 months post-JCAR017 infusion | 
| Quality of Life C30 questionnaire (EORTC-QLQ-C30) | EORTC-QLQ-C30 is composed of both multi-item scales and single item measures. These include five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting, and pain), a global health status/health-related quality of life (HRQoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. | Up to approximately 24 months post-JCAR017 infusion, for Phase I of Arm A and Arm B. | 
| European Quality of Life-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) | The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems) | Up to approximately 24 months post-JCAR017 infusion, for Phase I of Arm A and Arm B | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, CAR T cells, JCAR017, B-Cell Malignancies, non-Hodgkin lymphoma, chimeric antigen receptor, CC-220, Ibrutinib, relatlimab, nivolumab, CC-99282