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

Celgene62 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Interventions

JCAR017BIOLOGICAL

Gene modified autologous T cells

DurvalumabDRUG

Anti-PD-L1

CC-122DRUG

Pleiotropic Pathway Modifier

IbrutinibDRUG

Ibrutinib

CC-220DRUG

CC-220

RelatlimabDRUG

Relatlimab

NivolumabDRUG

Nivolumab

CC-99282DRUG

CC-99282

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Subject is ≥ 18 years of age at the time of signing the informed consent form (). 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. 4. 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: 1. Diffuse large B-cell lymphoma (DLBCL) Not otherwise specified (NOS) including transformed indolent Non-Hodgkin lymphoma (NHL) 2. Follicular lymphoma Grade 3B 3. T cell/histiocyte-rich large B-cell lymphoma 4. Epstein-Barr virus (EBV) positive DLBCL, NOS 5. Primary mediastinal (thymic) large B-cell lymphoma 6. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma) 5. 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. 6. Subject must have 1. Positron emission tomography (PET)-positive (Deauville score 4 or 5) and computed tomography (CT) measurable disease as per Lugano Classification 2. 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) 7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at screening 8. Adequate organ function 9. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals 10. Participants must agree to use effective contraception Exclusion Criteria: 1. 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. 2. 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. 3. Subject has any condition that confounds the ability to interpret data from the study based on investigator´s judgment. 4. 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: 1. Basal cell carcinoma of the skin 2. Squamous cell carcinoma of the skin 3. Carcinoma in situ of the cervix 4. Carcinoma in situ of the breast 5. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or prostate cancer that is curative. 6. Other completely resected stage 1 solid tumor with low risk for recurrence 5. Prior treatment with any prior gene therap y product 6. Prior treatment with any adoptive T cell therapy; prior hematopoietic stem cell transplant (HSCT) is allowed 7. Allogeneic HSCT within 90 days of leukapheresis 8. Prior treatment with the combination agent from the assigned arm: 1. Anti PD-1 or PD-L1 (Arm A and E) 2. CC-122 (Arm B) 3. CC-220 (Arm C) 4. Prior treatment with ibrutinib is not exclusionary for subjects on any study arm 5. Anti LAG-3 targeted agent (Arm E) 6. CC-99282 (Arm F) 9. Presence of acute or chronic graft-versus-host disease (GVHD) 10. Presence of the following: 1. Active hepatitis B or active hepatitis C infection 2. History of or active human immunodeficiency virus (HIV) infection 11. Uncontrolled bacterial, viral or fungal infection at the time of leukapheresis, lymphodepleting chemotherapy or JCAR017 infusion 12. 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) 13. 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 14. Subjects with active CNS or cerebrospinal fluid (CSF) involvement by malignancy 15. Pregnant or nursing (lactating) women. 16. Subjects with active auto immune disorders/processes or active neurological or inflammatory disorders 17. 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. 18. Progressive tumor invasion of venous or arterial vessels. 19. Deep venous thrombosis (DVT)/pulmonary embolism (PE) not managed on a stable regimen of anticoagulation.

Locations (9)

Local Institution - 011

Duarte, California, United States

Local Institution - 022

Atlanta, Georgia, United States

Local Institution - 014

Chicago, Illinois, United States

Local Institution - 012

Boston, Massachusetts, United States

Local Institution - 021

Boston, Massachusetts, United States

Local Institution - 015

Omaha, Nebraska, United States

Local Institution - 016

Philadelphia, Pennsylvania, United States

Local Institution - 020

Pittsburgh, Pennsylvania, United States

Local Institution - 013

Houston, Texas, United States

Outcomes

Primary Outcomes

Number of Participants With Dose-Limiting Toxicity (DLT)

Participants enrolled in Phase 1 are considered evaluable for DLTs if they received an infusion of conforming JCAR017 cell product and at least one dose of the combination agent and completed the specified DLT evaluation period or if they have received an infusion of conforming JCAR017 cell product and at least one dose of the combination agent and experience a DLT during the DLT evaluation period.

Time frame: From first dose of the combination agent until 1 month (28 days) after JCAR017 infusion (pre- JCAR017 cohort) or from JCAR017 infusion until 1 month (28 days) after the first dose of combination agent (post-JCAR017 cohort)

Complete Response Rate (CRR)

Percentage of participants achieving a complete response (CR). CR is complete radiologic response (CRR) and complete metabolic response (CMR). CR was measured using CT and PET and assessed for the presence of index and non-index lesions, spleen size, and the absence of new lesions or diseased bone marrow. To be considered as having CRR participants had to have all of the following: * Index lesions - longest transverse diameter of nodal lesions ≤ 1.5 cm and the absence of extranodal disease. * Non-index lesions - the absence of non-index lesions. * Spleen size \<13 cm * The absence of new lesions * Normal bone marrow assessment To be considered as having CMR participants had to have all of the following: * A score of 1, 2, or 3 with or without residual mass on 5-PS for index and non-index lesions. * The absence of new lesions * No evidence of FDG-avid disease in marrow and a normal bone marrow assessment

Time frame: At 3 and 6 months post-JCAR017 infusion.

Secondary Outcomes

European Organisation for Research and Treatment of Cancer - Quality of Life C30 Questionnaire (EORTC QLQ-C30) Scores - Phase 2

The EORTC QLQ-C30 is composed of 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). The questionnaire is scored on a 4-point Likert response scale: 1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much. The raw score is calculated as the average of the items that contribute to the scale. The final scores are calculated via linear transformation of raw scores and range from 0 to 100. For functional scales (physical, role, emotional, social, cognitive and global health) higher scores indicate better QoL. For symptom scales (fatigue, nausea and vomiting and pain) and single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) lower scores indicate fewer symptoms, i.e. better QoL.

Time frame: At baseline and 29 days and 57 days post JCAR017 dose

EuroQol- 5 Dimensions of Health Visual Analogue Scale (EQ-5D VAS) Scores - Phase 2

The EuroQol- 5 Dimensions of Health Visual Analogue Scale (EQ-5D VAS) records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are scored from 0 to 100 i.e., 'The worst health you can imagine' (score of 0) to 'The best health you can imagine' (score of 100). Higher scores indicate better health outcomes.

Time frame: At baseline and 1, 29, 57, 85, 180, 270, 365, 545, and 730 days post JCAR017 dose

Number of Participants With Adverse Events (AEs)

An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) is also considered an AE. All participants were monitored for AEs during the study. Assessments included monitoring of any or all of the following parameters: the participant's clinical symptoms, laboratory, pathological, radiological or surgical findings, physical examination findings, or findings from other tests and/or procedures.

Time frame: Up to 3 months after the dose of JCAR017 or after the last dose of the combination agent, whichever occurred last (an average of 6.5 months up until a max of 9.5 months)

Number of Participants With Severe Adverse Events (SAEs)

An SAE is any AE occurring at any dose that: * Results in death; * Is life-threatening (i.e., in the opinion of the Investigator, the participant is at immediate risk of death from the AE); * Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay); * Results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions); * Is a congenital anomaly/birth defect; * Constitutes an important medical event.

Time frame: Up to 3 months after the dose of JCAR017 or after the last dose of the combination agent, whichever occurred last (an average of 6.5 months up until a max of 9.5 months)

Change From Baseline in White Blood Cell and Platelet Numbers

White blood cell, and platelet counts. Baseline is defined as the last measurement on or prior to any study treatment.