A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-Cell Maturation Antigen (BCMA) in Participants With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of the study is to characterize safety of JNJ-68284528 and establish the recommended Phase 2 dose (RP2D) (Phase 1b) and to evaluate the efficacy of JNJ-68284528 (Phase 2).

Detailed Description
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This study will evaluate the safety and efficacy of JNJ-68284528. The study will include two phases. In Phase1b the study will enroll adults with multiple myeloma with interval assessments for potential dose escalation or de-escalation in subsequent participants. The dose selected at the completion of phase 1b will be used in Phase 2. Following consent, enrolled participants will undergo an apheresis procedure to collect cells for manufacture of investigational drug product (JNJ-68284528). Following manufacture of the drug product, participants will undergo lymphodepletion prior to infusion of JNJ-68284528. Participants will be followed for at least 2 years after study drug infusion, with long-term 15 year follow-up on a separate study. The study will evaluate safety, biomarkers, pharmacokinetic/pharmacodynamic evaluations and efficacy.

Official Title
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A Phase 1b-2, Open-Label Study of JNJ-68284528, A Chimeric Antigen Receptor T-Cell (CAR-T) Therapy Directed Against BCMA in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: JNJ-68284528


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have documented diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) diagnostic criteria Have measurable disease at Screening as defined by any of the following a) Serum monoclonal paraprotein (M-protein) level more than or equal to (>=) 1.0 gram per deciliter(g/dL) or urine M-protein level >=200 milligram per 24 hours (mg/24hr); or b) Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio Have received at least 3 prior multiple myeloma treatment lines of therapy or are double refractory to an immunomodulatory drug (IMiD) and proteasome inhibitor (PI) (refractory multiple myeloma as defined by IMWG consensus criteria). Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single lines of therapy a) Undergone at least 1 complete cycle of treatment for each line of therapy, unless progressive disease (PD) was the best response to the regimen Have received as part of previous therapy a PI, an IMiD, and an anti-CD38 antibody Participant must have documented evidence of progressive disease based on investigator's determination of response by the IMWG criteria on or within 12 months of their last line of therapy. Confirmation may be from either central or local testing. Also, participants with documented evidence of progressive disease (as above) within the previous 6 months and who are refractory or non-responsive to their most recent line of therapy afterwards are eligible Have Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1 Exclusion Criteria: Have received prior treatment with chimeric antigen receptor T (CAR-T) therapy directed at any target Have received any therapy that is targeted to B-cell maturation antigen (BCMA) Have following cardiac conditions: a) New York Heart Association (NYHA) stage III or IV congestive heart failure b) Myocardial infarction or coronary artery bypass graft (CABG) less than or equal to (<=) 6 months prior to enrollment c) History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration d) History of severe non-ischemic cardiomyopathy e) Impaired cardiac function (left ventricular ejection fraction [LVEF] less than [<]45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan (performed less than or equal to (<=) 8 weeks of apheresis) Received a cumulative dose of corticosteroids equivalent to >= 70 mg of prednisone within the 7 days prior to apheresis Have received either of the following: a) An allogenic stem cell transplant within 6 months before apheresis. Participants who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of graft-versus-host disease (GVHD) b) An autologous stem cell transplant less than or equal to (<=) 12 weeks before apheresis Have known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNJ-68284528<br>After lymphodepletion JNJ-68284528 will be administered as a single infusion. | Biological: JNJ-68284528<br>* JNJ-68284528 consist of autologous T lymphocytes transduced with LCAR-B38M, a lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants with Adverse Events | An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Phase 1b: Number of Participants with Adverse Events by Severity | An assessment of severity grade will be made according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), with the exception of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS and ICANS should be evaluated according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Phase 2: Overall Response Rate (ORR) | The ORR is defined as the proportion of participants who achieve partial response (PR) or better according to International Myeloma Working Group (IMWG) criteria as assessed by the Independent Review Committee (IRC). | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Number of Participants with Adverse Events | An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Levels of B-Cell Maturation Antigen (BCMA) Expressing Cells and Soluble BCMA | Levels of expression of BCMA-expressing plasma cells in the bone marrow as well as the level of soluble BCMA in blood will be reported. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Systemic Cytokine Concentrations | Serum cytokine concentrations (Interleukin [IL]-6, IL-15, IL-10, and Interferon [IFN-g]) will be measured for biomarker assessment. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Levels of CAR-T Cells | CAR-T cells markers including, but not limited to, CD4+, CD8+, CD25+, central memory, effector memory cells will be reported. An evaluation of cell populations may be performed by flow cytometry or cytometry by time of flight (CyTOF) or both and correlated with response. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Level of JNJ-68284528 T Cell Expansion (proliferation), and Persistence | Levels of JNJ-68284528 T cell expansion (proliferation), and persistence via monitoring CAR-T positive cell counts and CAR transgene level will be reported. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Number of Participants with Anti-JNJ-68284528 Antibodies | Number of participants exhibiting anti-drug antibodies for JNJ-68284528 will be reported. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Very Good Partial Response (VGPR) or Better Rate | The VGPR or better rate (stringent complete responses [sCR]+ complete response [CR]+VGPR), defined as the percentage of participants achieving VGPR or better response according to IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or greater than equal to (>=) 90 percent (%) reduction in serum M-protein plus urine M-protein less than (<) 100 milligram (mg)/24 hours, CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells (PCs) in bone marrow. sCR: CR plus normal free light chain (FLC) ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescencea or 2- to 4 color flow cytometry. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Percentage of Participants who Achieve Clinical Benefit Rate | Clinical benefit rate is the CR + VGPR + PR + minimal response [MR] based on IMWG defined response criteria. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Duration of Response (DOR) | DOR will be calculated among responders (with a PR or better response) from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in the IMWG criteria. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Progression-free Survival (PFS) | PFS defined as time from date of initial infusion of JNJ-68284528 to date of first documented disease progression, or death due to any cause, whichever occurs first. IMWG criteria for PD: Increase of 25% from lowest response value in anyone of following: Serum M-component (absolute increase must be >=0.5 gram per deciliter (g/dL), Urine M-component (absolute increase must be >=200 mg/24 hours), Participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase must be >10 milligrams per deciliter (mg/dL), participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Overall Survival (OS) | OS is measured from the date of the initial infusion of JNJ-68284528 to the date of the participant's death. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | MRD negative rate is defined as the proportion of participants who achieve MRD negative status by the respective time point. MRD negativity will be evaluated as a potential surrogate for PFS and OS in multiple myeloma treatment. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Time to Response (TTR) | TTR is defined as the time between date of the initial infusion of JNJ-68284528 and the first efficacy evaluation that the participant has met all criteria for PR or better. | Minimum 2 years after JNJ-68284528 infusion (Day 1) | 
| Change from Baseline in Health-related Quality of Life (HRQoL) as Measured by EORTC QLQ-C30 | HRQoL will be assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) items. Subscale and single item scores are reported on a 0-100 scale with higher scores representing better global health status, better functioning, and worst symptoms. | Baseline up to study completion (Minimum 2 years after JNJ-68284528 Infusion on Day 1) | 
| Change from Baseline in HRQoL as Measured by EORTC QLQ-MY20 | HRQoL will be assessed by the EORTC QLQ-Multiple Myeloma ((MY20) module items. Subscale and single item scores are reported on a 0-100 scale with higher scores representing better global health status, better functioning, and worst symptoms. | Baseline up to study completion (Minimum 2 years after JNJ-68284528 Infusion on Day 1) | 
| Change from Baseline in Participant-reported Health Status Measured by EQ-5D-5L | Participant-reported health status measured by the EuroQol Group 5-dimension, 5-level (EQ-5D-5L) questionnaire. A total utility score is reported based on the health status, ranging from 0 to 1, where higher values indicate better health utility. The visual analog scale ranges from 0 to 100 where higher values indicate better overall health status. | Baseline up to study completion (Minimum 2 years after JNJ-68284528 Infusion on Day 1) | 
| Change from Baseline in Global Health Status Using PGIC Scale | Global health status as measured by the Patient Global Impression of Change (PGIC) scale in overall health. The PGIC is a single verbal rating scale ranging from 1 = a lot better now to 7 = a lot worse now. | Baseline up to study completion (Minimum 2 years after JNJ-68284528 Infusion on Day 1) | 
| Change from Baseline in Pain Measured by PGIS Scale | Participant reported pain measured by Patient Global Impression of Severity (PGIS) Scale. The PGIS is a single item to assess pain severity. The 5-point verbal rating scale ranged from 1 (none) to 5 (very severe). | Baseline up to study completion (Minimum 2 years after JNJ-68284528 Infusion on Day 1) |