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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the overall minimal residual disease (MRD) negative rate of participants who receive JNJ-68284528.

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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: JNJ-68284528
* Drug: Lenalidomide
* Drug: Daratumumab
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort A: Received a minimum of 1 to a maximum of 3 prior lines of therapy including a proteasome inhibitor (PI) and immunomodulatory therapy (IMiD), and lenalidomide refractory per International Myeloma Working Group (IMWG) guidelines Cohort B: Received one line of prior therapy including a PI and an IMiD, and disease progression per IMWG criteria less than or equal to (<=) 12 months after treatment with autologous stem cell transplantation (ASCT) or <=12 months from the start of anti-myeloma therapy for participants who have not had an ASCT Cohort C: Previously treated with a PI, an IMiD, an anti-CD38 monoclonal antibody and B-cell maturation antigen (BCMA)-directed therapy Cohort D: Newly diagnosed multiple myeloma per IMWG with a history of 4 to 8 total cycles of initial therapy, including induction, high-dose therapy, and ASCT with or without consolidation Cohort E: Have newly diagnosed multiple myeloma without prior therapy (one cycle of prior therapy before enrollment is acceptable) and classified as high risk defined as either: 1) International Staging System (ISS) stage III criteria, Beta 2 microglobulin greater than or equal to (>=) 5.5 milligrams per liter (mg/L) (via local or central laboratory assessment) or 2) high risk cytogenetic features del(17/17p), t (14;16), t(14;20), 1q amplification (at least 4 total copies) in at least 20 percent (%) of the total plasma cell population Cohort F: Participant must have a documented efficacy response of very good partial response (VGPR) or better, without progressive disease prior to enrollment, as assessed per IMWG 2016 criteria Received initial therapy as specified below. The dose/schedule of cycles administered will be as per standard of care. It is acceptable for up to 1 cycle of the protocol-specified regimens to be missing one of the listed agents (example, held due to toxicity). Acceptable combinations include: At least 5 to 8 cycles of initial therapy with daratumumab, bortezomib, lenalidomide and dexamethasone (D-VRd). The dose/schedule of cycles administered will be as per standard of care or; at least 4 to 8 cycles of initial therapy with daratumumab, lenalidomide and dexamethasone (D-Rd) or; at least 4 to 8 cycles of initial therapy with a carfilzomib-based triplet or quadruplet regimen Cohort G: Not considered for high-dose chemotherapy with autologous stem cell transplantation (ASCT) due to: a) Ineligibility due to advanced age; or b) Ineligibility due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or c) Subject refusal of high-dose chemotherapy with ASCT as initial treatment Cohort H: Considered a candidate for high-dose chemotherapy with ASCT as initial treatment Cohorts A, B, C, E, G, H: Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 1.0 gram per deciliter (g/dL) or urine M-protein level >=200 milligrams (mg)/24 hours Light chain multiple myeloma in whom only measurable disease is by serum free light chain (FLC) levels in the serum: Serum immunoglobulin FLC >=10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio Cohort A: For participants with neither serum nor urine measurable disease, baseline positron emission tomography/ computed tomography (PET/CT) or whole -body magnetic resonance imaging (MRI) may be used to satisfy the measurable disease criteria. A minimum of one lesion with a bi-dimensional measurement of at least 1 centimeter (cm)*1 cm is required Cohorts B, C: For participants with neither serum nor urine measurable disease, baseline positron emission tomography/ computed tomography (PET/CT) or whole body magnetic resonance imaging (MRI) may be used to satisfy the measurable disease criteria Cohorts A, B, C, D, E, F, G, H: Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1 Exclusion Criteria: Cohorts A, B, D, F: Any therapy that is targeted to BCMA Cohorts A, B, C, D, F: Prior treatment with chimeric antigen receptor T (CAR-T) therapy directed at any target Cohorts A, B, C, D, F: Ongoing toxicity from previous anticancer therapy must resolve to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy Received a cumulative dose of corticosteroids equivalent to >=70 mg of prednisone within the 7 days (Cohort A, B, C, F) or 14 days (Cohort D) prior to apheresis Serious underlying medical condition, such as (a) evidence of active viral or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection; (b) active autoimmune disease or a history of autoimmune disease within 3 years; (c) overt clinical evidence of dementia or altered mental status; (d) any history of Parkinson's disease or other neurodegenerative disorder Cohorts A, B, C, D, E, F: Known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma Cohorts F, G, and H: Active malignancies (that is, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are: a) non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured; b) skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured; c) non-invasive cervical cancer treated within the last 24 months that is considered completely cured; d) localized prostate cancer (N0M0): with a Gleason score of greater than or equal to (=>)6, treated within the last 24 months or untreated and under surveillance, with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence, or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence, e) breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence; f) malignancy that is considered cured with minimal risk of recurrence Cohorts E, G, and H: Frailty index of >= 2 according to Myeloma Geriatric Assessment score

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>Single group assignment-Post lymphodepletion, JNJ-68284528 single infusion given to Part A participants: Cohort A(Progressive disease post 1-3 prior lines of therapy), Cohort B(Early relapse post front-line), Cohort C(Relapsed/refractory multiple myeloma post PI, IMiD,anti-CD38,anti-BCMA therapy), Cohort D(Less than CR post ASCT front-line therapy, some participants will receive JNJ-68284528 then lenalidomide), Cohort F(Newly diagnosed multiple myeloma [NDMM], standard risk [International Staging System Stage I/II] and post initial therapy); Cohort E(NDMM,transplant not planned,high risk disease) will first receive quadruplet induction regimen of daratumumab,bortezomib,lenalidomide and dexamethasone(D-VRd) then lymphodepletion and JNJ-68284528 then consolidation regimen of lenalidomide. Part B:Cohort G(NDMM,transplant not planned) will receive daratumumab, lenalidomide and dexamethasone followed by cilta-cel; Cohort H(NDMM,transplant-eligible) will receive D-VRd followed by cilta-cel. | Drug: JNJ-68284528<br>* Participants in Cohorts A,B,C, D, E, F, G, and H will receive JNJ-68284528 intravenously.<br>* Other names: Ciltacabtagene autoleucel (cilta-cel);Drug: Lenalidomide<br>* Some participants in Cohort D and all participants in Cohorts E, G, and H will also receive lenalidomide capsules orally.<br>Drug: Daratumumab<br>* Participants in Cohorts E, G, and H will also receive daratumumab subcutaneous (SC) injection.<br>Drug: Bortezomib<br>* Participants in Cohorts E and H will also receive bortezomib subcutaneously.<br>Drug: Dexamethasone<br>* Participants in Cohorts E, G, and H will also receive dexamethasone orally or intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts A, B, C, D, E, and F: Percentage of Participants with Negative Minimal Residual Disease (MRD) | MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate as defined by the International Myeloma Working Group (IMWG) criteria. | At least 1 year after JNJ-68284528 infusion on Day 1 | 
| Cohorts G and H: Percentage of Participants with Sustained MRD Negative Complete Response (CR) | Sustained MRD-negative CR is defined as participants with CR or better who sustain MRD-negative status, as determined by next-generation sequencing (NGS) or next generation flowcytometry (NGF) with sensitivity of 10^-5, for at least 12 months without any examination showing MRD positive status or progressive disease in between. | At least 1 year after JNJ-68284528 infusion on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieve a partial response (PR) or better according to the IMWG criteria. | Up to 2 years and 6 months | 
| Cohorts A, B, C, D, E, and F: 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. | Up to 2 years and 6 months | 
| Cohorts A, B, C, D, E, and F: Clinical Benefit Rate (CBR) | CBR is defined as the percentage of participants who achieve ORR (sCR + CR + VGPR + PR) + minimal response (MR) according to the IMWG criteria. | Up to 2 years and 6 months | 
| Duration of Response (DOR) | DOR will be calculated among responders from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease according to the IMWG criteria. | Up to 2 years and 6 months | 
| Time to Response (TTR) | TTR is defined as the time from the date of the initial infusion of JNJ-68284528 and the first efficacy evaluation that the participant has met all criteria for PR or better. | Up to 2 years and 6 months | 
| Cohorts A, B, C, D, E, and F: MRD Negative Rate at 12 Months for Participants who Achieve a Complete Response (CR) | MRD negative rate at 12 months for participants who achieved a complete response (CR) is defined as the percentage of participants who are MRD negative by bone marrow aspirate and meet the IMWG criteria for CR at 12 months after initial dose of JNJ-68284528 and before disease progression or starting subsequent therapy including retreatment of JNJ-68284528. | 12 months | 
| Time to MRD Negativity | Time to MRD negativity will be calculated in participants who are MRD negative by bone marrow aspirate from the date of the initial infusion of JNJ-68284528 to the initial date of reaching the MRD negative status. | Up to 2 years and 6 months | 
| Duration of MRD Negativity | Duration of MRD negativity will be calculated among participants who are MRD negative by bone marrow aspirate from the date of initial MRD negativity to the date when MRD is detected at the same threshold (10^-5). | Up to 2 years and 6 months | 
| Cohorts A, B, C, D, E, and F: MRD Negative Rate Across Clinical Response | MRD negative rate across clinical response groups will be assessed for all participants who achieved a complete response (CR) or stringent complete response (sCR) or very good partial response (VGPR) according to the IMWG criteria during or after the study treatment. MRD negative rate is defined as the percentage of participants who have negative MRD by bone marrow aspirate at any timepoint. | Up to 2 years and 6 months | 
| 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 will be evaluated according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. | Up to 2 years and 6 months | 
| Number of Participants with Adverse Events (AE) as a Measure of Safety and Tolerability | An AE 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. | Up to 2 years and 6 months | 
| Number of Participants with Laboratory Abnormalities | Number of participants with laboratory abnormalities will be reported. | Up to 2 years and 6 months | 
| Number of Participants with Vital Signs Abnormalities | Number of participants with vital signs abnormalities will be reported. | Up to 2 years and 6 months | 
| Cohorts A, B, C, D, E, and F: 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. | Up to 1 year | 
| Cohorts A, B, C, D, E, and F: Systemic Inflammatory Cytokine Concentrations | Blood cytokine concentrations (Interleukin [IL]-6, IL-15, IL-10, and Interferon [IFN-gamma]) will be measured for biomarker assessment. | Up to 1 year | 
| Cohorts A, B, C, D, E, and F: Levels 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. | Up to 1 year | 
| Cohorts A, B, C, D, E, and F: Number of Participants with Anti-JNJ-68284528 Antibodies | Number of participants exhibiting anti-drug antibodies for JNJ-68284528 will be reported. | Up to 1 year | 
| Cohorts G and H: Percentage of Participants with Complete Response (CR) or Better | CR or better is defined as the percentage of participants achieving CR or sCR prior to subsequent antimyeloma therapy in accordance with the IMWG criteria during or after the study treatment. | Up to 2 years 6 months | 
| Cohorts G and H: Percentage of Participants with MRD-negative CR or sCR | MRD-negative CR/sCR is defined as the percentage of participants who achieve MRD-negative status, as determined by NGS/NGF with sensitivity of 10^-5, at any time after enrollment and prior to progressive disease or subsequent antimyeloma therapy and who achieve CR/sCR or better. | Up to 2 years 6 months | 
| Cohorts G and H: Progression-free Survival on Next-line Therapy (PFS2) | PFS2 is defined as the time interval between the start of study treatment and date of event, which is defined as death from any cause or PD as assessed by investigator that starts after the next line of therapy, whichever occurs first. | Up to 2 years and 6 months | 
| Cohorts G and H: Overall Survival (OS) | OS is defined as the time from the start of study treatment to the date of the participant's death. | Up to 2 years and 6 months | 
| Cohorts G and H: Progression-free Survival (PFS) | PFS is defined as the time from the start of study treatment to the date of first documented disease progression, as defined in the IMWG criteria, or death due to any cause, whichever occurs first. | Up to 2 years and 6 months | 
| Cohorts G and H: Number of Participants with Measurable Replication Competent Lentivirus (RCL) in Whole Blood | Number of participants with measurable RCL in whole blood will be reported. | Up to 2 years and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cellular Therapy, CAR-T Therapy, BCMA CAR-T