Clinical trial NCT03548207: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2018-06-07
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1b: Number of Participants With Adverse Events as Per Severity
timeFrame: Day 1 up to 45.2 months
measure: Phase 2: Overall Response Rate (ORR)
timeFrame: Day 1 up to 45.2 months
Secondary outcomes:
measure: Phase 2: Number of Participants With Adverse Events (AEs) as Per Severity
timeFrame: Day 1 up to 45.2 months
measure: Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-68284528 Transgene
timeFrame: Pre and post dose on Day 1, and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Actual Sampling Time of Last Measurable Analyte Concentration (Tlast) of JNJ-68284528 Transgene
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Area Under the Plasma Concentration Versus Time Curve From Time 0 To Last Measurable Concentration (AUC0-last) of JNJ-68284528 Transgene
timeFrame: Pre and post dose on Day 1; Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinite Time (AUC0-infinity) of JNJ-68284528 Transgene
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of CD3+CAR+ Cells in Blood After a Single Infusion of JNJ-68284528
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: T Cell Persistence After a Single Infusion of JNJ-68284528
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Area Under the Plasma Concentration Versus Time Curve From Time 0 To Last Measurable Concentration (AUC0-last) of CD3+CAR+ Cells in Blood After a Single Infusion of JNJ-68284528
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinite Time (AUC0-infinity) of CD3+CAR+ Cells in Blood After a Single Infusion of JNJ-68284528
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Mean Concentration of Soluble B-cell Maturation Antigen (BCMA) Levels in Serum After Single Infusion of JNJ-68284528
timeFrame: Days 352 and 1024
measure: Number of Participants With Depletion of BCMA Expressing Cells
timeFrame: Pre dose (Day 1) up to 2 years
measure: Phase 1b and Phase 2: Serum Systemic Cytokine Concentrations
timeFrame: Pre-infusion and 2 hours post infusion on Day 1, Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100
measure: Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of CAR-T Cells (CD3+CAR+ Cells in Blood) After a Single Infusion of JNJ-68284528
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Maximum T Cell Expansion After a Single Infusion of JNJ-68284528
timeFrame: Pre and post dose on Day 1 and Days 2, 3, 7, 10, 14, 21, 28, 42, 56, 78, 100, then every 4 weeks up to 1 year, and at the time of progressive disease or at study completion for participants without progressive disease (up to approximately 2.5 years)
measure: Phase 1b and Phase 2: Percentage of Participants With Positive Antibodies to JNJ-68284528
timeFrame: Pre dose (Day 1) up to 2 years
measure: Phase 1b and Phase 2: Very Good Partial Response (VGPR) or Better Response Rate
timeFrame: Pre dose (Day 1) up to 45.2 months
measure: Phase 1b and Phase 2: Minimal Residual Disease (MRD) Negative Rate
timeFrame: Pre dose (Day 1) up to 45.2 months
measure: Phase 1b and Phase 2: Clinical Benefit Rate (CBR)
timeFrame: Pre dose (Day 1) up to 45.2 months
measure: Phase 1b and Phase 2: Duration of Response (DOR)
timeFrame: Pre dose (Day 1) up to first documented PD or death (up to 45.2 months)
measure: Phase 1b and Phase 2: Time to First Response
timeFrame: Pre dose (Day 1) up to 45.2 months
measure: Phase 1b and Phase 2: Progression-free Survival (PFS)
timeFrame: Pre dose (Day 1) up to 45.2 months
measure: Phase 1b and Phase 2: Overall Survival
timeFrame: Pre dose (Day 1) up to 45.2 months
measure: Phase 2 (US Population): Change From Baseline in EuroQol Five Dimension Questionnaire (EQ-5D-5L) Utility Score at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
measure: Phase 2 (Japan Population): Change From Baseline in EuroQol Five Dimension Questionnaire (EQ-5D-5L) Utility Score at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
measure: Phase 2 (US Population): Change From Baseline in EuroQol Five Dimension Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
measure: Phase 2 (Japan Population): Change From Baseline in EuroQol Five Dimension Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
measure: Phase 2 (US Population): Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Subscales at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
measure: Phase 2 (Japan Population): Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Subscales at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
measure: Phase 2: Change From Baseline in Patient Global Impression of Severity (PGIS) Score at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352, 380
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352, 380
measure: Phase 2: Patient Global Impression of Change (PGIC) Score at Days 28, 56, 78, 100
timeFrame: Days 28, 56, 78, 100
measure: Phase 2 (US Population): Change From Baseline in EORTC QLQ-MY20 at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296, 324, 352 and 380
measure: Phase 2 (Japan Population): Change From Baseline in EORTC QLQ-MY20 at Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
timeFrame: Baseline, Days 7, 28, 56, 78, 100, 128, 156, 184, 212, 240, 268, 296 and 324
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Cancer Center-Scottsdale
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Milwaukee
country: United States
facility: Froedtert Memorial
state: Wisconsin
city: Kyoto
country: Japan
facility: University Hospital Kyoto Perfectural University of Medicine
city: Nagoya
country: Japan
facility: Nagoya City University Hospital
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital
city: Shibuya
country: Japan
facility: Japanese Red Cross Medical Center
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
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citation: Van Oekelen O, Aleman A, Upadhyaya B, Schnakenberg S, Madduri D, Gavane S, Teruya-Feldstein J, Crary JF, Fowkes ME, Stacy CB, Kim-Schulze S, Rahman A, Lagana A, Brody JD, Merad M, Jagannath S, Parekh S. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nat Med. 2021 Dec;27(12):2099-2103. doi: 10.1038/s41591-021-01564-7. Epub 2021 Dec 10.
citation: Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, Stewart AK, Hari P, Htut M, Lesokhin A, Deol A, Munshi NC, O'Donnell E, Avigan D, Singh I, Zudaire E, Yeh TM, Allred AJ, Olyslager Y, Banerjee A, Jackson CC, Goldberg JD, Schecter JM, Deraedt W, Zhuang SH, Infante J, Geng D, Wu X, Carrasco-Alfonso MJ, Akram M, Hossain F, Rizvi S, Fan F, Lin Y, Martin T, Jagannath S. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021 Jul 24;398(10297):314-324. doi: 10.1016/S0140-6736(21)00933-8. Epub 2021 Jun 24.