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A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Cilta-cel, a CAR-T Therapy Directed Against BCMA Versus VRd Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom ASCT is Not Planned as Initial Therapy

NCT04923893

Description:

The purpose of this study is to compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS).

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT04923893

Trial Eligibility

Document

Title

  • Brief Title: A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Cilta-cel, a CAR-T Therapy Directed Against BCMA Versus VRd Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom ASCT is Not Planned as Initial Therapy
  • Official Title: A Phase 3 Randomized Study Comparing Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Ciltacabtagene Autoleucel, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

Clinical Trial IDs

  • ORG STUDY ID: CR109015
  • SECONDARY ID: 2021-001242-35
  • SECONDARY ID: 68284528MMY3004
  • NCT ID: NCT04923893

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
BortezomibArm A: VRd+Rd (Standard Therapy)
DexamethasoneArm A: VRd+Rd (Standard Therapy)
LenalidomideArm A: VRd+Rd (Standard Therapy)
Cilta-celJNJ-68284528Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
CyclophosphamideArm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)
FludarabineArm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)

Purpose

The purpose of this study is to compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS).

Detailed Description

      Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the production of
      monoclonal immunoglobulin (Ig) proteins or protein fragments (M proteins) that have lost
      their function. JNJ-68284528 (ciltacabtagene autoleucel [cilta-cel]) is an autologous
      chimeric antigen receptor T cell (CAR-T) therapy that targets B-cell maturation antigen
      (BCMA), a molecule expressed on the surface of mature B lymphocytes and malignant plasma
      cells. The primary hypothesis of this study is that in participants with newly diagnosed MM,
      treatment with VRd induction followed by a single administration of cilta-cel will
      significantly improve progression free survival compared to Bortezomib, Lenalidomide and
      Dexamethasone (VRd) induction followed by Rd maintenance. The study will screen participants
      with newly diagnosed MM who are not planned to receive autologous stem cell transplant (ASCT)
      as initial therapy. This study will be conducted in 4 phases: Screening (up to 28 days),
      Pre-randomization Treatment, Treatment, and Follow-up. Assessments like patient-reported
      outcome(s) (PROs), electrocardiogram (ECG), vital signs and pharmacokinetics will be
      performed during the study. Safety evaluations will include review of adverse events,
      laboratory test results, vital sign measurements, physical examination findings, assessment
      of cardiac function, Immune-Effector Cell-Associated Encephalopathy (ICE) and handwriting
      assessments (only for Arm B) and Eastern Cooperative Oncology Group (ECOG) performance
      status. Safety data will be periodically reviewed by an Independent Data Monitoring Committee
      (IDMC). The duration of the study is approximately 12 years 5 months.

Trial Arms

NameTypeDescriptionInterventions
Arm A: VRd+Rd (Standard Therapy)ExperimentalParticipants will receive bortezomib, lenalidomide, and dexamethasone (VRd) regimen for 6 cycles before randomization. Following randomization, participants in Arm A will receive 2 more cycles of VRd. In VRd treatment, participants will receive bortezomib 1.3 milligram per meter square (mg/m^2) subcutaneously (SC) on Days 1, 4, 8 and 11 of each cycle (Cycles 1 to 8), oral lenalidomide 25 mg on Days 1 to 14 of each cycle (Cycles 1 to 8) and oral dexamethasone 25 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (Cycles 1 to 8). Each cycle will consist of 21 days. After 8 cycles of VRd, treatment will continue with lenalidomide and dexamethasone (Rd) maintenance therapy. In Rd treatment, participants will receive oral lenalidomide 25 mg on Days 1 to 21 of each cycle and oral dexamethasone 40 mg on Days 1, 8, 15, and 22 of each cycle. Each cycle will consist of 28 days. Participants will continue to receive Rd until confirmed progressive disease or unacceptable toxicity.
  • Bortezomib
  • Dexamethasone
  • Lenalidomide
Arm B: VRd+Ciltacabtagene Autoleucel (Cilta-cel)ExperimentalParticipants will receive VRd regimen for 6 cycles before randomization. Following randomization, participants in Arm B will undergo apheresis and receive two more cycles of VRd as bridging therapy. In VRd treatment, participants will receive bortezomib 1.3 mg/m^2 SC on Days 1, 4, 8 and 11 of each cycle for Cycles 1 to 8; oral lenalidomide 25 mg on days 1 to 14 of each cycle for Cycles 1 to 8 and oral dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle for Cycles 1 to 8. Each cycle will consist of 21 days. After 8 cycles of VRd, participants will receive a conditioning regimen (cyclophosphamide 300 mg/m^2 intravenous [IV] and fludarabine 30 mg/m^2 IV daily for 3 days) and Cilta-cel infusion 0.75*10^6 chimeric antigen receptor (CAR)-positive viable T cells/kilogram (kg).
  • Bortezomib
  • Dexamethasone
  • Lenalidomide
  • Cilta-cel
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Documented diagnosis of multiple myeloma (MM) according to International Myeloma
             Working Group (IMWG) diagnostic criteria

          -  Measurable disease at screening as defined by any of the following: Serum monoclonal
             paraprotein (M-protein) level greater than or equal to (>=)1.0 gram per deciliter
             (g/dL) or urine M-protein level >=200 milligram (mg)/24 hours; or Light chain MM in
             whom only measurable disease is by serum free light chain (FLC) levels: Serum
             immunoglobin (Ig) free light chain >=10 milligrams per deciliter (mg/dL) and abnormal
             serum Ig kappa/lambda FLC ratio

          -  Eastern Cooperative Oncology Group Performance Status grade of 0 or 1

          -  Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT)
             due to: Ineligible due to advanced age; or Ineligible due to presence of comorbid
             condition(s) likely to have a negative impact on tolerability of high-dose
             chemotherapy with ASCT; or Deferral of high-dose chemotherapy with ASCT as initial
             treatment

          -  A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum
             (beta-human chorionic gonadotropin) tests prior to starting Bortezomib, Lenalidomide
             and Dexamethasone (VRd). The first test must be within 10 to 14 days prior to the
             start of VRd

          -  Clinical laboratory values meeting the following criteria during the screening phase:
             hemoglobin greater than (>)8.0 g/dL (>=5 millimoles per liter [mmol/L]), recombinant
             human erythropoietin use is permitted; platelets >=75 *10^9/L; absolute lymphocyte
             count >=0.3 *10^9/L; absolute neutrophil count (ANC) >=1.0 ×10^9/L (prior growth
             factor support is permitted but must be without support in the 7 days prior to the
             laboratory test); aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
             less than or equal to (<=) 3.0 * upper limit of normal (ULN); estimated glomerular
             filtration rate >=40 milliliter per minute/1.73 meter square (mL/min/1.73 m^2) based
             upon modified diet in renal disease formula (MDRD-4) calculation or a 24-hour urine
             collection; total bilirubin <=2.0 * ULN; except in participants with congenital
             hyperbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin <=2.0 *
             ULN is required)

        Exclusion Criteria:

          -  Frailty index of >=2 according to Myeloma Geriatric Assessment score

          -  Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
             National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE)
             Version 5

          -  Known active, or prior history of central nervous system (CNS) involvement or clinical
             signs of meningeal involvement of MM

          -  Stroke or seizure within 6 months of signing Informed Consent Form (ICF)

          -  Seropositive for human immunodeficiency virus (HIV)

          -  Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd

          -  Participant must not require continuous supplemental oxygen

          -  Hepatitis B infection

          -  Hepatitis C infection defined as (anti-hepatitis C virus [HCV] antibody positive or
             detectable HCV- ribonucleic acid [RNA]) or known to have a history of hepatitis C

          -  Prior treatment with chimeric antigen receptor T (CAR-T) therapy directed at any
             target

          -  Any therapy that is targeted to B-cell maturation antigen (BCMA)
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Up to 4 years and 5 months
Safety Issue:
Description:Progression-free survival is defined as the time from the date of randomization to the date of first documented Progressive Disease (PD), as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first.

Secondary Outcome Measures

Measure:Sustained Minimal Residual Disease (MRD) Negative CR
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Sustained MRD negative complete response (CR) as determined by next generation sequencing (NGS) with sensitivity of 10^-5, and defined by MRD negative CR plus at least 12 months durability of the MRD negative CR status.
Measure:MRD Negative CR at 9 Months
Time Frame:9 months
Safety Issue:
Description:MRD negative CR rate at 9 months is defined as the percentage of participants who achieve MRD negative CR status at 9±3 months after the randomization date.
Measure:Overall MRD Negative CR
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Overall MRD negative is defined as the percentage of participants who achieve MRD negativity at any time after the date of randomization before initiation of subsequent therapy.
Measure:Overall Survival (OS)
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Overall survival is measured from the date of randomization to the date of the participant's death.
Measure:Complete Response or Better
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:CR or better is defined as percentage of participants who achieve a CR response or Stringent Complete Response (sCR) response according to the IMWG criteria.
Measure:Time to Subsequent Anti-myeloma Therapy
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Time to subsequent anti-myeloma therapy is defined as the time from randomization to the start of subsequent anti-myeloma therapy.
Measure:Progression Free Survival on Next-line Therapy (PFS2)
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as PD as assessed by investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first.
Measure:Number of Participants with Adverse Events (AEs), Abnormalities in Laboratory Parameters, 12-Lead Electrocardiogram (ECG), Physical Examination, and Vital Signs
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Number of participants with AEs, abnormalities in laboratory parameters (complete blood count [CBC] with differential, coagulation, chimeric antigen receptor T cell [CAR-T] chemistry, full metabolic panel etc.), 12-lead ECG, physical examination, and vital signs will be reported.
Measure:Arm B: Systemic Cytokine Concentrations
Time Frame:Up to Day 112
Safety Issue:
Description:Serum or plasma proteomic profiling of cytokines (such as interleukin [IL] 6, IL-15, and IL 10) concentrations will be measured for biomarker assessment.
Measure:Arm B: Levels of Chimeric Antigen Receptor T cell (CAR-T) Cell Activation Markers
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:CAR-T cell activation 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.
Measure:Arm B: Level of Soluble B-cell Maturation Antigen (BCMA) and BCMA Expressing Cells
Time Frame:Up to 1 year
Safety Issue:
Description:Level of soluble BCMA and BCMA expressing cells will be reported.
Measure:Arm B: Levels of Cilta-cel Expansion (proliferation), and Persistence
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Levels of cilta-cel expansion (proliferation), and persistence via monitoring CAR-T positive cell counts and CAR transgene level will be reported.
Measure:Arm B: Number of Participants with Anti-cilta-cel Antibodies
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Number of participants with anti-cilta-cel antibodies will be reported.
Measure:Arm B: Number of Participants with Presence of Replication Competent Lentivirus
Time Frame:Up to 12 years and 5 months
Safety Issue:
Description:Number of participants with presence of replication competent lentivirus will be reported.
Measure:Change from Baseline in Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC-QLQ-C30) Scale Score
Time Frame:Baseline up to 12 years and 5 months
Safety Issue:
Description:The EORTC QLQ-C30 includes 30 items in 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, nausea/vomiting), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The responses are reported using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher score represents greater HRQoL, better functioning, and more (worse) symptoms.
Measure:Change from Baseline in Health-Related Quality of Life as Assessed by MySIm-Q Scale Score
Time Frame:Baseline up to 12 years and 5 months
Safety Issue:
Description:The MySIm-Q is a disease-specific PRO assessment complementary to the EORTC-QLQ-C30. It includes 17 items with recall period of "7 days" and responses are reported on a 5-point verbal rating scale. Item responses are scored from 0 to 4. Higher scores indicate greater severity/impact.
Measure:Change from Baseline in Health-Related Quality of Life as Assessed by European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) Scale Score
Time Frame:Baseline up to 12 years and 5 months
Safety Issue:
Description:The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems, where Level 1: no problem, Level 2: slight problems, Level 3: moderate problems, Level 4: severe problems and Level 5: extreme problems, plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).
Measure:Change from Baseline in Health-Related Quality of Life as Assessed by Patient Global Impression of Symptom Severity (PGIS) Scale Score
Time Frame:Baseline up to 12 years and 5 months
Safety Issue:
Description:The PGIS uses 2 items to assess the participant's perception of the severity of their disease symptoms and impact using a 5-point verbal rating scale. Score ranges from 1 (None) to 5 (Very Severe).
Measure:Patient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Items
Time Frame:Up to 161 days
Safety Issue:
Description:The National Cancer Institute's PRO-CTCAE is an item library of common adverse events experienced by people with cancer that are appropriate for self-reporting. Each symptom selected for inclusion can be rated by up to 3 attributes characterizing the presence/frequency, severity, and/or interference that ranges from 0 to 4 with higher scores indicating higher frequency or greater severity/impact.
Measure:Time to Worsening of Symptoms, Functioning and Overall Well-being
Time Frame:Up to 12 year and 5 months
Safety Issue:
Description:Time to worsening is measured as the interval from the date of randomization to the start date of worsening in MySIm-Q symptom, impact, or total scores.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Janssen Research & Development, LLC

Trial Keywords

  • Newly Diagnosed Multiple Myeloma
  • Cellular Therapy
  • CAR-T Therapy
  • BCMA CAR-T

Last Updated

August 20, 2021