Clinical Trials /

Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma

NCT04270409

Description:

Primary Objectives: - Safety run-in: To confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone in participants with high-risk smoldering multiple myeloma (SMM) - Randomized Phase 3: To demonstrate the clinical benefit of isatuximab in combination with lenalidomide and dexamethasone in the prolongation of progression-free survival when compared to lenalidomide and dexamethasone in participants with high-risk SMM Secondary Objectives: Safety run-in - To assess overall response rate (ORR) - To assess duration of response (DOR) - To assess minimal residual disease (MRD) negativity in participants achieving very good partial response (VGPR) or complete response (CR) - To assess time to diagnostic (SLiM CRAB) progression or death - To assess time to first-line treatment for multiple myeloma (MM) - To assess the potential immunogenicity of isatuximab - Impact of abnormal cytogenetic subtype Randomized Phase 3 - Key Secondary Objectives: To compare between the arms - MRD negativity - Sustained MRD negativity - Second progression-free survival (PFS2) - Overall survival Other Secondary Objectives: To evaluate in both arms - CR rate - ORR - DOR - Time to diagnostic (SLiM CRAB) progression - Time to first-line treatment for MM - Safety and tolerability - Pharmacokinetics (PK) - Potential of isatuximab immunogenicity - Clinical outcome assessments (COAs)

Related Conditions:
  • Smoldering Plasma Cell Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma
  • Official Title: A Phase 3 Randomized, Open Label, Multicenter Study of Isatuximab (SAR650984) in Combination With Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients With High-risk Smoldering Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: EFC15992
  • SECONDARY ID: 2019-003139-47
  • SECONDARY ID: U1111-1222-7068
  • NCT ID: NCT04270409

Conditions

  • Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Isatuximab SAR650984SarclisaIsatuximab, lenalidomide, and dexamethasone (ILd)
LenalidomideIsatuximab, lenalidomide, and dexamethasone (ILd)
DexamethasoneIsatuximab, lenalidomide, and dexamethasone (ILd)

Purpose

Primary Objectives: - Safety run-in: To confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone in participants with high-risk smoldering multiple myeloma (SMM) - Randomized Phase 3: To demonstrate the clinical benefit of isatuximab in combination with lenalidomide and dexamethasone in the prolongation of progression-free survival when compared to lenalidomide and dexamethasone in participants with high-risk SMM Secondary Objectives: Safety run-in - To assess overall response rate (ORR) - To assess duration of response (DOR) - To assess minimal residual disease (MRD) negativity in participants achieving very good partial response (VGPR) or complete response (CR) - To assess time to diagnostic (SLiM CRAB) progression or death - To assess time to first-line treatment for multiple myeloma (MM) - To assess the potential immunogenicity of isatuximab - Impact of abnormal cytogenetic subtype Randomized Phase 3 - Key Secondary Objectives: To compare between the arms - MRD negativity - Sustained MRD negativity - Second progression-free survival (PFS2) - Overall survival Other Secondary Objectives: To evaluate in both arms - CR rate - ORR - DOR - Time to diagnostic (SLiM CRAB) progression - Time to first-line treatment for MM - Safety and tolerability - Pharmacokinetics (PK) - Potential of isatuximab immunogenicity - Clinical outcome assessments (COAs)

Detailed Description

      Study duration is expected to be approximately 10 years, including a 28-day screening period,
      followed by an up to 36-month treatment period, and a follow-up period of approximately 7
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Isatuximab, lenalidomide, and dexamethasone (ILd)ExperimentalIsatuximab intravenous (IV) administration on Days 1, 8, 15, and 22 during Cycle 1 (28 days per cycle), and Days 1 and 15 during Cycles 2-12, and Day 1 during subsequent cycles; lenalidomide per os (PO) administration on Days 1 to 21; and dexamethasone IV administration only on Day 1 during Cycle 1 and PO on Days 8, 15 and 22 of Cycle 1 and Days 1, 8, 15, and 22 of subsequent cycles
  • Isatuximab SAR650984
  • Lenalidomide
  • Dexamethasone
Lenalidomide and dexamethasone (Ld)Active ComparatorLenalidomide PO administration on Days 1 to 21 and dexamethasone PO administration on Days 1, 8, 15, and 22 of every 28-day cycle
  • Lenalidomide
  • Dexamethasone

Eligibility Criteria

        Inclusion criteria:

          -  Participant must be at least 18 years of age inclusive or older

          -  Participants who are diagnosed within 5 years with SMM (per International Myeloma
             Working Group [IMWG] criteria), defined as serum M-protein ≥30 g/L or urinary
             M-protein ≥500 mg per 24 hour or both, and/or clonal bone marrow plasma cells (BMPCs)
             10% to <60%, and absence of myeloma defining events or other related conditions and
             with high-risk SMM

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or 2

          -  Capable of giving voluntary written informed consent

          -  Absolute neutrophil count (ANC) ≥1000/µL (1 × 109/L)

          -  Platelets ≥50,000/µL (50 × 109/L)

          -  Total bilirubin ≤3 mg/dL (except Gilbert syndrome, in which direct bilirubin should be
             ≤5 mg/dL)

          -  Alanine aminotransferase ≤3× upper limit of normal (ULN), aspartate aminotransferase ≤
             3 × ULN

        Exclusion criteria:

          -  Evidence of any of the following calcium, renal failure, anemia, bone lesions (CRAB)
             criteria or Myeloma Defining Events (SLiM CRAB) detailed below (attributable to the
             participants SMM involvement):

               -  Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11
                  mg/dL

               -  Renal insufficiency: Determined by glomerular filtration rate (GFR) <40
                  mL/min/1.73 m² (Modification of Diet in Renal Disease [MDRD] Formula) or serum
                  creatinine >2 mg/dL

               -  Anemia (hemoglobin 2 g/dL below lower limit of normal or <10 g/dL or both)
                  transfusion support or concurrent treatment with erythropoietin stimulating
                  agents is not permitted

               -  ≥ 1 bone lytic lesion of ≥5mm in size

               -  BMPCs ≥60%

               -  Serum involved/uninvolved FLC ratio ≥100

               -  Whole body magnetic resonance imaging (WB-MRI) or positron emission
                  tomography-computed tomography (PET-CT) with more than 1 focal lesion (≥5 mm in
                  diameter by MRI)

          -  Primary systemic and localized amyloid light-chain (immunoglobulin light chain)
             amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), standard risk
             smoldering myeloma, soft tissue plasmacytoma, symptomatic myeloma

          -  Uncontrolled infection within 28 days prior to randomization in Phase 3 or first study
             intervention administration in safety run-in

          -  Clinically significant cardiac disease, including:

               -  Myocardial infarction within 6 months with left ventricular dysfunction or
                  uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or
                  uncontrolled disease/condition related to or affecting cardiac function (eg,
                  unstable angina, congestive heart failure, New York Heart Association Class
                  III-IV)

               -  Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 5.0) or
                  clinically significant electrocardiogram (ECG) abnormalities

          -  Known acquired immunodeficiency syndrome (AIDS)-related illness or known human
             immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis
             A (defined as positive hepatitis A antigen or positive IgM). HIV serology at screening
             will be tested for German participants and any other country where required as per
             local regulations and serology hepatitis B and C at screening will be tested for all
             participants

               -  Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA

        Of note:

        Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but
        HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was
        started before initiation of IMP, the anti-HBV therapy and monitoring should continue
        throughout the study-treatment period.

        Patients with negative HBsAg and positive HBV DNA observed during screening period will be
        evaluated by a specialist for start of anti-viral treatment: study treatment could be
        proposed if HBV DNA becomes negative and all the other study criteria are still met.

        Active HCV infection: positive HCV RNA and negative anti-HCV

        Of note:

        Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV
        antibodies are eligible. The antiviral therapy for HCV should continue throughout the
        treatment period until seroconversion.

        Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV
        are eligible

          -  Malabsorption syndrome or any condition that can significantly impact the absorption
             of lenalidomide

          -  Any of the following within 3 months prior to randomization (or first study
             intervention administration in safety run-in cohort): treatment resistant peptic ulcer
             disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease,
             diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event

          -  Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3
             years of randomization (or first study intervention administration in safety run-in
             cohort)

          -  Prior exposure to approved or investigational treatments for SMM or MM (including but
             not limited to conventional chemotherapies, immunomodulatory imid drugs, or Proteasome
             inhibitors); concurrent use of bisphosphonates or receptor activator of nuclear factor
             kappa-B ligand (RANKL) inhibitor denosumab is not permitted; however, prior
             bisphosphonates or once-a-year intravenous bisphosphonate given for the treatment of
             osteoporosis is permitted

          -  Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent per
             day at the time of randomization (or first study intervention administration in safety
             run-in cohort)

          -  Women of childbearing potential or male participant with women of childbearing
             potential who do not agree to use a highly effective method of birth control

          -  Vaccination with a live vaccine 4 weeks before the start of the study drug. Seasonal
             flu vaccines that do not contain live virus are permitted

        The above information is not intended to contain all considerations relevant to a patient's
        potential participation in a clinical trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety assessment: adverse events (AEs)
Time Frame:Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)
Safety Issue:
Description:Number of participants with AEs

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria
Measure:Duration of response (DOR)
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Time from the date of the first response to date of progressive disease or death, whichever happens first
Measure:Minimal residual disease (MRD) negativity
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Number of participants for whom MRD is negative
Measure:Time to diagnostic (SLiM CRAB) progression or death
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause
Measure:Time to first-line treatment for multiple myeloma (MM)
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Time from randomization to first-line treatment for MM
Measure:Immunogenicity: Incidence of anti-drug antibodies (ADA)
Time Frame:Up to approximately 24 months
Safety Issue:
Description:Number of participants with anti-drug antibodies against isatuximab
Measure:Sustained MRD negativity
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)
Measure:Second PFS (PFS2)
Time Frame:Up to approximately 120 months
Safety Issue:
Description:Time from randomization to date of second objective progressive disease or death from any cause
Measure:Overall survival
Time Frame:Up to approximately 144 months
Safety Issue:
Description:Time from date of randomization to death from any cause
Measure:Complete response rate
Time Frame:Up to approximately 85 months
Safety Issue:
Description:Percentage of particpants with a CR as defined by 2016 IMWG response criteria
Measure:Safety assessment: adverse events (AEs)
Time Frame:Baseline to 30 days after last study treatment administration (up to approximately 100 months after first study treatment)
Safety Issue:
Description:Number of participants with AEs
Measure:Plasma concentration of isatuximab
Time Frame:Up to approximately 24 months
Safety Issue:
Description:Maximum concentration observed after the first infusion (Cmax)
Measure:European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
Time Frame:Baseline to follow-up (up to approximately 10 years)
Safety Issue:
Description:Mean change from baseline scores will be assessed, with responses ranging from 1=not at all to 4=very much or 1=very poor to 7=excellent; higher scores represent a better level of physical functioning
Measure:EORTC QLQ-MY20
Time Frame:Baseline to follow-up (up to approximately 10 years)
Safety Issue:
Description:Mean change from baseline in scores will be assessed using a 4-point scale, with responses ranging from 1=not at all to 4=very much; higher scores represent better perspectives of the future and higher level of symptomatology
Measure:EQ-5D-5L
Time Frame:Baseline to follow-up (up to approximately 10 years)
Safety Issue:
Description:Mean change from baseline scores will be assessed from 5 items, with responses ranging from 'no' to 'extreme problems'; health state utility values (HSUVs) are generated by multiplying the item scores by country specific value sets; health status is assessed via a VAS; higher scores = higher HSUV/health status
Measure:Economic questionnaire
Time Frame:Baseline to follow-up (up to approximately 10 years)
Safety Issue:
Description:Mean change from baseline scores will assess work productivity, resource utilization and working days missed by a caregiver; higher scores represent greater impact on work/productivity and resources
Measure:Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2)
Time Frame:End of treatment (up to approximately 10 years)
Safety Issue:
Description:Patient's qualitative assessment of treatment will be assessed using a 10 point visual analogue/numeric rating scale with response anchors of 'not beneficial at all' to 'extremely beneficial'; higher scores represent greater patient-perceived benefits of treatment

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sanofi

Trial Keywords

  • Anti-CD38 monoclonal antibody

Last Updated

June 14, 2021