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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

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ClinicalTrials.gov Identifier: NCT04270409
Recruitment Status : Recruiting
First Posted : February 17, 2020
Last Update Posted : December 21, 2022
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE February 13, 2020
First Posted Date  ICMJE February 17, 2020
Last Update Posted Date December 21, 2022
Actual Study Start Date  ICMJE June 16, 2020
Estimated Primary Completion Date June 1, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2022)
  • Plasma concentration of isatuximab: Cmax [ Time Frame: Up to approximately 24 months ]
    Maximum concentration observed after the first infusion (Cmax)
  • Receptor density/receptor occupancy (safety run-in) [ Time Frame: Baseline to Cycle 2 Day 1 (each cycle is 28 days) ]
    Change in CD38 receptor occupancy from baseline
  • Progression-free survival (PFS) randomized Phase 3 [ Time Frame: Up to approximately 85 months ]
    Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first
Original Primary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
  • 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) ]
    Number of participants with AEs
  • Plasma concentration of isatuximab: Cmax [ Time Frame: Up to approximately 24 months ]
    Maximum concentration observed after the first infusion (Cmax)
  • Receptor density/receptor occupancy (safety run-in) [ Time Frame: Baseline to Cycle 2 Day 1 (each cycle is 28 days) ]
    Change in CD38 receptor occupancy from baseline
  • Progression-free survival (PFS) [ Time Frame: Up to approximately 85 months ]
    Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2020)
  • Overall response rate (ORR) [ Time Frame: Up to approximately 85 months ]
    Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria
  • Duration of response (DOR) [ Time Frame: Up to approximately 85 months ]
    Time from the date of the first response to date of progressive disease or death, whichever happens first
  • Minimal residual disease (MRD) negativity [ Time Frame: Up to approximately 85 months ]
    Number of participants for whom MRD is negative
  • Time to diagnostic (SLiM CRAB) progression or death [ Time Frame: Up to approximately 85 months ]
    Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause
  • Time to first-line treatment for multiple myeloma (MM) [ Time Frame: Up to approximately 85 months ]
    Time from randomization to first-line treatment for MM
  • Immunogenicity: Incidence of anti-drug antibodies (ADA) [ Time Frame: Up to approximately 24 months ]
    Number of participants with anti-drug antibodies against isatuximab
  • Sustained MRD negativity [ Time Frame: Up to approximately 85 months ]
    Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)
  • Second PFS (PFS2) [ Time Frame: Up to approximately 120 months ]
    Time from randomization to date of second objective progressive disease or death from any cause
  • Overall survival [ Time Frame: Up to approximately 144 months ]
    Time from date of randomization to death from any cause
  • Complete response rate [ Time Frame: Up to approximately 85 months ]
    Percentage of particpants with a CR as defined by 2016 IMWG response criteria
  • 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) ]
    Number of participants with AEs
  • Plasma concentration of isatuximab [ Time Frame: Up to approximately 24 months ]
    Maximum concentration observed after the first infusion (Cmax)
  • European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [ Time Frame: Baseline to follow-up (up to approximately 10 years) ]
    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
  • EORTC QLQ-MY20 [ Time Frame: Baseline to follow-up (up to approximately 10 years) ]
    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
  • EQ-5D-5L [ Time Frame: Baseline to follow-up (up to approximately 10 years) ]
    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
  • Economic questionnaire [ Time Frame: Baseline to follow-up (up to approximately 10 years) ]
    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
  • Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) [ Time Frame: End of treatment (up to approximately 10 years) ]
    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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary

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 subjects 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Plasma Cell Myeloma
Intervention  ICMJE
  • Drug: Isatuximab SAR650984
    Pharmaceutical for: Solution for infusion Route of administration: Intravenous
    Other Name: Sarclisa
  • Drug: Lenalidomide
    Pharmaceutical form: Capsules Route of administration: Oral
  • Drug: Dexamethasone
    Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous
Study Arms  ICMJE
  • Experimental: Isatuximab, lenalidomide, and dexamethasone (ILd)
    Isatuximab 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
    Interventions:
    • Drug: Isatuximab SAR650984
    • Drug: Lenalidomide
    • Drug: Dexamethasone
  • Active Comparator: Lenalidomide and dexamethasone (Ld)
    Lenalidomide PO administration on Days 1 to 21 and dexamethasone PO administration on Days 1, 8, 15, and 22 of every 28-day cycle
    Interventions:
    • Drug: Lenalidomide
    • Drug: Dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 13, 2020)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2033
Estimated Primary Completion Date June 1, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • 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

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
    • BMPCs ≥60%
    • Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L
    • Whole body magnetic resonance imaging (WB-MRI) or positron emission tomography-computed tomography (PET-CT) with more than 1 bone focal lesion (≥5 mm in diameter by MRI)
  • Primary systemic 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 potential participation in a clinical trial.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com
Listed Location Countries  ICMJE Australia,   Brazil,   Canada,   China,   Czechia,   Denmark,   France,   Germany,   Greece,   Hungary,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Lithuania,   New Zealand,   Norway,   Poland,   Spain,   Sweden,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04270409
Other Study ID Numbers  ICMJE EFC15992
2019-003139-47 ( EudraCT Number )
U1111-1222-7068 ( Registry Identifier: ICTRP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
Current Responsible Party Sanofi
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Sanofi
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date December 20, 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP