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

Study Overview
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Brief Summary
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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 on participant outcome 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 biochemical progression Time to first-line treatment for MM Safety and tolerability Pharmacokinetics (PK) Potential of isatuximab immunogenicity Clinical outcome assessments (COAs)

Detailed Description
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Study duration is expected to be approximately 12 years, including a 42-day screening period, followed by an up to 36-month treatment period, and a follow-up period of approximately 9 years.

Official Title
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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

Conditions
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Plasma Cell Myeloma

Intervention / Treatment
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* Drug: Isatuximab SAR650984
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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 (AL) 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.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isatuximab, lenalidomide, and dexamethasone (ILd)<br>Participants will receive isatuximab [intravenous (IV) administration] in combination with lenalidomide [per os (PO) administration] and dexamethasone [IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days | Drug: Isatuximab SAR650984<br>* Pharmaceutical for: Solution for infusion Route of administration: Intravenous<br>* Other names: Sarclisa;Drug: Lenalidomide<br>* Pharmaceutical form: Capsules Route of administration: Oral<br>Drug: Dexamethasone<br>* Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous<br>|
| Active Comparator: Lenalidomide and dexamethasone (Ld)<br>Lenalidomide [PO administration] in combination with dexamethasone [PO administration] for 24 cycles. 1 cycle = 28 days | Drug: Lenalidomide<br>* Pharmaceutical form: Capsules Route of administration: Oral<br>Drug: Dexamethasone<br>* Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessment: adverse events (AEs)- Safety Run-in Part | Number of participants with AEs | Up to approximately 63 months | 
| Plasma concentration of isatuximab: Cmax- Safety Run-in Part | Maximum concentration observed after the first infusion (Cmax) | After first infusion in Cycle 1 in safety run-in part. 1 cycle = 28 days | 
| Receptor density/receptor occupancy Safety Run-in Part | Change in CD38 receptor occupancy from baseline | Baseline to Cycle 2 Day 1 (each cycle is 28 days) | 
| Progression-free survival (PFS) Randomized Phase 3 | 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 | Up to approximately 114 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR)- Safety Run-in Part and Randomized Phase 3 | Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria | Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively | 
| Duration of response (DOR)-Safety Run-in Part and Randomized Phase 3 | Time from the date of the first response to date of progressive disease or death, whichever happens first | Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively | 
| Minimal residual disease (MRD) negativity-Safety Run-in Part and Randomized Phase 3 | Number of participants for whom MRD is negative | Up to approximately 65 months | 
| Time to diagnostic (SLiM CRAB) progression or death -Safety Run-in Part and Randomized Phase 3 | Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause | Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively | 
| Time to first-line treatment for multiple myeloma (MM)- Safety Run-in Part and Randomized Phase 3 | Time from randomization to first-line treatment for MM | Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively | 
| Immunogenicity: Incidence of anti-drug antibodies (ADA)- Safety Run-in Part | Number of participants with anti-drug antibodies against isatuximab | Up to approximately 27 months | 
| Sustained MRD negativity- Randomized Phase 3 | Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment) | Up to approximately 65 months | 
| Second PFS (PFS2) Randomized Phase 3 | Time from randomization to date of second objective progressive disease or death from any cause | Up to approximately 144 months | 
| Overall survival- Randomized Phase 3 | Time from date of randomization to death from any cause | Up to approximately 144 months | 
| PFS and OS in participants with cytogenetic abnormalities- Safety Run-In and Randomized Part | Association of cytogenetic abnormalities with survival outcomes | Up to approximately 63 and 114 months for Safety Run-in Part and Randomized Phase 3, respectively | 
| Complete response rate - Randomized Phase 3 | Percentage of particpants with a CR as defined by 2016 IMWG response criteria | Up to approximately 114 months | 
| Time to biochemical progression - Randomized Phase 3 | Time to biochemical progression is defined as the time from randomization to the date of biochemical progression based on IRC assessment. | Up to approximately 114 months | 
| Safety assessment: adverse events (AEs)- Randomized Phase 3 | Number of participants with AEs | Up to approximately 144 months | 
| Plasma concentration of isatuximab- Randomized Phase 3 | Concentration observed just before treatment administration during repeated dosing (Ctrough) after IV administration | At predose of Cycle 2 Day 1 and Cycle 6 Day 1 | 
| European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30-Randomized Phase 3 | 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 | Baseline to follow-up (up to approximately 7 years) | 
| EORTC QLQ-MY20 - Randomized Phase 3 | 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 | Baseline to follow-up (up to approximately 7 years) | 
| EQ-5D-5L Randomized Phase 3 | 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 | Baseline to follow-up (up to approximately 7 years) | 
| Randomized Phase 3: HRUPQ - Randomized Phase 3 | Mean change from baseline in Health resource utilization and productivity questionnaire (HRUPQ) scores. HRUPQ will assess health care resource utilization of HRSM and the impact of HRSM on employment/work higher scores = greater impact on work/productivity, resources | Baseline to follow-up (up to approximately 7 years) | 
| Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2) Randomized Phase 3 | 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 | End of treatment (up to approximately 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-CD38 monoclonal antibody