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 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 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)

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04270409
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Sanofi
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Clinical Sciences & Operations
Principal Investigator Affiliation	Sanofi
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Recruiting
Countries	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
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Plasma Cell Myeloma

Additional Details

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.

Arms & Interventions

Arms

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

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: - Isatuximab SAR650984

Pharmaceutical for: Solution for infusion Route of administration: Intravenous

Drug: - Lenalidomide

Pharmaceutical form: Capsules Route of administration: Oral

Drug: - Dexamethasone

Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

UCLA-Site Number:8400010, Los Angeles, California

Status

Recruiting

Address

UCLA-Site Number:8400010

Los Angeles, California, 90024

Site Contact

Clinical Trial Finder