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

• ClinicalTrials.gov Identifier: NCT04270409
• Recruitment Status: Active, not recruiting
• First Posted: February 17, 2020
• Last Update Posted: March 8, 2024
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: February 13, 2020
• First Posted Date: February 17, 2020
• Last Update Posted Date: March 8, 2024
• Actual Study Start Date: June 16, 2020
• Estimated Primary Completion Date: November 11, 2030 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 25, 2023)

• Safety assessment: adverse events (AEs)- Safety Run-in Part [ Time Frame: Up to approximately 63 months ]
  Number of participants with AEs
• Plasma concentration of isatuximab: Cmax- Safety Run-in Part [ Time Frame: After first infusion in Cycle 1 in safety run-in part. 1 cycle = 28 days ]
  Maximum concentration observed after the first infusion (Cmax)
• Receptor density/receptor occupancy Safety Run-in Part [ 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 114 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 (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

Current Secondary Outcome Measures (submitted: April 25, 2023)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief 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
• 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

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 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: 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Plasma Cell Myeloma

Intervention

• 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
• Drug: Montelukast or equivalent
  Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: As per local commercial product; Route of administration: Oral;
• Drug: Acetaminophen
  AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: As per local commercial product; Route of administration: Oral
• Drug: Diphenhydramine or equivalent
  AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: As per local commercial product; Route of administration: Intravenous
• Drug: Methylprednisolone or equivalent
  AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: As per local commercial product; Route of administration: Intravenous

Study Arms

• Experimental: Isatuximab, lenalidomide, and dexamethasone (ILd)
  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. Participants may receive other treatments as pre-medication.
  Interventions:

  • Drug: Isatuximab SAR650984
  • Drug: Lenalidomide
  • Drug: Dexamethasone
  • Drug: Montelukast or equivalent
  • Drug: Acetaminophen
  • Drug: Diphenhydramine or equivalent
  • Drug: Methylprednisolone or equivalent
• Active Comparator: Lenalidomide and dexamethasone (Ld)
  Lenalidomide [PO administration] in combination with dexamethasone [PO administration] for 24 cycles. 1 cycle = 28 days
  Interventions:

  • Drug: Lenalidomide
  • Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: February 14, 2024): 337
• Original Estimated Enrollment (submitted: February 13, 2020): 300
• Estimated Study Completion Date: October 10, 2033
• Estimated Primary Completion Date: November 11, 2030 (Final data collection date for primary outcome measure)

Eligibility 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 (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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location 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

Administrative Information

• NCT Number: NCT04270409
• Other Study ID Numbers: EFC15992; U1111-1222-7068 ( Registry Identifier: ICTRP ); 2023-507419-37 ( Registry Identifier: CTIS (EU) ); 2019-003139-47 ( EudraCT Number )
• 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

• 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: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: March 2024