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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04270409
Recruitment Status : Active, not recruiting
First Posted : February 17, 2020
Last Update Posted : March 8, 2024
Sponsor:
Information provided by (Responsible Party):
Sanofi

Study Description
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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)

Condition or disease Intervention/treatment Phase
Plasma Cell Myeloma Drug: Isatuximab SAR650984 Drug: Lenalidomide Drug: Dexamethasone Drug: Montelukast or equivalent Drug: Acetaminophen Drug: Diphenhydramine or equivalent Drug: Methylprednisolone or equivalent Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 337 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : June 16, 2020
Estimated Primary Completion Date : November 11, 2030
Estimated Study Completion Date : October 10, 2033

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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Arm Intervention/treatment
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.
 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
Active Comparator: Lenalidomide and dexamethasone (Ld)
Lenalidomide [PO administration] in combination with dexamethasone [PO administration] for 24 cycles. 1 cycle = 28 days
 Drug: Lenalidomide
Pharmaceutical form: Capsules Route of administration: Oral

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


Outcome Measures
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Primary Outcome Measures :
  1. Safety assessment: adverse events (AEs)- Safety Run-in Part [ Time Frame: Up to approximately 63 months ]
    Number of participants with AEs

  2. 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)

  3. 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

  4. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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

  9. Overall survival- Randomized Phase 3 [ Time Frame: Up to approximately 144 months ]
    Time from date of randomization to death from any cause

  10. 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

  11. 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

  12. 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.

  13. Safety assessment: adverse events (AEs)- Randomized Phase 3 [ Time Frame: Up to approximately 144 months ]
    Number of participants with AEs

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04270409


Locations
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Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
More Information
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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT04270409    
Other Study ID Numbers: EFC15992
U1111-1222-7068 ( Registry Identifier: ICTRP )
2023-507419-37 ( Registry Identifier: CTIS (EU) )
2019-003139-47 ( EudraCT Number )
First Posted: February 17, 2020    Key Record Dates
Last Update Posted: March 8, 2024
Last Verified: March 2024
Individual Participant Data (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

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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
Keywords provided by Sanofi:
Anti-CD38 monoclonal antibody
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Smoldering Multiple Myeloma
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
 Precancerous Conditions
Hypergammaglobulinemia
Acetaminophen
Diphenhydramine
Promethazine
Dexamethasone
Methylprednisolone
Lenalidomide
Montelukast
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents