Clinical Benefit of SAR650984, Bortezomib, Lenalidomide and Dexamethasone Combination in NDMM Patients Not Eligible for Transplant

Study Overview
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Brief Summary
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Primary Objective: -To demonstrate the benefit of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone in the prolongation of progression free survival (PFS) as compared to bortezomib, lenalidomide, and dexamethasone, in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant. Secondary Objectives: To evaluate in both randomized (isatuximab, bortezomib, lenalidomide and dexamethasone combination (IVRd) and bortezomib, lenalidomide and dexamethasone combination (VRd)) arms: Complete response (CR) rate, as defined by the International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) negativity rate in patients with CR. Very good partial response or better rate, as defined by the IMWG criteria. Overall survival (OS). To evaluate the overall response rate (ORR) as per IMWG criteria. To evaluate the time to progression (TTP) overall and by MRD status. To evaluate PFS by MRD status. To evaluate the duration of response (DOR) overall and by MRD status. To evaluate time to first response (TT1R). To evaluate time to best response (TTBR). To evaluate progression-free survival on next line of therapy (PFS2). To evaluate the sustained MRD negativity >12 months rate. To evaluate safety. To determine the pharmacokinetic (PK) profile of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (IVRd arm only). To evaluate the immunogenicity of isatuximab in patients receiving isatuximab (IVRd and crossover arms). To assess disease-specific and generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility, and health status.

Detailed Description
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The duration of the study for each patient will include a screening period of up to 4 weeks, an induction period of 24 weeks (4 cycles with a duration of 42 ± 3 days), a continuous treatment period and a crossover period (when applicable). The cycle duration is 28 ± 3 days during the continuous treatment and crossover periods.

Official Title
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A Phase 3 Randomized, Open-label, Multicenter Study Assessing the Clinical Benefit of Isatuximab (SAR650984) in Combination With Bortezomib (Velcade®), Lenalidomide and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Not Eligible for Transplant

Conditions
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Plasma Cell Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria : Multiple myeloma (IMWG criteria). Newly diagnosed multiple myeloma not eligible for transplant due to age (≥ 65 years) or patients < 65 years with comorbidities impacting possibility of transplant. Evidence of measurable disease. Written informed consent. Exclusion criteria: Age < 18 years. Prior treatment for multiple myeloma. Any other prior or ongoing disease/health conditions incompatible with the study objectives. Organ function values not met. Eastern Cooperative Oncology Group (ECOG) Performance Status ( PS) > 2. Hypersensitivity to the study medications. Pregnant, breastfeeding, or woman of child bearing potential unwilling to use recommended contraception methods. Male participants who disagree to follow the study contraceptive counseling. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Parallel and crossover
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isatuximab/Bortezomib/Lenalidomide/Dexamethasone = IVRd arm<br>Induction treatment with 4x6-week cycles with intravenous (IV) isatuximab + subcutaneous (SC) bortezomib + oral lenalidomide + IV or oral dexamethasone Continuous treatment with 4-week cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV)<br>* Other names: Sarclisa;Drug: Bortezomib<br>* Pharmaceutical form: Lyophilized powder for injection Route of administration: Subcutaneous<br>* Other names: Velcade®;Drug: Lenalidomide<br>* Pharmaceutical form: Capsules Route of administration: Oral<br>Drug: Dexamethasone<br>* Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous<br>|
| Active Comparator: Bortezomib/Lenalidomide/Dexamethasone = VRd arm<br>Induction treatment with 4x6-week cycles with SC bortezomib + oral lenalidomide + IV or oral dexamethasone Continuous treatment with 4-week cycles with oral lenalidomide + IV or oral dexamethasone | Drug: Bortezomib<br>* Pharmaceutical form: Lyophilized powder for injection Route of administration: Subcutaneous<br>* Other names: Velcade®;Drug: Lenalidomide<br>* Pharmaceutical form: Capsules Route of administration: Oral<br>Drug: Dexamethasone<br>* Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous<br>|
| Other: Isatuximab/Lenalidomide/Dexamethasone = IRd crossover arm<br>4-weeks cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone | Drug: Isatuximab SAR650984<br>* Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV)<br>* Other names: Sarclisa;Drug: Lenalidomide<br>* Pharmaceutical form: Capsules Route of administration: Oral<br>Drug: Dexamethasone<br>* Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Defined as the time from the date of randomization to the date of first documentation of progression disease (PD) as determined by the independent review committee (IRC) or the date of death from any cause, whichever occurs first. | Up to approximately 100 months after the First Patient In (FPI) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CR) | Defined as the proportion of patients with CR and stringent complete response (sCR) as assessed by the IRC using the IMWG criteria. | Up to approximately 100 months after the FPI | 
| Minimal residual disease (MRD) negativity rate for patients with CR | Proportion of patients with CR for whom MRD measurement is negative | Up to approximately 100 months after the FPI | 
| Very good partial response (VGPR) or better rate | Proportion of patients with sCR, CR and VGPR as assessed by the IRC using the International Myeloma Working Group (IMWG) criteria | Up to approximately 100 months after the FPI | 
| Overall survival (OS) | Defined as the time from the date of randomization to death from any cause | Up to approximately 110 months after the FPI | 
| Overall response rate (ORR) | Proportion of patients with best overall response (BOR) recorded as sCR, CR, VGPR, or partial response (PR) as assessed by the IRC using the IMWG criteria | Up to approximately 100 months after the FPI assessment | 
| Time to progression (TTP) | Defined as the time from randomization to date of first documentation of PD as assessed by the IRC using the IMWG criteria | Up to approximately 100 months after FPI | 
| Duration of response (DOR) | Defined as the time from date of first IRC determined response to date of first IRC PD or death, whichever occurs first for patients achieving sCR, CR, VGPR, or PR | Up to approximately 100 months after the FPI | 
| Time to first response (TT1R) | Time from randomization to the first IRC determined response (PR or better) that is subsequently confirmed | Up to approximately 100 months after the FPI | 
| Time to best response (TTBR) | Defined as the time from randomization to the date of first occurrence of IRC determined best response (PR or better) that is subsequently confirmed | Up to approximately 100 months after the FPI | 
| PFS on next line of therapy (PFS2) | Defined as the time from randomization to the date of first documentation of disease progression (as assessed by investigator) after initiation of further anti-myeloma treatment, or death from any cause, whichever occurs first | Up to approximately 110 months after the FPI | 
| PFS in MRD negative patients | Defined as the time from the date of randomization to the date of first documentation of PD or the date of death from any cause, whichever comes first in MRD negative patients | Up to approximately 100 months after the FPI | 
| Sustained MRD negativity ≥12 months rate | Defined as the proportion of patients with the maintenance of MRD negativity confirmed ≥12 months apart with no MRD positive test in between. | Up to approximately 100 months after the FPI | 
| Adverse Events | Treatment-emergent adverse events/serious adverse events (TEAEs/SAEs) including infusion associated reactions (IARs), second primary malignancies, laboratory parameters, vital signs, weight, ECOG PS, and findings from physical examination | Up to 30 days after end of treatment (EOT) visit | 
| Assessment of PK parameter: Ctrough | Isatuximab: Pre-dose plasma isatuximab concentration (Ctrough) | Cycle 1 Day 8/Day 15/Day 29 (pre-dose) and Day 1 (pre-dose) of Cycle 2, 3, 4, 5, 6, 7, 8, 9 and 10 (Duration of each cycle for Cycles 1-4: 6 weeks; Duration of each cycle for Cycles 5-10: 4 weeks) | 
| Immunogenicity | Presence of anti-drug antibodies against isatuximab | Up to approximately 100 months after the FPI | 
| Patient reported outcome (PRO): QLQ-C30 | Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30) | Up to approximately 100 months after the FPI | 
| PRO: QLQ-MY20 | Disease- and treatment-related quality of life will be assessed using the EORTC myeloma module (QLQ-MY20) questionnaire | Up to approximately 100 months after the FPI | 
| PRO: EQ-5D-5L | Health state utility and health status will be assessed using the European Quality of Life Group questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L) | Up to approximately 100 months after the FPI | 

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