Study of Isatuximab Combined With Bortezomib + Cyclophosphamide + Dexamethasone (VCD) and Bortezomib + Lenalidomide + Dexamethasone (VRD) in Newly Diagnosed Multiple Myeloma (MM) Non Eligible for Transplant or No Intent for Immediate Transplantation

Sponsor

Sanofi (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02513186

Collaborator

(none)

Enrollment

Locations

Arm

129

Anticipated Duration (Months)

7.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objectives:

VCDI cohort:
To determine the maximum tolerated dose (MTD) and recommended dose (RD) of SAR650984 isatuximab when administered in combination with bortezomib (Velcade®) , cyclophosphamide, and dexamethasone (VCDI) based on the dose-limiting toxicity(ies) (DLTs) observed in patients with newly diagnosed multiple myeloma non-eligible for transplantation
To evaluate safety and preliminary efficacy (overall response rate and complete response rate) of isatuximab administered at the selected dose in combination with bortezomib based regimin VCDI according to IMWG criteria.
VRDI Part A cohort and Part B cohort:
To evaluate the preliminary efficacy (complete response [CR] rate) of isatuximab administered at the selected dose in combination with bortezomib based regimen: VRDI, (bortezomib, lenalidomide, dexamethasone) according to IMWG criteria in adult patients with newly diagnosed MM non eligible for transplantation.

Secondary Objectives:

VCDI cohort:
To characterize the overall safety profile of SAR650984 in combination with VCD regimen, including cumulative toxicities.
To characterize the pharmacokinetic (PK) profile of SAR650984/isatuximab and each combination drug in VCDI regimen.
To evaluate the immunogenicity of SAR650984 in combination treatments.
To evaluate the preliminary efficacy of VCDI regimen in terms of duration of response and progression-free survival.
To assess the relationship between clinical effects (adverse event [AE] and/or tumor response) and CD38 receptor density.
VRDI Part A cohort and Part B cohort:
To characterize the overall safety profile of isatuximab in combination with VRD regimen.
To evaluate the infusion duration (only applicable for VRDI Part B cohort)
To characterize the PK profile of isatuximab and each combination drug in VRDI regimen.
To evaluate the immunogenicity of isatuximab in combination treatments.
To evaluate the preliminary efficacy of VRDI regimen in terms of ORR, DOR, and PFS.
To evaluate the impact of M protein measurement without isatuximab interference (via the SEBIA HYDRASHIFT 2/4 isatuximab IFE test) on CR and BOR assessment.
To assess the relationship between clinical effects (AE and/or tumor response) and CD38 receptor density (only applicable for VRDI Part A cohort).
To assess MRD negativity rate in patients achieving a CR or VGPR and explore correlation with clinical outcome.

Condition or Disease	Intervention/Treatment	Phase
Plasma Cell Myeloma	Drug: lenalidomide Drug: bortezomib Drug: cyclophosphamide Drug: dexamethasone Drug: isatuximab SAR650984	Phase 1

Detailed Description

The duration of the study for an individual patient will include:

A period to assess eligibility (screening or baseline period) of up to 3 weeks for VCDI cohort, up to 28 days for VRDI cohort;
for patients in the VCDI cohort: a treatment period including up to 12 induction treatment cycles (50-week duration).
for patients in the VRDI cohort: a treatment period including up to 4 induction cycles (24 week duration).
Following induction, both cohorts have maintenance periods consisting of 4 week cycles until progression, unacceptable AE, or patient willingness to discontinue and an end-of-treatment visit at least 30 days following the last administration of treatment.
Patients that discontinue therapy for reasons other than progression will have follow-up visits until progression or until the patient receives another anticancer therapy, whichever is earlier.

Study Design

Study Type:

Interventional

Actual Enrollment :

90 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Dose Escalation, Safety, Pharmacokinetic, Pharmacodynamic and Preliminary Efficacy Study of SAR650984 (Isatuximab) Administered Intravenously in Combination With Bortezomib - Based Regimens in Adult Patients With Newly Diagnosed Multiple Myeloma Non Eligible for Transplantation or No Intent for Immediate Transplantation

Actual Study Start Date :

Sep 30, 2015

Anticipated Primary Completion Date :

Jul 1, 2026

Anticipated Study Completion Date :

Jul 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Isatuximab VCDI cohort: Isatuximab (escalating dose) + bortezomib + cyclophosphamide + dexamethasone (VCDI): Induction phase will be 50 weeks (12 cycles). The duration of a cycle will be 42 days (6 weeks) for Cycle 1 (C1) and 28 days (4 weeks) for subsequent cycles. The duration of a cycle of the maintenance phase will be 28 days (4 weeks). After C12, isatuximab will be administered at its initial assigned dose and dexamethasone once every 28 days. VRDI cohort parts A and B: Isatuximab + bortezomib + dexamethasone + lenalidomide (VRDI): Induction phase will be 24 weeks (4 cycles at 6 weeks/cycle). The duration of a cycle of the maintenance phase will be 28 days (4 weeks). Maintenance therapy may continue until disease progression, unacceptable AE or patient willingness to discontinue. VRDI Part A: Enrollment to begin after the VCDI cohort is completed. VRDI Part B: Enrollment to begin after the VRDI part A is completed.	Drug: lenalidomide Pharmaceutical form: tablet Route of administration: oral Other Names: Revlimid Drug: bortezomib Pharmaceutical form: lyophilized powder for subcutaneous injection Route of administration: subcutaneous Other Names: Velcade Drug: cyclophosphamide Pharmaceutical form: tablet Route of administration: oral Other Names: Endoxan Drug: dexamethasone Pharmaceutical form: tablet or solution for infusion Route of administration: oral or intravenous Drug: isatuximab SAR650984 Pharmaceutical form: solution for infusion Route of administration: intravenous Other Names: Sarclisa

Arm

Intervention/Treatment

Experimental: Isatuximab

VCDI cohort: Isatuximab (escalating dose) + bortezomib + cyclophosphamide + dexamethasone (VCDI): Induction phase will be 50 weeks (12 cycles). The duration of a cycle will be 42 days (6 weeks) for Cycle 1 (C1) and 28 days (4 weeks) for subsequent cycles. The duration of a cycle of the maintenance phase will be 28 days (4 weeks). After C12, isatuximab will be administered at its initial assigned dose and dexamethasone once every 28 days. VRDI cohort parts A and B: Isatuximab + bortezomib + dexamethasone + lenalidomide (VRDI): Induction phase will be 24 weeks (4 cycles at 6 weeks/cycle). The duration of a cycle of the maintenance phase will be 28 days (4 weeks). Maintenance therapy may continue until disease progression, unacceptable AE or patient willingness to discontinue. VRDI Part A: Enrollment to begin after the VCDI cohort is completed. VRDI Part B: Enrollment to begin after the VRDI part A is completed.

Drug: lenalidomide

Pharmaceutical form: tablet Route of administration: oral

Other Names:

Revlimid

Drug: bortezomib

Pharmaceutical form: lyophilized powder for subcutaneous injection Route of administration: subcutaneous

Other Names:

Velcade

Drug: cyclophosphamide

Pharmaceutical form: tablet Route of administration: oral

Other Names:

Endoxan

Drug: dexamethasone

Pharmaceutical form: tablet or solution for infusion Route of administration: oral or intravenous

Drug: isatuximab SAR650984

Pharmaceutical form: solution for infusion Route of administration: intravenous

Other Names:

Sarclisa

Outcome Measures

Primary Outcome Measures

Assessment of dose-limiting toxicities (DLTs) in VCDI cohort [Up to 6 weeks per treated patient]
Overall response rate (VCDI) [Up to 34 weeks of treatment (induction phase)]
Complete response rate (VCDI) [Up to 34 weeks of treatment (induction phase)]
Complete response rate (VRDI) [Up to 104 weeks of treatment (induction and maintenance phase) in VRDI part A and part B cohorts]

Secondary Outcome Measures

Number of patients with adverse events (AEs), clinically significant changes in laboratory tests and vital signs according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.03 grade scaling [VCDI: Up to approximately 106 weeks, VRDI Part A and Part B: Up to approximately 104 weeks]
Overall response rate (VRDI) [Up to 104 weeks of treatment (induction and maintenance phase) in VRDI part A and part B cohorts]
Infusion duration [VRDI Part B: Up to 104 weeks of treatment]
Assessment of PK parameter: Partial area under the serum concentration time curve (AUC) [VCDI: Up to approximately 42 weeks, VRDI: Up to approximately 48 weeks]
Assessment of PK parameter: Maximum observed concentration (Cmax) [VCDI: Up to approximately 42 weeks, VRDI: Up to approximately 48 weeks]
Levels of human antidrug antibodies (ADA) [VCDI: Up to approximately 42 weeks, VRDI: Up to approximately 48 weeks]
Duration of response - time [VCDI and VRDI: Until treatment discontinuation by the last patient]
Progression-free survival for VCDI [VCDI: 30 months after LPI]
Progression-free survival for VRDI [VRDI Part A and Part B: 24 months after LPI]
MRD negativity rate [Up to 3 years of treatment (induction and maintenance phase) in VRDI part A and part B cohorts]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Newly diagnosed patients with measurable multiple myeloma defined as at least one of the following:

Serum M protein ≥1 g/dL (≥10 g/L).
Urine M protein ≥200 mg/24 hours.
Serum free light chain (sFLC) assay: involved free light chain assay ≥10 mg/dL (≥100 mg/L) and an abnormal sFLC ratio (<0.26 or >1.65).

Patients with ultra-high risk smoldering multiple myeloma fulfilling the International Myeloma Working Group criteria are eligible.

Patient is not eligible for transplant.

Patient with no immediate intent for transplant as per investigator's decision are also eligible for VRDI Part B cohort only.

Exclusion criteria:

Eastern Cooperative Oncology Group performance status >2.

Poor bone marrow reserve.

Poor organ function.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Investigational Site Number 250002	Nantes Cedex 01	France	44093
2	Investigational Site Number 250003	Pierre Benite	France	69495
3	Investigational Site Number 250001	Toulouse Cedex 9	France	31059
4	Investigational Site Number 276003	Berlin	Germany	12200
5	Investigational Site Number 276002	Leipzig	Germany	04103
6	Investigational Site Number 380003	Milano	Italy	20132
7	Investigational Site Number 380002	Roma	Italy	00161
8	Investigational Site Number 380001	Torino	Italy	10126
9	Investigational Site Number 724003	Madrid	Spain	28041
10	Investigational Site Number 724001	Pamplona	Spain	31008
11	Investigational Site Number 724002	Salamanca	Spain	37007
12	Investigational Site Number 724004	Santander	Spain	39008