Clinical trial NCT02513186: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Plasma Cell Myeloma
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2015-07-31
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 or no intent for immediate 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.

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.

Eligibility criteria: 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 intent for immediate 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.

Primary outcomes:
measure: Assessment of dose-limiting toxicities (DLTs) in VCDI cohort
timeFrame: Up to 6 weeks per treated patient
measure: Overall response rate (VCDI)
timeFrame: Up to 34 weeks of treatment (induction phase)
measure: Complete response rate (VCDI)
timeFrame: Up to 34 weeks of treatment (induction phase)
measure: Complete response rate (VRDI)
timeFrame: Up to 104 weeks of treatment (induction and maintenance phase) in VRDI part A and part B cohorts
Secondary outcomes:
measure: 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
timeFrame: VCDI: Up to approximately 106 weeks, VRDI Part A and Part B: Up to approximately 104 weeks
measure: Overall response rate (VRDI)
timeFrame: Up to 104 weeks of treatment (induction and maintenance phase) in VRDI part A and part B cohorts
measure: Infusion duration
timeFrame: VRDI Part B: Up to 104 weeks of treatment
measure: Assessment of PK parameter: Partial area under the serum concentration time curve (AUC)
timeFrame: VCDI: Up to approximately 42 weeks, VRDI: Up to approximately 48 weeks
measure: Assessment of PK parameter: Maximum observed concentration (Cmax)
timeFrame: VCDI: Up to approximately 42 weeks, VRDI: Up to approximately 48 weeks
measure: Levels of human antidrug antibodies (ADA)
timeFrame: VCDI: Up to approximately 42 weeks, VRDI: Up to approximately 48 weeks
measure: Duration of response - time
timeFrame: VCDI and VRDI: Until treatment discontinuation by the last patient
measure: Progression-free survival for VCDI
timeFrame: VCDI: 30 months after LPI
measure: Progression-free survival for VRDI
timeFrame: VRDI Part A and Part B: 24 months after LPI
measure: MRD negativity rate
timeFrame: Up to 3 years of treatment (induction and maintenance phase) in VRDI part A and part B cohorts
Other outcomes:
Locations:
city: Nantes Cedex 01
country: France
facility: Investigational Site Number : 250002
city: Pierre Benite
country: France
facility: Investigational Site Number : 250003
city: TOULOUSE Cedex 9
country: France
facility: Investigational Site Number : 250001
city: Berlin
country: Germany
facility: Investigational Site Number : 276003
city: Leipzig
country: Germany
facility: Investigational Site Number : 276002
city: Milano
country: Italy
facility: Investigational Site Number : 380003
city: Roma
country: Italy
facility: Investigational Site Number : 380002
city: Torino
country: Italy
facility: Investigational Site Number : 380001
city: Santander
country: Spain
facility: Investigational Site Number : 724004
state: Cantabria
city: Pamplona
country: Spain
facility: Investigational Site Number : 724001
state: Navarra
city: Madrid
country: Spain
facility: Investigational Site Number : 724003
city: Salamanca
country: Spain
facility: Investigational Site Number : 724002
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: