Phase 1/2 Dose Escalation and Efficacy Study of Anti-CD38 Monoclonal Antibody in Patients With Selected CD38+ Hematological Malignancies

ID: NCT01084252
Status: Recruiting
Phase: Phase 1/Phase 2
Start Date: May 11, 2010
First Submitted: March 09, 2010
Last Updated: February 22, 2018
Results: N/A
Organization: Sanofi
Sponsors & Collaborators: Sanofi
Location: Argentina, Belgium, Brazil, Chile, Finland, France, Greece, Israel, Italy, Mexico, Peru, Russian Federation, Spain, Turkey, Ukraine, United Kingdom, United States
Conditions: Hematological Malignancy
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Study Description

Brief Summary

Primary Objective:

Phase 1:

To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).

Phase 2 (stage 1):

To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.

Phase 2 (stage 2):

To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm).

Secondary Objectives:

Phase 1:

- To characterize the global safety profile including cumulative toxicities.

- To evaluate the pharmacokinetic (PK) profile of Isatuximab in the proposed dosing schedule(s).

- To assess the pharmacodynamics (PD), immune response, and preliminary disease response.

Phase 2 (stage 1): to evaluate the following objectives for Isatuximab as single agent:

- Safety

- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Phase 2 (stage 2): to evaluate the following objectives in each arm (ISA and ISAdex):

- Safety

- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Detailed Description

The Phase 1 study duration for an individual patient will include a screening period for inclusion of up to 2 weeks, treatment with Isatuximab QW (every week) or Q2W (every 2 weeks) unless discontinued earlier due to safety or disease progression. Patients will be followed for a minimum of 30 days following the last use of study drug or more than 30 days in case of unresolved toxicity, or up to initiation of another anticancer treatment.

The Phase 2 study duration for an individual patient will include a screening period for inclusion of up to 3 weeks, then a treatment period and a follow up period. Treatment will continue until disease progression, unacceptable adverse reactions or other reasons for discontinuation. Patients will be followed every 3 months following the last use of study drug until death or study cutoff whichever comes first.
Condition or disease Intervention/treatment Phase

Hematological Malignancy

Drug: Isatuximab SAR650984
Other Names
Drug: Dexamethasone
Other Names
Drug: Dexamethasone
Other Names
Phase 1/Phase 2

Tracking Information

First Submitted DateMarch 09, 2010
Last Update Posted DateFebruary 22, 2018
Start DateMay 11, 2010
Anticipated Completion DateFebruary 13, 2019
Primary Completion DateFebruary 13, 2019
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Overall Response Rate [Time Frame: 4 months]

  • Dose Limiting Toxicities (DLTs) [Time Frame: 4 weeks]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Safety as assessed from adverse events reporting, laboratory tests, vital signs according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.0 grade scaling [Time Frame: Up to end of treatment + 30 days, up to a maximum study duration of 36 months]

  • Main PK parameters : Partial area under the serum concentration time curve (AUC), maximum observed concentration (Cmax), Time to reach Cmax (tmax) [Time Frame: Up to end of treatment + 60 days]

  • Main PD Biomarker : CD38 receptor occupancy and receptor density [Time Frame: Up to end of treatment]

  • Immune response : levels of human anti-human antibodies [Time Frame: Up to end of treatment + 60 days]

  • Duration of Response [Time Frame: 12 months from last patient in]

  • Patient reported outcomes [Time Frame: Every 4 weeks up to end of treatment]

  • Overall Survival [Time Frame: 12 months from last patient in]

  • Clinical Benefit Rate [Time Frame: 12 months from last patient in]

  • Progression Free Survival [Time Frame: 12 months from last patient in]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitlePhase 1/2 Dose Escalation and Efficacy Study of Anti-CD38 Monoclonal Antibody in Patients With Selected CD38+ Hematological Malignancies
Official TitleA Phase I/2 Dose Escalation Safety, Pharmacokinetic and Efficacy Study of Multiple Intravenous Administrations of a Humanized Monoclonal Antibody (SAR650984) Against CD38 in Patients With Selected CD38+ Hematological Malignancies
Brief Summary

Primary Objective:

Phase 1:

To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).

Phase 2 (stage 1):

To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.

Phase 2 (stage 2):

To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm).

Secondary Objectives:

Phase 1:

- To characterize the global safety profile including cumulative toxicities.

- To evaluate the pharmacokinetic (PK) profile of Isatuximab in the proposed dosing schedule(s).

- To assess the pharmacodynamics (PD), immune response, and preliminary disease response.

Phase 2 (stage 1): to evaluate the following objectives for Isatuximab as single agent:

- Safety

- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Phase 2 (stage 2): to evaluate the following objectives in each arm (ISA and ISAdex):

- Safety

- Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Detailed Description

The Phase 1 study duration for an individual patient will include a screening period for inclusion of up to 2 weeks, treatment with Isatuximab QW (every week) or Q2W (every 2 weeks) unless discontinued earlier due to safety or disease progression. Patients will be followed for a minimum of 30 days following the last use of study drug or more than 30 days in case of unresolved toxicity, or up to initiation of another anticancer treatment.

The Phase 2 study duration for an individual patient will include a screening period for inclusion of up to 3 weeks, then a treatment period and a follow up period. Treatment will continue until disease progression, unacceptable adverse reactions or other reasons for discontinuation. Patients will be followed every 3 months following the last use of study drug until death or study cutoff whichever comes first.

Study TypeInterventional
Study PhasePhase 1/Phase 2
Estimated Enrollment
341
Allocation
Randomized
Interventional Model
Parallel Assignment
Masking
None (Open Label)
Primary Purpose
Treatment
Conditions
Hematological Malignancy
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion Route of administration: intravenous

Other Names
Drug: Dexamethasone

Pharmaceutical form: solution for infusion Route of administration: intravenous

Other Names
Drug: Dexamethasone

Pharmaceutical form: tablet Route of administration: oral

Other Names
Study Groups/Cohorts
ISA Arm
Phase 1: Accelerated dose escalation phase (1 patient/cohort), two administrations every two weeks (Q2W) per dose cohort. Followed by basic dose escalation phase evaluating Isatuximab administration weekly (QW) and Q2W with 3-6 patients/cohort treated until disease progression or unsatisfactory safety. Cohort 1-10 will enroll patients with CD38+ hematological malignancies and cohort 11 onwards will enroll patients with multiple myeloma only. Two expansion cohorts will evaluate the recommended Phase 2 dose (RP2D) in standard risk and high risk multiple myeloma patients. Phase 2: Stage 1 will further evaluate four randomized arms. Arm 1: Dose 1 Q2W, Arm 2: Dose 2 Q2W, Arm 3: Dose 2 Q2W for 2 cycles then every 4 weeks (Q4W), Arm 4: Dose 3 QW for 1 cycle then Q2W. Stage 2 will use the dose and schedule determined from stage 1 ie Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks.

ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.

Study Arms
Experimental ISA Arm
Phase 1: Accelerated dose escalation phase (1 patient/cohort), two administrations every two weeks (Q2W) per dose cohort. Followed by basic dose escalation phase evaluating Isatuximab administration weekly (QW) and Q2W with 3-6 patients/cohort treated until disease progression or unsatisfactory safety. Cohort 1-10 will enroll patients with CD38+ hematological malignancies and cohort 11 onwards will enroll patients with multiple myeloma only. Two expansion cohorts will evaluate the recommended Phase 2 dose (RP2D) in standard risk and high risk multiple myeloma patients. Phase 2: Stage 1 will further evaluate four randomized arms. Arm 1: Dose 1 Q2W, Arm 2: Dose 2 Q2W, Arm 3: Dose 2 Q2W for 2 cycles then every 4 weeks (Q4W), Arm 4: Dose 3 QW for 1 cycle then Q2W. Stage 2 will use the dose and schedule determined from stage 1 ie Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks.
Drug : Isatuximab SAR650984
Pharmaceutical form: solution for infusion Route of administration: intravenous

Experimental ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.
Drug : Isatuximab SAR650984
Pharmaceutical form: solution for infusion Route of administration: intravenous

Experimental ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.
Drug : Dexamethasone
Pharmaceutical form: solution for infusion Route of administration: intravenous

Experimental ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.
Drug : Dexamethasone
Pharmaceutical form: tablet Route of administration: oral

Arm Intervention/Treatment
Experimental ISA Arm
Phase 1: Accelerated dose escalation phase (1 patient/cohort), two administrations every two weeks (Q2W) per dose cohort. Followed by basic dose escalation phase evaluating Isatuximab administration weekly (QW) and Q2W with 3-6 patients/cohort treated until disease progression or unsatisfactory safety. Cohort 1-10 will enroll patients with CD38+ hematological malignancies and cohort 11 onwards will enroll patients with multiple myeloma only. Two expansion cohorts will evaluate the recommended Phase 2 dose (RP2D) in standard risk and high risk multiple myeloma patients. Phase 2: Stage 1 will further evaluate four randomized arms. Arm 1: Dose 1 Q2W, Arm 2: Dose 2 Q2W, Arm 3: Dose 2 Q2W for 2 cycles then every 4 weeks (Q4W), Arm 4: Dose 3 QW for 1 cycle then Q2W. Stage 2 will use the dose and schedule determined from stage 1 ie Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks.
Drug : Isatuximab SAR650984
Experimental ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.
Drug : Isatuximab SAR650984
Experimental ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.
Drug : Dexamethasone
Experimental ISAdex arm
Phase 2 (stage 2) : Isatuximab Dose 3 every week for 4 infusions followed by Dose 3 every 2 weeks and dexamethasone Dose 4 IV or per os (Dose 5 for ≥75y.o patients) on days 1, 8, 15, 22 of each cycle.
Drug : Dexamethasone

Recruitment Information

Recruitment Status:Recruiting
Enrollment341
Completion DateFebruary 13, 2019
Eligibility Criteria: Inclusion criteria:
Phase 1:
- For dose escalation cohorts, patients with confirmed selected CD38+ hematological malignancies as specified below who have progressed on after standard therapy or for whom there is no effective standard therapy (refractory/relapsed patients). B-cell Non-Hodgkin-lymphoma/leukemia (NHL) patients having at least 1 measurable lesion. Multiple myeloma (MM) patients with measurable M-protein serum and/or 24-hour urine. Acute myeloid leukemia (AML) patients, all types except M3 based on French-American-British (FAB) classification. Acute Lymphoblastic Leukemia (B-cell ALL) patients. Chronic lymphocytic leukemia (CLL) patients.
- For expansion cohorts, patients with relapsed/refractory MM with measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg (24-hr urine)) or elevated serum free light chains (FLC) >10 mg/dL with abnormal FLC ratio) who have progressed on or after standard therapy that includes an iMiD and a proteasome inhibitor and who meet the protocol defined criteria for standard risk or high risk.
Phase 2:
- Patients must have a known diagnosis of multiple myeloma with evidence of measurable disease, and have evidence of disease progression based on International Myeloma Working Group (IMWG) criteria: Serum M-protein ≥1 g/dL, or urine M-protein ≥200 mg/24 hours or in the absence of measurable m-protein, serum FLC ≥10 mg/dL, and abnormal serum immunoglobulin kappa lambda FLC ratio (<0.26 or >1.65).
- Patients must have received at least three prior lines of therapy for MM and must include treatment with an Immunomodulatory drug (IMiD) (for ≥2 cycles or ≥2 months of treatment) and a proteasome inhibitor (PI) (for ≥2 cycles or ≥2 months of treatment) OR patients whose disease is double refractory to an IMiD and a PI. For patients who have received more than 1 type of IMiD and PI, their disease must be refractory to the most recent one.
- Patients must have achieved a minimal response or better to at least one prior line of therapy.
- Patients must have received an alkylating agent (≥2 cycles or ≥2 months) either alone or in combination with other MM treatments.
- Stage 2 only: Patients must have evidence of disease progression on or after the most recent prior regimen based on IMWG criteria.
Exclusion criteria:
Phase 1:
- Karnofsky performance status <60
- Poor bone marrow reserve
- Poor organ function
- Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that is not amenable to pre-medication with steroids and H2 blockers
- Any serious active disease (including clinically significant infection that is chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, could interfere with the safety, the compliance with the study or with the interpretation of the results
- Any severe underlying medical conditions including presence of laboratory abnormalities, which could impair the ability to participate in the study or the interpretation of its results
Phase 2:
- Patients with multiple myeloma immunoglobulin M (IgM) subtype
- Previous treatment with any anti-CD38 therapy
- Patients with concurrent plasma cell leukemia
- Patients with known or suspected amyloidosis
- Karnofsky performance status <60 (stage 1)/ECOG Performance status >2 (stage 2).
- Poor bone marrow reserve
- Poor organ function
- Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that is not amenable to pre-medication with steroids and H2 blockers
- Any serious active disease (including clinically significant infection that is chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, could interfere with the safety, the compliance with the study or with the interpretation of the results
- Any severe underlying medical conditions including presence of laboratory abnormalities, which could impair the ability to participate in the study or the interpretation of its results
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
Argentina
Belgium
Brazil
Chile
Finland
France
Greece
Israel
Italy
Mexico
Peru
Russian Federation
Spain
Turkey
Ukraine
United Kingdom
United States
Austria

Administrative Information

NCT Number:NCT01084252
Other Study ID Numbers
TED10893
U1111-1116-5472
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Sanofi
Collaborators
Not Available
Investigators
Study Director
Clinical Sciences & Operations
Sanofi