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

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ClinicalTrials.gov Identifier: NCT01084252
Recruitment Status : Active, not recruiting
First Posted : March 10, 2010
Last Update Posted : October 7, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE March 9, 2010
First Posted Date  ICMJE March 10, 2010
Last Update Posted Date October 7, 2019
Actual Study Start Date  ICMJE May 11, 2010
Actual Primary Completion Date December 21, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2014)
  • Dose Limiting Toxicities (DLTs) [ Time Frame: 4 weeks ]
  • Overall Response Rate [ Time Frame: 4 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: March 9, 2010)
Dose Limiting Toxicities (DLTs) [ Time Frame: 4 weeks ]
Change History Complete list of historical versions of study NCT01084252 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2016)
  • 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  ICMJE
 (submitted: March 9, 2010)
  • 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: 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 Frame: end of treatment + 60 days - PK will be assessed at cycle 1, cycle 2 and at the end of treatment during the accelarated phase and cycle 1,2,3,4 and at the end of treatment during the basic phase ]
  • Main PD Biomarker : CD38 receptor occupancy [ Time Frame: every 4 weeks up to a maximum duration study duration of 36 months ]
  • Immune response : levels of human anti-human antibodies [ Time Frame: end of treatment + 60 days ]
  • Preliminary activity assessment with criteria depending on type of hematological malignancies [ Time Frame: every 4 weeks, up to end of treatment + 30days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1/2 Dose Escalation and Efficacy Study of Anti-CD38 Monoclonal Antibody in Patients With Selected CD38+ Hematological Malignancies
Official Title  ICMJE A 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hematological Malignancy
Intervention  ICMJE
  • Drug: Isatuximab SAR650984

    Pharmaceutical form: solution for infusion

    Route of administration: intravenous

  • Drug: Dexamethasone

    Pharmaceutical form: solution for infusion

    Route of administration: intravenous

  • Drug: Dexamethasone

    Pharmaceutical form: tablet

    Route of administration: oral

Study Arms  ICMJE
  • 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.

    Intervention: 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.
    Interventions:
    • Drug: Isatuximab SAR650984
    • Drug: Dexamethasone
    • Drug: Dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 23, 2016)
341
Original Estimated Enrollment  ICMJE
 (submitted: March 9, 2010)
60
Estimated Study Completion Date  ICMJE December 2020
Actual Primary Completion Date December 21, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Belgium,   Brazil,   Chile,   Finland,   France,   Greece,   Israel,   Italy,   Mexico,   Peru,   Russian Federation,   Spain,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries Austria
 
Administrative Information
NCT Number  ICMJE NCT01084252
Other Study ID Numbers  ICMJE TED10893
U1111-1116-5472 ( Other Identifier: UTN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP