Clinical Trials /

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

NCT01084252

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Multiple Myeloma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: TED10893
  • SECONDARY ID: U1111-1116-5472
  • NCT ID: NCT01084252

Conditions

  • Hematological Malignancy

Interventions

DrugSynonymsArms
Isatuximab SAR650984ISA Arm
DexamethasoneISAdex arm
DexamethasoneISAdex arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
ISA ArmExperimentalPhase 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.
  • Isatuximab SAR650984
ISAdex armExperimentalPhase 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.
  • Isatuximab SAR650984
  • Dexamethasone
  • Dexamethasone

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicities (DLTs)
Time Frame:4 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Main PD Biomarker : CD38 receptor occupancy and receptor density
Time Frame:Up to end of treatment
Safety Issue:
Description:
Measure:Immune response : levels of human anti-human antibodies
Time Frame:Up to end of treatment + 60 days
Safety Issue:
Description:
Measure:Duration of Response
Time Frame:12 months from last patient in
Safety Issue:
Description:
Measure:Patient reported outcomes
Time Frame:Every 4 weeks up to end of treatment
Safety Issue:
Description:
Measure:Overall Survival
Time Frame:12 months from last patient in
Safety Issue:
Description:
Measure:Clinical Benefit Rate
Time Frame:12 months from last patient in
Safety Issue:
Description:
Measure:Progression Free Survival
Time Frame:12 months from last patient in
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Sanofi

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