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

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

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.
• Participant-reported changes in health-related quality of life, symptoms of multiple myeloma and generic health status.
• Pharmacokinetic profile of Isatuximab.
• Immunogenicity of Isatuximab.
• Investigate the relationship between CD38 receptor density and CD38 receptor occupancy (Stage 1 only) on multiple myeloma cells and parameters of clinical response.

The Phase 1 study duration for an individual participant included 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. Participants were 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 participant included a screening period for inclusion of up to 3 weeks, then a treatment period and a follow up period. Treatment was continued until disease progression, unacceptable adverse reactions or other reasons for discontinuation. Participants were followed every 3 months following the last use of study drug until death or study cutoff, whichever came first.

Inclusion criteria:

Phase 1:

• For dose escalation cohorts, participants with confirmed selected CD38+ hematological malignancies as specified below who had progressed on after standard therapy or for whom there was no effective standard therapy (refractory/relapsed participants). B-cell Non-Hodgkin-lymphoma/leukemia (NHL) participants with at least 1 measurable lesion. Multiple myeloma (MM) participants with measurable M-protein serum and/or 24-hour urine. Acute myeloid leukemia (AML) participants, all types except M3 based on French-American-British (FAB) classification. Acute Lymphoblastic Leukemia (B-cell ALL) participants. Chronic lymphocytic leukemia (CLL) participants.
• For expansion cohorts, participants 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 had progressed on or after standard therapy that included an Immunomodulatory drug (IMiD) and a proteasome inhibitor and who met the protocol defined criteria for standard risk or high risk.

Phase 2:

• Participants had 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).
• Participants who received at least three prior lines of therapy for MM and had treatment with an IMiD (for >=2 cycles or >=2 months of treatment) and a proteasome inhibitor (PI) (for >=2 cycles or >=2 months of treatment) OR participants whose disease was double refractory to an IMiD and a PI. For participants who had received more than 1 type of IMiD and PI, their disease must be refractory to the most recent one.
• Participants who had achieved a minimal response or better to at least one prior line of therapy.
• Participants who had received an alkylating agent (>=2 cycles or >=2 months) either alone or in combination with other MM treatments.
• Stage 2 only: Participants who had 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 was not amenable to pre-medication with steroids and H2 blockers
• Any serious active disease (including clinically significant infection that was chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, interfered 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:

• Participants with multiple myeloma immunoglobulin M (IgM) subtype
• Previous treatment with any anti-CD38 therapy
• Participants with concurrent plasma cell leukemia
• Participants with known or suspected amyloidosis
• Karnofsky performance status <60 (stage 1)/Eastern Cooperative Oncology Group (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 was not amenable to pre-medication with steroids and H2 blockers
• Any serious active disease (including clinically significant infection that was chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, interfered 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 impaired the ability to participate in the study or the interpretation of its results

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