Clinical trial NCT02812706: Isatuximab Single Agent Study in Japanese Relapsed AND Refractory Multiple Myeloma Patients
Official title: A Phase I/II Study of Isatuximab (Anti-CD38 mAb) Administered as a Single Agent in Japanese Patients With Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2016-06-24
Enrollment: 36
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Primary Objectives:

* Phase I: To evaluate safety and tolerability of isatuximab in Japanese participants with relapsed and refractory multiple myeloma.
* Phase II: To evaluate efficacy of isatuximab at recommended dose and to further evaluate the overall response rate (ORR) of isatuximab in Japanese participants with relapsed and refractory multiple myeloma.

Secondary Objectives:

* To evaluate the safety including immunogenicity of isatuximab. The severity, frequency and incidence of all adverse events were assessed.
* To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing schedule.
* To assess the efficacy using International Myeloma Working Group (IMWG) uniform response criteria.
* To assess the relationship between Baseline cluster of differentiation 38 (CD38) receptor density on multiple myeloma cells and efficacy.

Detailed description: The study duration for an individual participant included a screening period for inclusion of up to 21 days, the treatment period consisting of 28-day cycles and a follow-up period. Treatment with isatuximab might continue until disease progression, unacceptable adverse event, or other reason for discontinuation.

Eligibility criteria: Inclusion criteria:

* Males or females, age 20 years or older.
* Participants had a known diagnosis of symptomatic multiple myeloma.
* Participants had received at least 3 prior lines of therapies OR participants whose disease was double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI).
* Participants had been responsive (i.e., minimal response \[MR\] or better) to at least one prior line of therapy.
* Refractory to the most recently received IMiD or PI included therapy.
* Participants with measurable disease defined as at least one of the following:
* Immunoglobulin G (IgG) Type: Serum M-protein \>=1 gram per deciliter (g/dL) (\>=10 g/L);
* Immunoglobulin A (IgA) and D Type: Serum M-protein, quantification should be performed;
* Urine M-protein ≥200 mg/24 hours.
* Participants with a Eastern Cooperative Oncology Group (ECOG) performance status \<=2.

Exclusion criteria:

* Participants treated with any anti-CD38 agent.
* Diagnosed or treated for another malignancy within 5 years prior to enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in-situ malignancy, or low-risk prostate cancer after curative therapy.
* Prior anticancer therapy (chemotherapy, targeted agents, immunotherapy) within 21 days prior to the first drug infusion unless otherwise specified below:
* Alkylating agents (e.g., Melphalan) within 28 days prior to the first dose of study treatment.
* Steroids treatment (e.g., prednisone greater than (\>)10 mg/day orally or equivalent except patients being treated for adrenal insufficiency/replacement therapy or treated for inhalation corticosteroids) within 14 days prior to the first dose of study treatment.
* Participated in another clinical trial within 30 days prior to the first dose of study treatment.
* Participants treated with systemic radiation therapy within 4 weeks prior to the first dose of study treatment OR Localized radiation therapy within 1 week prior to the first dose of study treatment.
* Major surgical procedure within 4 weeks prior to the first dose of study treatment.
* Any toxicity Grade \>=2 (excluding alopecia, neutropenia or neuropathy) related to any prior anti-cancer therapy according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
* Neuropathy Grade \>=3 or painful peripheral neuropathy Grade \>=2.
* History of significant cardiovascular disease unless the disease within the past 6 months was well-controlled.
* Previously received an allogenic stem cell transplant.
* Diagnosed Crow-Fukase (POEMS) syndrome OR plasma cell leukemia.
* Participants with known or suspected amyloidosis.
* Participants with Waldenstrom's macroglobulinemia OR Multiple myeloma IgM subtype.
* Participants with active infection.
* Known human immunodeficiency virus (HIV) or active hepatitis B or C viral infection.
* Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation.
* 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.
* Hypersensitivity or history of intolerance to boron or mannitol, sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to pre-medication with steroids and H2 blockers or would prohibit further treatment with these agents.

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

Primary outcomes:
measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (28 days)
measure: Phase 2: Percentage of Participants With Overall Response (OR)
timeFrame: From the date of the first response until the primary analysis data cut-off date of 31 July 2018 (median duration of follow-up was 24.14 weeks)
Secondary outcomes:
measure: Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug up to 30 days after the last dose of study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)
measure: Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug up to 30 days after the last dose of study drug administration (maximum duration of exposure: up to 248 weeks)
measure: Phase 1: Percentage of Participants With Overall Response (OR)
timeFrame: From the date of the first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)
measure: Phase 1: Duration of Response (DOR)
timeFrame: From the date of the first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)
measure: Phase 2: Percentage of Participants With Clinical Benefit (CB)
timeFrame: From date of first study treatment administration until first documented response, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
measure: Phase 2: Overall Survival (OS)
timeFrame: From date of first study treatment administration to the date of death due to any cause (maximum duration of exposure: up to 248 weeks)
measure: Phase 2: Progression Free Survival (PFS)
timeFrame: From date of first study treatment administration until disease progression or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
measure: Phase 2: Duration of Response (DOR)
timeFrame: From the date of first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
measure: Phase 2: Time to Progression (TTP)
timeFrame: From date of first study treatment administration until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)
measure: Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab
timeFrame: End of infusion on Day 1 of Cycle 1
measure: Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab
timeFrame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), end of infusion (EOI) and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)
measure: Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab
timeFrame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), EOI and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)
measure: Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab
timeFrame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), EOI and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)
measure: Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab
timeFrame: Pre-infusion on Cycle 1 Day 8 (C1 D8), C1 D15, C1 D22, C2 D1, C2 D15, C3 D1, C3 D15, C4 D1, C4 D15, C5 D1, C5 D15, C6 D1, C6 D15, C7 D1, C7 D15, C8 D1, C8 D15, C9 D1, C9 D15, C10 D1, C10 D15, C11 D1
measure: Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab
timeFrame: Multiple timepoints from Cycle 1 to Cycle 10
measure: Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab
timeFrame: Multiple timepoints from Cycle 1 to Cycle 10
measure: Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab
timeFrame: Pre-infusion on C1 D8, C1 D15, C1 D22, C2 D1, C2 D15, C3 D1, C3 D15, C4 D1, C4 D15, C5 D1, C5 D15, C6 D1, C6 D15, C7 D1, C7 D15, C8 D1, C8 D15, C9 D1, C9 D15, C10 D1, C10 D15
measure: Phase 1 and 2: CD38 Receptor Density at Baseline
timeFrame: At Baseline (Day 1)
measure: Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab
timeFrame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1, and 137 weeks for Cohort 2)
measure: Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab
timeFrame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 248 weeks)
Other outcomes:
Locations:
city: Nagoya-shi
country: Japan
facility: Investigational Site Number :392001
state: Aichi
city: Shibukawa-shi
country: Japan
facility: Investigational Site Number :392005
state: Gunma
city: Hiroshima-shi
country: Japan
facility: Investigational Site Number :392010
state: Hiroshima
city: Kanazawa-shi
country: Japan
facility: Investigational Site Number :392015
state: Ishikawa
city: Kyoto-shi
country: Japan
facility: Investigational Site Number :392016
state: Kyoto
city: Suwa-shi
country: Japan
facility: Investigational Site Number :392008
state: Nagano
city: Okayama-shi
country: Japan
facility: Investigational Site Number :392003
state: Okayama
city: Osaka-shi
country: Japan
facility: Investigational Site Number :392009
state: Osaka
city: Suita-shi
country: Japan
facility: Investigational Site Number :392013
state: Osaka
city: Sunto-gun
country: Japan
facility: Investigational Site Number :392017
state: Shizuoka
city: Chuo-ku
country: Japan
facility: Investigational Site Number :392012
state: Tokyo
city: Shibuya-ku
country: Japan
facility: Investigational Site Number :392002
state: Tokyo
city: Yamagata-shi
country: Japan
facility: Investigational Site Number :392011
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Sunami K, Fuchida SI, Suzuki K, Ri M, Matsumoto M, Shimazaki C, Asaoku H, Shibayama H, Ishizawa K, Takamatsu H, Ikeda T, Maruyama D, Imada K, Uchiyama M, Kiguchi T, Iyama S, Murakami H, Onishi R, Tada K, Iida S. Anti-CD38 antibody isatuximab monotherapy for Japanese individuals with relapsed/refractory multiple myeloma: An update of the phase 1/2 ISLANDs study. Hematol Oncol. 2023 Aug;41(3):442-452. doi: 10.1002/hon.3105. Epub 2022 Dec 15.
citation: Sunami K, Suzuki K, Ri M, Matsumoto M, Shimazaki C, Asaoku H, Shibayama H, Ishizawa K, Takamatsu H, Ikeda T, Maruyama D, Kaneko H, Uchiyama M, Kiguchi T, Iyama S, Murakami H, Takahashi K, Tada K, Mace S, Guillemin-Paveau H, Iida S. Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study. Cancer Sci. 2020 Dec;111(12):4526-4539. doi: 10.1111/cas.14657. Epub 2020 Oct 15.