Isatuximab Single Agent Study in Japanese Relapsed AND Refractory Multiple Myeloma Patients

Multiple Myeloma Clinical Trial

— Islands  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02812706
• Other study ID #: TED14095
• Secondary ID: U1111-1175-0679
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 5, 2016
• Est. completion date: September 28, 2022

Study information

• Verified date: September 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: September 28, 2022
• Est. primary completion date: July 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Isatuximab SAR650984
Pharmaceutical form: solution Route of administration: intravenous

Locations

Country	Name	City	State
Japan	Investigational Site Number :392012	Chuo-ku	Tokyo
Japan	Investigational Site Number :392010	Hiroshima-shi	Hiroshima
Japan	Investigational Site Number :392015	Kanazawa-shi	Ishikawa
Japan	Investigational Site Number :392016	Kyoto-shi	Kyoto
Japan	Investigational Site Number :392001	Nagoya-shi	Aichi
Japan	Investigational Site Number :392003	Okayama-shi	Okayama
Japan	Investigational Site Number :392009	Osaka-shi	Osaka
Japan	Investigational Site Number :392005	Shibukawa-shi	Gunma
Japan	Investigational Site Number :392002	Shibuya-ku	Tokyo
Japan	Investigational Site Number :392013	Suita-shi	Osaka
Japan	Investigational Site Number :392017	Sunto-gun	Shizuoka
Japan	Investigational Site Number :392008	Suwa-shi	Nagano
Japan	Investigational Site Number :392011	Yamagata-shi

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Country where clinical trial is conducted

Japan, 

References & Publications (2)

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 f — View 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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)	DLTs: AEs occurring during 1st treatment cycle, assessed per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03. DLTs included: Hematologic DLTs: Grade(G) 4 neutropenia(N) lasting greater than or equal to (>=) 5 days; G3 to G4 N with fever or microbiologically or radiographically documented infection; G4 thrombocytopenia lasting for >=5 days; thrombocytopenia, treatment delay greater than (>)14 days due to hematologic toxicity. Non-hematologic DLTs: G>=3 non-hematological AE, excluding G3 fatigue, G 3 to 4 electrolyte abnormalities, G3 nausea/vomiting/diarrhea if responsive to optimal medical management within 48 hours or allergic reaction/ hypersensitivity attributed to isatuximab; AE that required treatment delay for >14 days. Any other toxicity deemed by Investigator or sponsor to be dose-limiting, regardless of the grade, was also considered DLT.	Cycle 1 (28 days)
Primary	Phase 2: Percentage of Participants With Overall Response (OR)	Percentage of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) assessed by International Myeloma Working Group (IMWG) uniform response criteria. sCR: CR as defined plus normal FLC ratio & absence of clonal cells in bone marrow. CR: negative immunofixation on serum & urine; disappearance of any soft tissue plasmacytomas; <5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum & urine M-protein detectable by immunofixation; >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h; >90% decrease in difference between involved & uninvolved FLC levels required. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M protein by >=90%/<200 mg/24 h; if serum & urine M-protein unmeasurable:>=50% decrease in difference between involved & uninvolved FLC; if serum & urine M-protein not measurable:>=50% reduction in plasma cells required, in place of M-protein.	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	Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).	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)
Secondary	Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs are defined as AEs that develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).	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)
Secondary	Phase 1: Percentage of Participants With Overall Response (OR)	Percentage of participants with sCR, CR, VGPR, and PR assessed by IMWG uniform response criteria. sCR: CR as defined plus normal FLC ratio & absence of clonal cells in bone marrow. CR: negative immunofixation on serum & urine; disappearance of any soft tissue plasmacytomas; <5 percentage (%) plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum & urine M-protein detectable by immunofixation; >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24 hour (h); >90% decrease in difference between involved & uninvolved FLC levels required. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M protein by >=90%/<200 mg/24 h; if serum & urine M-protein unmeasurable:>=50% decrease in difference between involved & uninvolved FLC; if serum & urine M-protein not measurable:>=50% reduction in plasma cells required, in place of M-protein.	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)
Secondary	Phase 1: Duration of Response (DOR)	DOR: time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): increase (inc.) of >=25% from lowest response value in any one of following: serum M-component (absolute inc.>=0.5 g/dL) and/or; urine M-component (absolute inc.>=200 mg/24h) and/or, in participants without measurable serum & urine M-protein: difference between involved & uninvolved FLC levels (absolute inc. >10 mg/dL); in participants without measurable serum & urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute % >=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.	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)
Secondary	Phase 2: Percentage of Participants With Clinical Benefit (CB)	CB defined as percentage of participants with sCR, CR, VGPR, PR or Minor/minimal response (MR) assessed by IMWG criteria. sCR: CR as defined plus normal FLC ratio & absence of clonal cells. CR: negative immunofixation on serum & urine; disappearance of any soft tissue plasmacytomas; <5% plasma cells in bone marrow; normal FLC ratio: 0.26-1.65. VGPR: serum & urine M-protein detectable by immunofixation; >=90% reduction in serum M-protein plus urine M-protein level <100 mg/24h; >90% decrease in difference between involved & uninvolved FLC levels required. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M protein by >=90%/<200 mg/24 h; if serum & urine M-protein unmeasurable:>=50% decrease in difference between involved & uninvolved FLC; if serum & urine M-protein not measurable:>=50% reduction in plasma cells required. MR: >=25% but <=49% reduction of serum M protein and reduction in 24h urine M protein by 50-89%; 25-49% reduction in size of soft tissue plasmacytomas.	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)
Secondary	Phase 2: Overall Survival (OS)	Overall survival was defined as the time interval (in months) from the date of first study treatment administration to death due to any cause. In the absence of the confirmation of death before the cut-off date, OS was censored at the last date the participant was known to be alive or at the study cut-off date, whichever was earlier. Analysis was performed by Kaplan-Meier method.	From date of first study treatment administration to the date of death due to any cause (maximum duration of exposure: up to 248 weeks)
Secondary	Phase 2: Progression Free Survival (PFS)	PFS was defined as the time interval (in months) from date of first study treatment administration until disease progression or death due to any cause, whichever comes first. In absence of PD or death, PFS was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of >=25% in any one of following: serum M-component absolute (abs.) inc. >=0.5 g/dL) and/or; urine M-component (abs. inc. >=200 mg/24h) and/or, in participants without measurable serum & urine M-protein, difference between involved & uninvolved FLC levels (abs. inc. >10 mg/dL); in participants without measurable serum & urine M-protein & without measurable disease by FLC levels: bone marrow plasma cell % (abs. % >=10%); definite development of new bone lesions or soft tissue plasmacytomas or definite inc. in size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia.	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)
Secondary	Phase 2: Duration of Response (DOR)	DOR was defined as time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria):inc. of >=25% from lowest response value in any one of following: serum M-component (absolute inc.>=0.5 g/dL) and/or; urine M-component (absolute inc.>=200 mg/24h) and/or, in participants without measurable serum & urine M-protein: difference between involved & uninvolved FLC levels (absolute inc.>10 mg/dL); in participants without measurable serum & urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% >=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.	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)
Secondary	Phase 2: Time to Progression (TTP)	TTP: time interval (in months) from date of first study treatment administration to date of first assessed disease progression. In absence of disease progression, TTP was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of >=25% from lowest response value in any one of following: serum M-component (absolute inc.>=0.5 g/dL) and/or; urine M-component (absolute inc.>=200 mg/24h) and/or, in participants without measurable serum & urine M-protein: difference between involved & uninvolved FLC levels (absolute inc.>10 mg/dL); in participants without measurable serum & urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% >=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.	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)
Secondary	Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab	Ceoi is the plasma concentration observed at the end of intravenous infusion.	End of infusion on Day 1 of Cycle 1
Secondary	Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab	Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis.	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)
Secondary	Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab	Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion.	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)
Secondary	Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab	AUC was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval.	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)
Secondary	Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab	Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.	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
Secondary	Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab	Cmax was predicted using population pharmacokinetic model.	Multiple timepoints from Cycle 1 to Cycle 10
Secondary	Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab	AUC was predicted using population pharmacokinetic model.	Multiple timepoints from Cycle 1 to Cycle 10
Secondary	Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab	Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.	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
Secondary	Phase 1 and 2: CD38 Receptor Density at Baseline	CD38 receptor density assessed from bone marrow aspirates for responder and non-responders' participants was reported.	At Baseline (Day 1)
Secondary	Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab	ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment & posttreatment samples of at least two titer steps, during the ADA on-study observation period.	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)
Secondary	Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab	ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment & posttreatment samples of at least two titer steps, during the ADA on-study observation period.	From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 248 weeks)