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Completed

NCT Number: NCT02812706

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

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.

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Key information

Conditions

Multiple Myeloma Blood Protein Disorders Cardiovascular Diseases Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders Hemostatic Disorders Immune System Diseases Immunoproliferative Disorders Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type Neoplasms, Plasma Cell Paraproteinemias Vascular Diseases

Age range

20 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Investigational Site Number :392001, Nagoya, Aichi-ken, Japan

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

isatuximab SAR650984

Drug

Pharmaceutical form: solution Route of administration: intravenous

Other names: Sarclisa

Primary outcomes

  1. Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

    Time frame: Cycle 1 (28 days)

    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.

  2. Phase 2: Percentage of Participants With Overall Response (OR)

    Time frame: 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)

    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.

Secondary outcomes

  1. Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

    Time frame: 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)

    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).

  2. Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

    Time frame: 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)

    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).

  3. Phase 1: Percentage of Participants With Overall Response (OR)

    Time frame: 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)

    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.

  4. Phase 1: Duration of Response (DOR)

    Time frame: 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)

    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.

  5. Phase 2: Percentage of Participants With Clinical Benefit (CB)

    Time frame: 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)

    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.

  6. Phase 2: Overall Survival (OS)

    Time frame: From date of first study treatment administration to the date of death due to any cause (maximum duration of exposure: up to 248 weeks)

    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.

  7. Phase 2: Progression Free Survival (PFS)

    Time frame: 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)

    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.

  8. Phase 2: Duration of Response (DOR)

    Time frame: 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)

    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.

  9. Phase 2: Time to Progression (TTP)

    Time frame: 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)

    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.

  10. Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab

    Time frame: End of infusion on Day 1 of Cycle 1

    Ceoi is the plasma concentration observed at the end of intravenous infusion.

  11. Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab

    Time frame: 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)

    Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis.

  12. Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab

    Time frame: 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)

    Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion.

  13. Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab

    Time frame: 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)

    AUC was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval.

  14. Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab

    Time frame: 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

    Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.

  15. Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab

    Time frame: Multiple timepoints from Cycle 1 to Cycle 10

    Cmax was predicted using population pharmacokinetic model.

  16. Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab

    Time frame: Multiple timepoints from Cycle 1 to Cycle 10

    AUC was predicted using population pharmacokinetic model.

  17. Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab

    Time frame: 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

    Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.

  18. Phase 1 and 2: CD38 Receptor Density at Baseline

    Time frame: At Baseline (Day 1)

    CD38 receptor density assessed from bone marrow aspirates for responder and non-responders' participants was reported.

  19. Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab

    Time frame: 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)

    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.

  20. Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab

    Time frame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 248 weeks)

    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.

Sponsors and collaborators

Lead sponsor

Sanofi

Industry

Registry information

Official study 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

Acronym: Islands

Important dates

Study start
2016
Primary completion
2018
Study completion
2022
First posted
Jun 24, 2016
Registry last updated
Apr 1, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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