Phase 1/2 Dose Escalation and Efficacy Study of Anti-CD38 Monoclonal Antibody in Patients With Selected CD38+ Hematological Malignancies
- Conditions
- Hematological Malignancy
- Interventions
- Registration Number
- NCT01084252
- Lead Sponsor
- Sanofi
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 351
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1: Isatuximab 3mg/kg Q2W Isatuximab SAR650984 Participants with CD38+ HM, received Isatuximab 3 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 1:Isatuximab <=1 mg/kg Q2W Isatuximab SAR650984 Participants with CD38+ hematological malignancies (HM), received Isatuximab at any one of the dose less than or equal to (\<=) 1 milligram per kilogram (mg/kg) (i.e. either 0.0001 mg/kg or 0.001 mg/kg or 0.01 mg/kg or 0.03 mg/kg or 0.1 mg/kg or 0.3 mg/kg or 1 mg/kg) as intravenous (IV) infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal by participant, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 1: Isatuximab 5 mg/kg Q2W Isatuximab SAR650984 Participants with CD38+ HM, received Isatuximab 5 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase1:Isatuximab (CD38+HM and Standard Risk Multiple Myeloma) Isatuximab SAR650984 Participants with CD38+ HM along with participants with standard risk multiple myeloma were included this arm and, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 1:Isatuximab (CD38 + HM and High Risk Multiple Myeloma) Isatuximab SAR650984 Participants with CD38+ HM along with participants with high risk multiple myeloma, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 1: Isatuximab 10 mg/kg QW Isatuximab SAR650984 Participants with CD38+ HM, received Isatuximab 10 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 1: Isatuximab 20 mg/kg Q2W Isatuximab SAR650984 Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 1: Isatuximab 20 mg/kg QW Isatuximab SAR650984 Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). Phase 2 Stage 1a: Isatuximab 3 mg/kg Q2W Isatuximab SAR650984 Participants with multiple Myeloma received Isatuximab 3 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable adverse event (AE), disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). Phase 2 Stage 1a: Isatuximab 10 mg/kg Q2W Isatuximab SAR650984 Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). Phase2 Stage1a:Isatuximab 10mg/kg Q2W; Then Q4W Isatuximab SAR650984 Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion Q2W, i.e. on Day 1 and Day 15 of Cycle 1 and 2 (each cycle 28 days), then every 4 week (Q4W), i.e. on Day 1 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). Phase 2 Stage 1b: Isatuximab 20mg/kg QW and Then Q2W Isatuximab SAR650984 Participants with multiple Myeloma received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1, 8, 15 and 22 of Cycle 1 and 2 (each cycle 28 days), then Q2W, i.e. on Day 1 and Day 15 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 92 weeks). Phase 2 Stage 2: Isatuximab Alone Isatuximab SAR650984 Participants with relapsed or relapsed/refractory multiple myeloma (RRMM), received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks). Phase 2 Stage 2: Isatuximab + Dexamethasone Isatuximab SAR650984 Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than \[\<\] 75 years of age; 20 mg/day \[greater than or equal to \[\>=\] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks). Phase 2 Stage 2: Isatuximab + Dexamethasone Dexamethasone Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than \[\<\] 75 years of age; 20 mg/day \[greater than or equal to \[\>=\] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks).
- Primary Outcome Measures
Name Time Method Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) Day 1 of Cycle 1 up to Day 14 of Cycle 2 DLTs were assessed using the national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03. DLTs were defined as any Grade 3 or higher non-hematological toxicity (with the exception of allergic reaction/hypersensitivity), Grade 4 neutropenia and/or Grade 4 thrombocytopenia lasting longer than 5 days, attributed to isatuximab. Any other toxicity that the Investigator and the Sponsor deemed to be dose-limiting, regardless of the grade, was also considered as DLT.
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) From Baseline up to 30 days after the last dose (maximum duration: 120 weeks ) Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
Phase 2 Stage 1: Percentage of Participants With Overall Response (OR) According to International Myeloma Working Group (IMWG) Uniform Response Criteria From the date of randomization until disease progression or death or data cut-off (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for Stage 1b arm) OR defined as participants with stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) or partial response (PR) . Based on IMWG, CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; sCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein and urine M-protein level \<100 mg/24 hours; PR: \>=50% reduction of serum M-Protein and reduction in urinary M-protein by \>=90% or to \<200 mg/24 hours; \>=50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a \>=50% reduction in plasma cells in place of M-protein if present at baseline.
Phase 2 Stage 2: Percentage of Participants With Overall Response According to Updated IMWG Response Criteria From the date of randomization to date of death from any cause (maximum duration: 97 weeks) OR: participants with sCR or CR or VGPR or PR. As per updated IMWG, CR: Negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65 in participants with only FLC disease; sCR: CR and normal FLC ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein and urine M-protein level \<100 mg/24 hours, \>90% decrease in the difference between involved and uninvolved FLC levels; PR: \>=50% reduction of serum M-Protein and reduction in urinary M-protein by \>=90% or to \<200 mg/24 hours; \>=50% decrease in the difference between involved and uninvolved FLC levels in place of M-protein criteria or \>=50% reduction in plasma cells in place of M-protein if present at baseline.
- Secondary Outcome Measures
Name Time Method Phase 2 Stage 2: Percentage of Participants With Clinical Benefit From the date of randomization to the date of first documentation of progression or death (maximum duration: 97 weeks ) Clinical benefit:participants with sCR, CR, VGPR, PR or MR, per IMWG criteria, determined by IAC. CR:negative immunofixation on serum \& urine, disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates,normal FLC ratio(0.26-1.65) in participants with only FLC disease.sCR:CR+normal FLC ratio, absence of clonal cells in bone marrow biopsy.VGPR:serum \& urine M-component detectable by immunofixation, not on electrophoresis/,\>=90% reduction in serum M-component plus urine M-component level \<100mg/24h/,\>=90% decrease in difference between involved and uninvolved FLC levels; PR:\>=50% reduction of serum M-protein, reduction in 24h urinary M-protein by \>=90%/\<200mg/24h,\>50% decrease in difference between involved and uninvolved FLC in place of M-protein criteria, \>=50% reduction in size/number of soft tissue plasmacytomas. MR:\>=25 but \<49% reduction in serum M-protein,reduction in 24h urine M-protein by 50-89%, 25-49% reduction in size of soft tissue plasmacytomas
Phase 2 Stage 1: Progression Free Survival (PFS) From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) PFS was defined as the time interval from the date of first isatuximab administration to the date of the first IAC-confirmed disease progression (PD) or date of death due to any cause, whichever came first. As per IMWG criteria, PD: Increase of \> 25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be \> 0.5 g/dL), Urine M-component and/or (the absolute increase must be \> 200 mg/24 h), \> 10mg/dL decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria, \>10% absolute percentage of bone marrow plasma cell, definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas, development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.65 mmol/L) that attributed solely to the plasma cell proliferative disorder. Analysis was performed by Kaplan-Meier method.
Phase 2 Stage 2: Progression Free Survival From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 97 weeks) PFS was defined as the time interval from the date of first isatuximab administration to the date of the first IAC-confirmed disease progression or the date of death due to any cause, whichever came first. As per IMWG criteria, PD: Increase of \>25% from lowest response value in any one of the following: Serum M-component (the absolute increase must be \>0.5 g/dL)4 and/or Urine M-component (the absolute increase must be \>200 mg/24 h) and/or \>10 mg/dL decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria, ≥10% bone marrow plasma cell, development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) attributed solely to the plasma cell proliferative disorder. Analysis was performed by Kaplan-Meier method.
Phase 2 Stage 1: Overall Survival (OS) From the date of randomization to date of death from any cause (maximum duration 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) OS was defined as the time interval from the date of first Isatuximab administration to death from any cause. Analysis was performed by Kaplan-Meier method.
Phase 2 Stage 2: Overall Survival From the date of randomization to date of death from any cause (maximum duration: 97 weeks) OS was defined as the time interval from the date of first Isatuximab administration to death from any cause. Analysis was performed by Kaplan-Meier method.
Phase 2 Stage 1: Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Scores: Global Health Status Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10 and End of Treatment (EOT: anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea/vomiting, pain) \& other single items. For each item, high score = high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health \& quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 \& 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.
Phase 2 Stage 1: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20) Scores: Disease Symptom Subscale Score Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10 and EOT (anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with MM. It has 4 subscales: body image, future perspective), and 2 symptoms scales (disease symptoms and side-effects of treatment). Disease symptoms subscale used 4-point scale ranged from 1= 'Not at All' to 4= 'Very Much'. Scores were averaged, and transformed to 0 -100 scale, where higher scores = more symptoms and lower health-related quality of life (HRQL) and lower score = less symptoms and more HRQL.
Phase 2 Stage 1: Change From Baseline in Euro Quality of Life 5 Dimension (EQ-5D) Generic Health Status - Visual Analogue Scale Scores Baseline, Day 1 of Cycles 4, 7, 10, 13, 16, 19, and EOT (anytime up to 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0 = worst imaginable health state and 100 = best imaginable health state.
Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 1 Week Interval Pre-dose, at the end of infusion, 1 hour and 168 hours post dose on Day 1 of Cycle 1 Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 2 Weeks Interval Cycle 1, Day 1: pre-dose, at the end of infusion, 168 and 336 hours post-infusion Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 4 Weeks Interval Cycle 1, Day 1: pre-dose, at the end of infusion, 168, 336, and 672 hours post-infusion Pharmacokinetic Assessment: Phase 2 Stage 2: Plasma Concentration of Isatuximab Before Treatment Administration (Ctrough) At Days 7, 14 and 28 Pharmacokinetic Assessment: Phase 2 Stage 2: Accumulation Ratio of Isatuximab Based on Ctrough Cycle 2, Day 1; Cycle 1, Day 8; Cycle 4, Day 1 Ctrough is the plasma concentration observed before treatment administration. For 1st category, the accumulation ratio was calculated by dividing Ctrough value of Cycle 2 Day 1 by Cycle 1 Day 8 and for second category, accumulation ratio was calculated by dividing Ctrough value of Cycle 4 Day 1 by Cycle 1 Day 8.
Immunogenicity Assessment: Phase 2 Stage 2: Number of Participants With Anti-drug Antibodies to Isatuximab Up to 97 weeks ADA response was categorized as: treatment induced and treatment boosted response. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period (defined as the time from the first isatuximab administration until end of Phase 2 Stage 2) in participants without preexisting ADA (defined as: ADA that were present in samples drawn before treatment), including participants without pre-treatment (before treatment) samples. Treatment boosted ADA was defined as pre-existing ADA that increased at least 2 titer steps between pre-treatment (before treatment) and post-treatment.
Pharmacokinetic (PK) Assessment: Phase 1: Plasma Concentration of Isatuximab Observed at the End of an Intravenous Infusion (Ceoi) Cycle 1 Day 1 and Cycle 3 Day 1: At the end of infusion Ceoi was defined as the plasma concentration of Isatuximab at end of infusion. Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose levels (reported under one arm, i.e. Phase 1: Isatuximab \<=1mg/kg in participant flow). Analysis was performed on PK population: participants who gave informed consent, received at least one dose (even if incomplete) of isatuximab, had an assessable PK parameter.
PK Assessment: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Isatuximab For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose levels (reported under one arm, i.e. Phase 1: Isatuximab \<=1mg/kg in participant flow). Analysis was performed on PK population.
PK Assessment: Phase 1: Time to Reach Maximum Plasma Concentration Observed (Tmax) of Isatuximab For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion Data for this outcome measure was planned to be collected and analyzed separately for dose 0.3 mg/kg, 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03 and 0.1 dose levels (reported under one arm, i.e. Phase 1: Isatuximab \<=1mg/kg in participant flow). Analysis was performed on PK population.
PK Assessment: Phase 1: Plasma Concentration of Isatuximab at Week 1, 2 and 3 Week 1, 2 and 3 Data for this outcome measure was planned to be collected and analyzed only for dose 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03, 0.1 and 0.3 mg/kg dose levels (reported under one arm, i.e. Phase 1: Isatuximab \<=1mg/kg in participant flow).
PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First Week (0-168 Hours) (AUC1W) For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 168 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 168 hr post-infusion Data for this outcome measure was planned to be collected and analyzed only for dose 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03, 0.1 and 0.3 mg/kg dose levels (reported under one arm, i.e. Phase 1: Isatuximab \<=1mg/kg in participant flow).
PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First 2 Weeks (0-336 Hours) (AUC2W) For Q2W:Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 3, 7, 24, 48 and 336 hr post-infusion; For QW: Cycle 1,Day 1: pre-dose, 15 min after start of infusion, at the end of infusion, 4, 24, 48, 72 and 336 hr post-infusion Data for this outcome measure was planned to be collected and analyzed only for dose 1 mg/kg and not for 0.0001, 0.001, 0.01, 0.03, 0.1 and 0.3 mg/kg dose levels (reported under one arm, i.e. Phase 1: Isatuximab \<=1mg/kg in participant flow).
Pharmacodynamic (PD) Assessment: Phase 1: Change From Baseline in Serum/Plasma Markers Cycle 1 Day 1 Serum/plasma markers included: tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1-β), interleukin 6 (IL-6) and interferon-gamma (IFN-Gamma). Due to change in planned analysis, data for high-sensitivity C-reactive protein (hs-CRP) and CD38 was not collected and analyzed.
Immunogenicity Assessment: Phase 1: Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response Up to 120 weeks ADA response was categorized as: treatment induced and treatment boosted response. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period (defined as the time from the first isatuximab administration until end of Phase 1) in participants without preexisting ADA (defined as: ADA that were present in samples drawn before treatment), including participants without pre-treatment (before treatment) samples. Treatment boosted ADA was defined as pre-existing ADA that increased at least 2 titer steps between pre-treatment (before treatment) and post-treatment.
Clinical Assessment: Phase 1: Percentage of Participants With Overall Response and Clinical Benefit: Assessed Using European Society for Blood and Marrow Transplantation (EBMT) Criteria From the date of randomization to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks) OR defined as participants with complete response (CR) or partial response (PR) as best overall response (BOR). Clinical benefit: participants with minimal response (MR) or better as BOR. BOR: best sequential response from start of treatment through the entire study excluding any time point following start of other treatment. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, \<5% plasma cells in bone marrow aspirates, no increase in size or number of lytic bone lesions. PR: \>=50% reduction of serum M-protein, reduction in 24 h urinary M-protein by \>=90% or \<200mg, \>=50% reduction in size/number of soft tissue plasmacytomas, no increase in size or number of lytic bone lesions. MR: 25 to 49% reduction in serum M-protein, 50-89% reduction in 24h urine M-protein, 25-49% reduction in size of soft tissue plasmacytomas, no increase in size or number of lytic bone lesions.
Clinical Assessment: Phase 1: Duration of Response (DOR) From the date of first response to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks) DOR: time from first response (PR or better) to first documented tumor progression/death. Progression as per EBMT: \>25% increase in serum monoclonal paraprotein level, which must also be an absolute increase of \>= 5 g/l: confirmed by \>=1 repeated investigation; \>25% increase in 24h urinary light chain excretion, which must also be an absolute increase of \>=200 mg/24 h:confirmed by \>=1 repeated investigation; \>25% increase in plasma cells in a bone marrow aspirate/on trephine biopsy, which must also be an absolute increase of \>= 10%; definite increase in size of existing bone lesions/soft tissue plasmacytomas; development of new bone lesions/soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium \>11·5 mg/dl or 2·8 mmol/l) not attributable to any other cause. PR: \>=50% reduction of serum M-protein, reduction in 24h urinary M-protein by \>=90% or \<200mg, \>=50% reduction in size/number of soft tissue plasmacytomas, no increase in size/number of lytic bone lesions.
Clinical Assessment: Phase 1: Time to First Response (TTR) From the date of first dose administration to the date of first response or death (due to any cause) (maximum duration: 120 weeks) TTR was defined as the time from first dose of isatuximab to first response (PR or better). PR: \>=50% reduction of serum M-protein, reduction in 24 h urinary M-protein by \>=90% or \<200mg, \>=50% reduction in size/number of soft tissue plasmacytomas, no increase in size or number of lytic bone lesions.
Clinical Assessment: Phase 1: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Karnofsky Performance Status)-Shift From Baseline Value to Best Value During Treatment At baseline, during treatment (Day 1 up to 120 weeks) ECOG performance status was measured on a 4 point scale to assess participant's performance status. 0=Normal, fully functional; 1=Fatigue without significant decrease in daily activity; 2=Fatigue with significant impairment of daily activities or bed rest \<50% of waking hours; 3=Bed rest/sitting \>50% of waking hours; 4=Bedridden or unable to care for self, where lower score indicated good performance status. Number of participants with Baseline ECOG PS score and corresponding changes to the best values (categorized as: Baseline ECOG 1, During Treatment ECOG 0; Baseline ECOG 2, During Treatment ECOG 0; Baseline ECOG 2, During Treatment ECOG 1) are reported.
Clinical Assessment: Phase 1: Number of Participants With Eastern Cooperative Oncology Group Performance Status (Karnofsky Performance Status)-Shift From Baseline Value to Worst Value During Treatment At baseline, during treatment (up to 120 weeks) ECOG performance status was measured on a 4 point scale to assess participant's performance status. 0=Normal, fully functional; 1=Fatigue without significant decrease in daily activity; 2=Fatigue with significant impairment of daily activities or bed rest \<50% of waking hours; 3=Bed rest/sitting\>50% of waking hours; 4=Bedridden or unable to care for self, where higher score indicated worst performance status. Number of participants with Baseline ECOG PS score and corresponding changes to the worst values (categorized as: Baseline ECOG 0, During Treatment ECOG 1; Baseline ECOG 2, During Treatment ECOG 1; Baseline ECOG 0, During Treatment ECOG 2; Baseline ECOG 1, During Treatment ECOG 2; Baseline ECOG 0, During Treatment ECOG 3; Baseline ECOG 1, During Treatment ECOG 3; Baseline ECOG 2, During Treatment ECOG 3) are reported.
Phase 2 Stage 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) From Baseline up to 30 days after the last dose (maximum duration: 414 weeks for Stage 1a and 92 weeks for Stage 1b) Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
Phase 2 Stage 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) From Baseline up to 30 days after the last dose (maximum duration: 301 weeks) AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
Phase 2 Stage 1: Duration of Response From the date of first response until disease progression or death or data cut-off (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) DOR:Time from date of 1st IAC determined response (\>= PR) that was subsequently confirmed, to date of first IAC determined PD/death, whichever happened earlier. updated IMWG criteria- PR:\>=50% decrease in difference between involved and uninvolved FLC levels in place of M-protein criteria or a \>=50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline a \>=50% reduction in size of soft tissue plasmacytomas; PD: Increase of 25% from lowest response value in any of following: Serum M-protein \>=0.5 g/dL absolute increase and/or urine M-protein \>=200 mg/24 hours absolute increase and/or \>10 mg/dL absolute increase in difference between involved and uninvolved FLC levels, \>=10% bone marrow plasma cells (PCs), development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas, development of hypercalcemia (corrected serum calcium \>11·5 mg/dl) attributed to PC proliferation disorder.
Phase 2 Stage 2: Duration of Response From the date of first response until disease progression or death or data cut-off (maximum duration: 97 weeks) DOR: Time from date of 1st IAC determined response (\>= PR) that was subsequently confirmed, to date of 1st IAC determined PD or death, whichever happened earlier. As per updated IMWG criteria-PR: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to \<200 mg/24 hours. ≥50% decrease in difference between involved and uninvolved FLC levels in place of M-protein criteria or ≥50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline ≥50% reduction in size of soft tissue plasmacytomas; PD: Increase of \>25% from lowest response value in any one of following: Serum M-component (absolute increase must be \>0.5 g/dL)4 and/or Urine M-component (absolute increase must be \>200 mg/24 h) and/or \>10 mg/dL absolute increase in difference between involved and uninvolved FLC levels, \>=10% bone marrow plasma cell, development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) attributed solely to plasma cell proliferative disorder.
Phase 2 Stage 1: Percentage of Participants With Clinical Benefit From the date of randomization to the date of first documentation of progression or death (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm) Clinical benefit: participants with sCR, CR, VGPR, PR or MR as per IMWG criteria, determined by IAC. CR: negative immunofixation on serum \& urine, disappearance of any soft tissue plasmacytomas,\<5% PCs in bone marrow aspirates. sCR: CR + normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. VGPR: serum \& urine M-component detectable by immunofixation, not on electrophoresis/,\>=90% reduction in serum M-component plus urine M-component level \<100mg/24hours; PR: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to \<200 mg/24 hours, ≥50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a ≥50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline, ≥50% size reduction in soft tissue plasmacytomas. MR:\>=25 but \<49% reduction in serum M-protein, reduction in 24h urine M-protein by 50-89%, 25-49% size reduction in soft tissue plasmacytomas.
Trial Locations
- Locations (59)
Investigational Site Number : 724008
🇪🇸Sevilla, Spain
Investigational Site Number : 792002
🇹🇷Ankara, Turkey
Investigational Site Number : 792005
🇹🇷Ankara, Turkey
Investigational Site Number : 792001
🇹🇷İstanbul, Turkey
Investigational Site Number : 792004
🇹🇷Samsun, Turkey
Investigational Site Number : 804001
🇺🇦Kyiv, Ukraine
Investigational Site Number : 804004
🇺🇦Vinnytsia, Ukraine
Investigational Site Number : 804002
🇺🇦Zaporizhzhya, Ukraine
Investigational Site Number : 056001
🇧🇪Antwerpen, Belgium
Investigational Site Number : 380001
🇮🇹Bologna, Italy
Investigational Site Number : 604001
🇵🇪Arequipa, Peru
Investigational Site Number : 250004
🇫🇷Pierre Benite, France
Investigational Site Number : 604002
🇵🇪Lima, Peru
Investigational Site Number : 643002
🇷🇺Moscow, Russian Federation
Investigational Site Number : 250001
🇫🇷TOULOUSE Cedex 9, France
Mayo Clinic Site Number : 840003
🇺🇸Scottsdale, Arizona, United States
UCSF MS Center Site Number : 840005
🇺🇸San Francisco, California, United States
Emory University Site Number : 840009
🇺🇸Atlanta, Georgia, United States
University of Chicago Site Number : 840010
🇺🇸Chicago, Illinois, United States
The University Of Michigan Site Number : 840022
🇺🇸Ann Arbor, Michigan, United States
Karmanos Cancer Center Site Number : 840027
🇺🇸Detroit, Michigan, United States
Mayo Clinic of Rochester Site Number : 840018
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine Site Number : 840013
🇺🇸Saint Louis, Missouri, United States
The Cancer Center At Hackensack University Medical Site Number : 840011
🇺🇸Hackensack, New Jersey, United States
Memorial Sloan-Kettering Cancer Center Site Number : 840014
🇺🇸New York, New York, United States
Duke University Medical College Site Number : 840016
🇺🇸Durham, North Carolina, United States
University of Cincinnati Site Number : 840004
🇺🇸Cincinnati, Ohio, United States
Vanderbilt University Site Number : 840001
🇺🇸Nashville, Tennessee, United States
Huntsman Cancer Institute at the University of Utah Site Number : 840002
🇺🇸Salt Lake City, Utah, United States
Fred Hutchinson Cancer Research Center Site Number : 840012
🇺🇸Seattle, Washington, United States
Medical College of Wisconsin Site Number : 840017
🇺🇸Milwaukee, Wisconsin, United States
Investigational Site Number : 032003
🇦🇷Capital Federal, Buenos Aires, Argentina
Investigational Site Number : 032002
🇦🇷Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
Investigational Site Number : 032001
🇦🇷Ciudad de Buenos Aires, Buenos Aires, Argentina
Hospital Mae de Deus Site Number : 076003
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital de Amor - Hospital do Cancer de Barretos - Fundacao Pio XII Site Number : 076001
🇧🇷Barretos, São Paulo, Brazil
Investigational Site Number : 376002
🇮🇱Tel HaShomer, Israel
Clínica São Germano Site Number : 076002
🇧🇷Sao Paulo, São Paulo, Brazil
Instituto COI de Educacao e Pesquisa Site Number : 076004
🇧🇷Rio De Janeiro, Brazil
Investigational Site Number : 152001
🇨🇱Temuco, La Araucanía, Chile
Investigational Site Number : 246001
🇫🇮Helsinki, Finland
Investigational Site Number : 246002
🇫🇮Turku, Finland
Investigational Site Number : 250003
🇫🇷Nantes Cedex 01, France
Investigational Site Number : 300001
🇬🇷Athens, Greece
Investigational Site Number : 376004
🇮🇱Jerusalem, Israel
Investigational Site Number : 380002
🇮🇹Torino, Italy
Investigational Site Number : 484003
🇲🇽San Luis Potosi, San Luis Potosí, Mexico
Investigational Site Number : 484001
🇲🇽Monterrey, Mexico
Investigational Site Number : 724006
🇪🇸Valencia, Valenciana, Comunidad, Spain
Investigational Site Number : 724004
🇪🇸Madrid, Spain
Investigational Site Number : 724001
🇪🇸Salamanca, Spain
Investigational Site Number : 643003
🇷🇺Novosibirsk, Russian Federation
Investigational Site Number : 643001
🇷🇺Petrozavodsk, Russian Federation
Investigational Site Number : 643004
🇷🇺Saint-Petersburg, Russian Federation
Investigational Site Number : 724005
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number : 724007
🇪🇸Badalona, Catalunya [Cataluña], Spain
Investigational Site Number : 724002
🇪🇸Pamplona, Navarra, Spain
Investigational Site Number : 826002
🇬🇧Southampton, Hampshire, United Kingdom
Investigational Site Number : 826001
🇬🇧Nottingham, Nottinghamshire, United Kingdom
Related News
Phase 1 study of isatuximab monotherapy in Chinese patients with relapsed/refractory ...
- Prev
- 1
- Next