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

A Phase I/2 Dose Escalation Safety, Pharmacokinetic and Efficacy Study of Multiple Intravenous Administrations of a Humanized Monoclonal Antibody (SAR650984) Against CD38 in Patients With Selected CD38+ Hematological Malignancies

Primary Objective:

Phase 1:

To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR650984 (Isatuximab).

Phase 2 (stage 1):

To evaluate the activity of single-agent Isatuximab at different doses/schedules and to select dose and regimen to further evaluate the overall response rate (ORR) of Isatuximab as single agent or in combination with dexamethasone.

Phase 2 (stage 2):

To evaluate the activity in terms of overall response rate (ORR) of Isatuximab at the selected dose/schedule from stage1, as single agent (ISA arm) and in combination with dexamethasone (ISAdex arm).

Secondary Objectives:

Phase 1:

• To characterize the global safety profile including cumulative toxicities.
• To evaluate the pharmacokinetic (PK) profile of Isatuximab in the proposed dosing schedule(s).
• To assess the pharmacodynamics (PD), immune response, and preliminary disease response.

Phase 2 (stage 1): to evaluate the following objectives for Isatuximab as single agent:

• Safety
• Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.

Phase 2 (stage 2): to evaluate the following objectives in each arm (ISA and ISAdex):

• Safety
• Efficacy as measured by duration of response, clinical benefit rate, progression free survival, overall survival.
• Participant-reported changes in health-related quality of life, symptoms of multiple myeloma and generic health status.
• Pharmacokinetic profile of Isatuximab.
• Immunogenicity of Isatuximab.
• Investigate the relationship between CD38 receptor density and CD38 receptor occupancy (Stage 1 only) on multiple myeloma cells and parameters of clinical response.

Study Overview

• Status: Completed
• Conditions: Hematological Malignancy
• Intervention / Treatment: Drug: Isatuximab SAR650984; Drug: Dexamethasone; Drug: Dexamethasone

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.

• Study Type: Interventional
• Enrollment (Actual): 351
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1181ACH
    • Investigational Site Number 032002
  • Capital Federal, Argentina, C1425ASS
    • Investigational Site Number 032003
  • Ciudad De Buenos Aires, Argentina, C1426ANZ
    • Investigational Site Number 032001
• Belgium
  • Antwerpen, Belgium, 2060
    • Investigational Site Number 056001
• Brazil
  • Barretos, Brazil, 14784-400
    • Investigational Site Number 076001
  • Porto Alegre, Brazil, 90470-340
    • Investigational Site Number 076003
  • Rio De Janeiro, Brazil, 22793-080
    • Investigational Site Number 076004
  • Sao Paulo, Brazil, 04537-081
    • Investigational Site Number 076002
• Chile
  • Temuco, Chile, 4810469
    • Investigational Site Number 152001
• Finland
  • Helsinki, Finland, 00029
    • Investigational Site Number 246001
  • Turku, Finland, 20521
    • Investigational Site Number 246002
• France
  • Nantes Cedex 01, France, 44093
    • Investigational Site Number 250003
  • Pierre Benite, France, 69310
    • Investigational Site Number 250004
  • Toulouse Cedex 9, France, 31059
    • Investigational Site Number 250001
• Greece
  • Athens, Greece, 11528
    • Investigational Site Number 300001
• Israel
  • Jerusalem, Israel, 91120
    • Investigational Site Number 376004
  • Tel Hashomer, Israel, 52621
    • Investigational Site Number 376002
• Italy
  • Bologna, Italy, 40138
    • Investigational Site Number 380001
  • Torino, Italy, 10126
    • Investigational Site Number 380002
• Mexico
  • Monterrey, Mexico, 64460
    • Investigational Site Number 484001
  • San Luis Potosi, Mexico, 78419
    • Investigational Site Number 484003
• Peru
  • Arequipa, Peru
    • Investigational Site Number 604001
  • Lima, Peru, LIMA 34
    • Investigational Site Number 604002
• Russian Federation
  • Moscow, Russian Federation, 125284
    • Investigational Site Number 643002
  • Novosibirsk, Russian Federation, 630087
    • Investigational Site Number 643003
  • Petrozavodsk, Russian Federation, 185019
    • Investigational Site Number 643001
  • Saint-Petersburg, Russian Federation, 194291
    • Investigational Site Number 643004
• Spain
  • Badalona, Spain, 08916
    • Investigational Site Number 724007
  • Barcelona, Spain, 08036
    • Investigational Site Number 724005
  • Madrid, Spain, 28041
    • Investigational Site Number 724004
  • Pamplona, Spain, 31008
    • Investigational Site Number 724002
  • Salamanca, Spain, 37007
    • Investigational Site Number 724001
  • Sevilla, Spain, 41013
    • Investigational Site Number 724008
  • Valencia, Spain, 46017
    • Investigational Site Number 724006
• Turkey
  • Ankara, Turkey, 06200
    • Investigational Site Number 792002
  • Ankara, Turkey, 06500
    • Investigational Site Number 792005
  • Samsun, Turkey, 55139
    • Investigational Site Number 792004
  • İstanbul, Turkey
    • Investigational Site Number 792001
• Ukraine
  • Kyiv, Ukraine, 04112
    • Investigational Site Number 804001
  • Vinnitsya, Ukraine, 21018
    • Investigational Site Number 804004
  • Zaporizhzhya, Ukraine, 69600
    • Investigational Site Number 804002
• United Kingdom
  • Nottingham, United Kingdom, NG5 1PB
    • Investigational Site Number 826001
  • Southampton, United Kingdom, SO16 6YD
    • Investigational Site Number 826002
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85054
      • Investigational Site Number 840003
  • California
    • San Francisco, California, United States, 94117
      • Investigational Site Number 840005
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Investigational Site Number 840009
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Investigational Site Number 840010
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0759
      • Investigational Site Number 840022
    • Detroit, Michigan, United States, 48201
      • Investigational Site Number 840027
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Investigational Site Number 840018
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Investigational Site Number 840013
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Investigational Site Number 840011
  • New York
    • New York, New York, United States, 10021
      • Investigational Site Number 840014
  • North Carolina
    • Durham, North Carolina, United States, 27707
      • Investigational Site Number 840016
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0542
      • Investigational Site Number 840004
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Investigational Site Number 840001
  • Utah
    • Salt Lake City, Utah, United States, 84112-5550
      • Investigational Site Number 840002
  • Washington
    • Seattle, Washington, United States, 98109
      • Investigational Site Number 840012
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Investigational Site Number 840017

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

Phase 1:

• For dose escalation cohorts, participants with confirmed selected CD38+ hematological malignancies as specified below who had progressed on after standard therapy or for whom there was no effective standard therapy (refractory/relapsed participants). B-cell Non-Hodgkin-lymphoma/leukemia (NHL) participants with at least 1 measurable lesion. Multiple myeloma (MM) participants with measurable M-protein serum and/or 24-hour urine. Acute myeloid leukemia (AML) participants, all types except M3 based on French-American-British (FAB) classification. Acute Lymphoblastic Leukemia (B-cell ALL) participants. Chronic lymphocytic leukemia (CLL) participants.
• For expansion cohorts, participants with relapsed/refractory MM with measurable M-protein (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg (24-hr urine)) or elevated serum free light chains (FLC) >10 mg/dL with abnormal FLC ratio) who had progressed on or after standard therapy that included an Immunomodulatory drug (IMiD) and a proteasome inhibitor and who met the protocol defined criteria for standard risk or high risk.

Phase 2:

• Participants had a known diagnosis of multiple myeloma with evidence of measurable disease, and have evidence of disease progression based on International Myeloma Working Group (IMWG) criteria: Serum M-protein ≥1 g/dL, or urine M-protein >=200 mg/24 hours or in the absence of measurable m-protein, serum FLC >=10 mg/dL, and abnormal serum immunoglobulin kappa lambda FLC ratio (<0.26 or >1.65).
• Participants who received at least three prior lines of therapy for MM and had treatment with an IMiD (for >=2 cycles or >=2 months of treatment) and a proteasome inhibitor (PI) (for >=2 cycles or >=2 months of treatment) OR participants whose disease was double refractory to an IMiD and a PI. For participants who had received more than 1 type of IMiD and PI, their disease must be refractory to the most recent one.
• Participants who had achieved a minimal response or better to at least one prior line of therapy.
• Participants who had received an alkylating agent (>=2 cycles or >=2 months) either alone or in combination with other MM treatments.
• Stage 2 only: Participants who had evidence of disease progression on or after the most recent prior regimen based on IMWG criteria.

Exclusion criteria:

Phase 1:

• Karnofsky performance status <60
• Poor bone marrow reserve
• Poor organ function
• Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that was not amenable to pre-medication with steroids and H2 blockers
• Any serious active disease (including clinically significant infection that was chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, interfered with the safety, the compliance with the study or with the interpretation of the results
• Any severe underlying medical conditions including presence of laboratory abnormalities, which could impair the ability to participate in the study or the interpretation of its results

Phase 2:

• Participants with multiple myeloma immunoglobulin M (IgM) subtype
• Previous treatment with any anti-CD38 therapy
• Participants with concurrent plasma cell leukemia
• Participants with known or suspected amyloidosis
• Karnofsky performance status <60 (stage 1)/Eastern Cooperative Oncology Group (ECOG) Performance status >2 (stage 2).
• Poor bone marrow reserve
• Poor organ function
• Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or known hypersensitivity to any of the components of the study therapy that was not amenable to pre-medication with steroids and H2 blockers
• Any serious active disease (including clinically significant infection that was chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the investigator, interfered with the safety, the compliance with the study or with the interpretation of the results
• Any severe underlying medical conditions including presence of laboratory abnormalities, which impaired the ability to participate in the study or the interpretation of its results

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1:Isatuximab <=1 mg/kg Q2W; 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 1: Isatuximab 3mg/kg Q2W; 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 1: Isatuximab 5 mg/kg Q2W; 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase1:Isatuximab (CD38+HM and Standard Risk Multiple Myeloma); 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 1:Isatuximab (CD38 + HM and High Risk Multiple Myeloma); 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 1: Isatuximab 10 mg/kg QW; 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 1: Isatuximab 20 mg/kg Q2W; 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 1: Isatuximab 20 mg/kg QW; 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 2 Stage 1a: Isatuximab 3 mg/kg Q2W; 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: 77 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 2 Stage 1a: Isatuximab 10 mg/kg Q2W; 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: 77 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase2 Stage1a:Isatuximab 10mg/kg Q2W; Then Q4W; 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: 77 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 2 Stage 1b: Isatuximab 20mg/kg QW and Then Q2W; 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: 53 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 2 Stage 2: Isatuximab Alone; 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: 97 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa
Experimental: Phase 2 Stage 2: Isatuximab + 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: 97 weeks).	Drug: Isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Names: Sarclisa; Drug: Dexamethasone; Pharmaceutical form: solution for infusion Route of administration: intravenous; Drug: Dexamethasone; Pharmaceutical form: tablet Route of administration: oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)	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.	Day 1 of Cycle 1 up to Day 14 of Cycle 2
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	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.	From Baseline up to 30 days after the last dose (maximum duration: 120 weeks )
Phase 2 Stage 1: Percentage of Participants With Overall Response (OR) According to International Myeloma Working Group (IMWG) Uniform Response Criteria	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.	From the date of randomization until disease progression or death or data cut-off (maximum duration: 77 weeks )
Phase 2 Stage 2: Percentage of Participants With Overall Response According to Updated IMWG Response Criteria	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.	From the date of randomization to date of death from any cause (maximum duration: 97 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) Assessment: Phase 1: Plasma Concentration of Isatuximab Observed at the End of an Intravenous Infusion (Ceoi)	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.	Cycle 1 Day 1 and Cycle 3 Day 1: At the end of infusion
PK Assessment: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Isatuximab	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.	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
PK Assessment: Phase 1: Time to Reach Maximum Plasma Concentration Observed (Tmax) of Isatuximab	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.	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
PK Assessment: Phase 1: Plasma Concentration of Isatuximab at 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).	Week 1, 2 and 3
PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First Week (0-168 Hours) (AUC1W)	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).	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
PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First 2 Weeks (0-336 Hours) (AUC2W)	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).	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
Pharmacodynamic (PD) Assessment: Phase 1: Change From Baseline in Serum/Plasma Markers	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.	Cycle 1 Day 1
Immunogenicity Assessment: Phase 1: Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response	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.	Up to 120 weeks
Clinical Assessment: Phase 1: Percentage of Participants With Overall Response and Clinical Benefit: Assessed Using European Society for Blood and Marrow Transplantation (EBMT) Criteria	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.	From the date of randomization to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks)
Clinical Assessment: Phase 1: Duration of Response (DOR)	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.	From the date of first response to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks)
Clinical Assessment: Phase 1: Time to First Response (TTR)	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.	From the date of first dose administration to the date of first response or death (due to any cause) (maximum duration: 120 weeks)
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	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.	At baseline, during treatment (Day 1 up to 120 weeks)
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	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.	At baseline, during treatment (up to 120 weeks)
Phase 2 Stage 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	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.	From Baseline up to 30 days after the last dose (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm)
Phase 2 Stage 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	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.	From Baseline up to 30 days after the last dose (maximum duration: 97 weeks)
Phase 2 Stage 1: Duration of Response	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.	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)
Phase 2 Stage 2: Duration of Response	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.	From the date of first response until disease progression or death or data cut-off (maximum duration: 97 weeks)
Phase 2 Stage 1: Percentage of Participants With Clinical Benefit	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.	From Baseline up to 30 days after the last dose (maximum duration: 77 weeks for Stage 1a arms and 53 weeks for stage 1b arm)
Phase 2 Stage 2: Percentage of Participants With Clinical Benefit	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	From the date of randomization to the date of first documentation of progression or death (maximum duration: 97 weeks )
Phase 2 Stage 1: Progression Free Survival (PFS)	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.	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)
Phase 2 Stage 2: Progression Free Survival	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.	From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 97 weeks)
Phase 2 Stage 1: Overall Survival (OS)	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.	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)
Phase 2 Stage 2: Overall Survival	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.	From the date of randomization to date of death from any cause (maximum duration: 97 weeks)
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	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.	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)
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	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.	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)
Phase 2 Stage 1: Change From Baseline in Euro Quality of Life 5 Dimension (EQ-5D) Generic Health Status - Visual Analogue Scale Scores	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.	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)
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 Day 1, 8, and 22
Pharmacokinetic Assessment: Phase 2 Stage 2: Accumulation Ratio of Isatuximab Based on Ctrough	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.	Cycle 2, Day 1; Cycle 1, Day 8; Cycle 4, Day 1
Immunogenicity Assessment: Phase 2 Stage 2: Number of Participants With Anti-drug Antibodies to Isatuximab	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.	Up to 97 weeks

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

General Publications

• Dimopoulos M, Bringhen S, Anttila P, Capra M, Cavo M, Cole C, Gasparetto C, Hungria V, Jenner M, Vorobyev V, Ruiz EY, Yin JY, Saleem R, Hellet M, Mace S, Paiva B, Vij R. Isatuximab as monotherapy and combined with dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2021 Mar 4;137(9):1154-1165. doi: 10.1182/blood.2020008209.
• Mikhael J, Richter J, Vij R, Cole C, Zonder J, Kaufman JL, Bensinger W, Dimopoulos M, Lendvai N, Hari P, Ocio EM, Gasparetto C, Kumar S, Oprea C, Chiron M, Brillac C, Charpentier E, San-Miguel J, Martin T. A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma. Leukemia. 2020 Dec;34(12):3298-3309. doi: 10.1038/s41375-020-0857-2. Epub 2020 May 14.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2010
• Primary Completion (Actual): December 21, 2018
• Study Completion (Actual): July 13, 2023

Study Registration Dates

• First Submitted: March 9, 2010
• First Submitted That Met QC Criteria: March 9, 2010
• First Posted (Estimated): March 10, 2010

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Anti-CD38 monoclonal antibody
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101
• Other Study ID Numbers: TED10893; U1111-1116-5472 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org