Clinical Trial: NCT01084252 - My Cancer Genome

NCT01084252

Description:

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.

Related Conditions:

Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Chronic Lymphocytic Leukemia
Multiple Myeloma
Non-Hodgkin Lymphoma

Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT01084252

Trial Eligibility

Document

Title

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

Clinical Trial IDs

ORG STUDY ID: TED10893
SECONDARY ID: U1111-1116-5472
NCT ID: NCT01084252

Conditions

Hematological Malignancy

Interventions

Drug	Synonyms	Arms
Isatuximab SAR650984	Sarclisa	Phase 1: Isatuximab 10 mg/kg QW
Dexamethasone		Phase 2 Stage 2: Isatuximab + Dexamethasone
Dexamethasone		Phase 2 Stage 2: Isatuximab + Dexamethasone

Purpose

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.

Trial Arms

Name	Type	Description	Interventions
Phase 1:Isatuximab <=1 mg/kg Q2W	Experimental	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).	Isatuximab SAR650984
Phase 1: Isatuximab 3mg/kg Q2W	Experimental	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).	Isatuximab SAR650984
Phase 1: Isatuximab 5 mg/kg Q2W	Experimental	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).	Isatuximab SAR650984
Phase1:Isatuximab (CD38+HM and Standard Risk Multiple Myeloma)	Experimental	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).	Isatuximab SAR650984
Phase 1:Isatuximab (CD38 + HM and High Risk Multiple Myeloma)	Experimental	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).	Isatuximab SAR650984
Phase 1: Isatuximab 10 mg/kg QW	Experimental	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).	Isatuximab SAR650984
Phase 1: Isatuximab 20 mg/kg Q2W	Experimental	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).	Isatuximab SAR650984
Phase 1: Isatuximab 20 mg/kg QW	Experimental	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).	Isatuximab SAR650984
Phase 2 Stage 1a: Isatuximab 3 mg/kg Q2W	Experimental	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).	Isatuximab SAR650984
Phase 2 Stage 1a: Isatuximab 10 mg/kg Q2W	Experimental	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).	Isatuximab SAR650984
Phase2 Stage1a:Isatuximab 10mg/kg Q2W; Then Q4W	Experimental	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).	Isatuximab SAR650984
Phase 2 Stage 1b: Isatuximab 20mg/kg QW and Then Q2W	Experimental	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).	Isatuximab SAR650984
Phase 2 Stage 2: Isatuximab Alone	Experimental	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).	Isatuximab SAR650984
Phase 2 Stage 2: Isatuximab + Dexamethasone	Experimental	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).	Isatuximab SAR650984 Dexamethasone Dexamethasone

Eligibility Criteria

        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.

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame:	Day 1 of Cycle 1 up to Day 14 of Cycle 2
Safety Issue:
Description:	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.

Secondary Outcome Measures

Measure:	Pharmacokinetic (PK) Assessment: Phase 1: Plasma Concentration of Isatuximab Observed at the End of an Intravenous Infusion (Ceoi)
Time Frame:	Cycle 1 Day 1 and Cycle 3 Day 1: At the end of infusion
Safety Issue:
Description:	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.

Measure:	PK Assessment: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Isatuximab
Time Frame:	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
Safety Issue:
Description:	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.

Measure:	PK Assessment: Phase 1: Time to Reach Maximum Plasma Concentration Observed (Tmax) of Isatuximab
Time Frame:	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
Safety Issue:
Description:	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.

Measure:	PK Assessment: Phase 1: Plasma Concentration of Isatuximab at Week 1, 2 and 3
Time Frame:	Week 1, 2 and 3
Safety Issue:
Description:	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).

Measure:	PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First Week (0-168 Hours) (AUC1W)
Time Frame:	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
Safety Issue:
Description:	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).

Measure:	PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First 2 Weeks (0-336 Hours) (AUC2W)
Time Frame:	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
Safety Issue:
Description:	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).

Measure:	Pharmacodynamic (PD) Assessment: Phase 1: Change From Baseline in Serum/Plasma Markers
Time Frame:	Cycle 1 Day 1
Safety Issue:
Description:	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.

Measure:	Immunogenicity Assessment: Phase 1: Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response
Time Frame:	Up to 120 weeks
Safety Issue:
Description:	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.

Measure:	Clinical Assessment: Phase 1: Percentage of Participants With Overall Response and Clinical Benefit: Assessed Using European Society for Blood and Marrow Transplantation (EBMT) Criteria
Time Frame:	From the date of randomization to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks)
Safety Issue:
Description:	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.

Measure:	Clinical Assessment: Phase 1: Duration of Response (DOR)
Time Frame:	From the date of first response to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks)
Safety Issue:
Description:	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.

Measure:	Clinical Assessment: Phase 1: Time to First Response (TTR)
Time Frame:	From the date of first dose administration to the date of first response or death (due to any cause) (maximum duration: 120 weeks)
Safety Issue:
Description:	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.

Measure:	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
Time Frame:	At baseline, during treatment (Day 1 up to 120 weeks)
Safety Issue:
Description:	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.

Measure:	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
Time Frame:	At baseline, during treatment (up to 120 weeks)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Time Frame:	From Baseline up to 30 days after the last dose (maximum duration: 97 weeks)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 1: Duration of Response
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 2: Duration of Response
Time Frame:	From the date of first response until disease progression or death or data cut-off (maximum duration: 97 weeks)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 1: Percentage of Participants With Clinical Benefit
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 2: Percentage of Participants With Clinical Benefit
Time Frame:	From the date of randomization to the date of first documentation of progression or death (maximum duration: 97 weeks )
Safety Issue:
Description:	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

Measure:	Phase 2 Stage 1: Progression Free Survival (PFS)
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 2: Progression Free Survival
Time Frame:	From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 97 weeks)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 1: Overall Survival (OS)
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 2: Overall Survival
Time Frame:	From the date of randomization to date of death from any cause (maximum duration: 97 weeks)
Safety Issue:
Description:	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.

Measure:	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
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	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
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Phase 2 Stage 1: Change From Baseline in Euro Quality of Life 5 Dimension (EQ-5D) Generic Health Status - Visual Analogue Scale Scores
Time Frame:	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)
Safety Issue:
Description:	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.

Measure:	Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 1 Week Interval
Time Frame:	Pre-dose, at the end of infusion, 1 hour and 168 hours post dose on Day 1 of Cycle 1
Safety Issue:
Description:

Measure:	Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 2 Weeks Interval
Time Frame:	Cycle 1, Day 1: pre-dose, at the end of infusion, 168 and 336 hours post-infusion
Safety Issue:
Description:

Measure:	Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 4 Weeks Interval
Time Frame:	Cycle 1, Day 1: pre-dose, at the end of infusion, 168, 336, and 672 hours post-infusion
Safety Issue:
Description:

Measure:	Pharmacokinetic Assessment: Phase 2 Stage 2: Plasma Concentration of Isatuximab Before Treatment Administration (Ctrough)
Time Frame:	At Day 1, 8, and 22
Safety Issue:
Description:

Measure:	Pharmacokinetic Assessment: Phase 2 Stage 2: Accumulation Ratio of Isatuximab Based on Ctrough
Time Frame:	Cycle 2, Day 1; Cycle 1, Day 8; Cycle 4, Day 1
Safety Issue:
Description:	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.

Measure:	Immunogenicity Assessment: Phase 2 Stage 2: Number of Participants With Anti-drug Antibodies to Isatuximab
Time Frame:	Up to 97 weeks
Safety Issue:
Description:	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.

Details

Phase:	Phase 1/Phase 2
Primary Purpose:	Interventional
Overall Status:	Active, not recruiting
Lead Sponsor:	Sanofi

Trial Keywords

Anti-CD38 monoclonal antibody

Last Updated

April 20, 2021

Clinical Trials /

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