Clinical trial NCT01084252: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematological Malignancy
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2010-03-10
Enrollment: 351
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Day 1 of Cycle 1 up to Day 14 of Cycle 2
measure: Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From Baseline up to 30 days after the last dose (maximum duration: 120 weeks )
measure: Phase 2 Stage 1: Percentage of Participants With Overall Response (OR) According to International Myeloma Working Group (IMWG) Uniform Response Criteria
timeFrame: 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)
measure: Phase 2 Stage 2: Percentage of Participants With Overall Response According to Updated IMWG Response Criteria
timeFrame: From the date of randomization to date of death from any cause (maximum duration: 97 weeks)
Secondary outcomes:
measure: Pharmacokinetic (PK) Assessment: Phase 1: Plasma Concentration of Isatuximab Observed at the End of an Intravenous Infusion (Ceoi)
timeFrame: Cycle 1 Day 1 and Cycle 3 Day 1: At the end of infusion
measure: PK Assessment: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Isatuximab
timeFrame: 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
measure: PK Assessment: Phase 1: Time to Reach Maximum Plasma Concentration Observed (Tmax) of Isatuximab
timeFrame: 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
measure: PK Assessment: Phase 1: Plasma Concentration of Isatuximab at Week 1, 2 and 3
timeFrame: Week 1, 2 and 3
measure: PK Assessment: Phase 1: Predicted Cumulative Area Under the Plasma Concentration Curve (AUC) of Isatuximab Over the First Week (0-168 Hours) (AUC1W)
timeFrame: 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
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)
timeFrame: 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
measure: Pharmacodynamic (PD) Assessment: Phase 1: Change From Baseline in Serum/Plasma Markers
timeFrame: Cycle 1 Day 1
measure: Immunogenicity Assessment: Phase 1: Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response
timeFrame: Up to 120 weeks
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
timeFrame: From the date of randomization to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks)
measure: Clinical Assessment: Phase 1: Duration of Response (DOR)
timeFrame: From the date of first response to the date of first documentation of progression or death (due to any cause) (maximum duration: 120 weeks)
measure: Clinical Assessment: Phase 1: Time to First Response (TTR)
timeFrame: From the date of first dose administration to the date of first response or death (due to any cause) (maximum duration: 120 weeks)
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
timeFrame: At baseline, during treatment (Day 1 up to 120 weeks)
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
timeFrame: At baseline, during treatment (up to 120 weeks)
measure: Phase 2 Stage 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From Baseline up to 30 days after the last dose (maximum duration: 414 weeks for Stage 1a and 92 weeks for Stage 1b)
measure: Phase 2 Stage 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From Baseline up to 30 days after the last dose (maximum duration: 301 weeks)
measure: Phase 2 Stage 1: Duration of Response
timeFrame: 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)
measure: Phase 2 Stage 2: Duration of Response
timeFrame: From the date of first response until disease progression or death or data cut-off (maximum duration: 97 weeks)
measure: Phase 2 Stage 1: Percentage of Participants With Clinical Benefit
timeFrame: 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)
measure: Phase 2 Stage 2: Percentage of Participants With Clinical Benefit
timeFrame: From the date of randomization to the date of first documentation of progression or death (maximum duration: 97 weeks )
measure: Phase 2 Stage 1: Progression Free Survival (PFS)
timeFrame: 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)
measure: Phase 2 Stage 2: Progression Free Survival
timeFrame: From the date of the first dose administration until progression or death, whichever occurred first (maximum duration: 97 weeks)
measure: Phase 2 Stage 1: Overall Survival (OS)
timeFrame: 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)
measure: Phase 2 Stage 2: Overall Survival
timeFrame: From the date of randomization to date of death from any cause (maximum duration: 97 weeks)
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
timeFrame: 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)
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
timeFrame: 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)
measure: Phase 2 Stage 1: Change From Baseline in Euro Quality of Life 5 Dimension (EQ-5D) Generic Health Status - Visual Analogue Scale Scores
timeFrame: 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)
measure: Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 1 Week Interval
timeFrame: Pre-dose, at the end of infusion, 1 hour and 168 hours post dose on Day 1 of Cycle 1
measure: Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 2 Weeks Interval
timeFrame: Cycle 1, Day 1: pre-dose, at the end of infusion, 168 and 336 hours post-infusion
measure: Pharmacokinetic Assessment: Phase 2 Stage 2: Area Under the Plasma Concentration Versus Time Curve of Isatuximab Over 4 Weeks Interval
timeFrame: Cycle 1, Day 1: pre-dose, at the end of infusion, 168, 336, and 672 hours post-infusion
measure: Pharmacokinetic Assessment: Phase 2 Stage 2: Plasma Concentration of Isatuximab Before Treatment Administration (Ctrough)
timeFrame: At Days 7, 14 and 28
measure: Pharmacokinetic Assessment: Phase 2 Stage 2: Accumulation Ratio of Isatuximab Based on Ctrough
timeFrame: Cycle 2, Day 1; Cycle 1, Day 8; Cycle 4, Day 1
measure: Immunogenicity Assessment: Phase 2 Stage 2: Number of Participants With Anti-drug Antibodies to Isatuximab
timeFrame: Up to 97 weeks
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Site Number : 840003
state: Arizona
city: San Francisco
country: United States
facility: UCSF MS Center Site Number : 840005
state: California
city: Atlanta
country: United States
facility: Emory University Site Number : 840009
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Site Number : 840010
state: Illinois
city: Ann Arbor
country: United States
facility: The University Of Michigan Site Number : 840022
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Center Site Number : 840027
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic of Rochester Site Number : 840018
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine Site Number : 840013
state: Missouri
city: Hackensack
country: United States
facility: The Cancer Center At Hackensack University Medical Site Number : 840011
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center Site Number : 840014
state: New York
city: Durham
country: United States
facility: Duke University Medical College Site Number : 840016
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Site Number : 840004
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Site Number : 840001
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at the University of Utah Site Number : 840002
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center Site Number : 840012
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Site Number : 840017
state: Wisconsin
city: Capital Federal
country: Argentina
facility: Investigational Site Number : 032003
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Investigational Site Number : 032002
state: Buenos Aires
city: Ciudad de Buenos Aires
country: Argentina
facility: Investigational Site Number : 032001
state: Buenos Aires
city: Antwerpen
country: Belgium
facility: Investigational Site Number : 056001
city: Porto Alegre
country: Brazil
facility: Hospital Mae de Deus Site Number : 076003
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Hospital de Amor - Hospital do Cancer de Barretos - Fundacao Pio XII Site Number : 076001
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Clínica São Germano Site Number : 076002
state: São Paulo
city: Rio De Janeiro
country: Brazil
facility: Instituto COI de Educacao e Pesquisa Site Number : 076004
city: Temuco
country: Chile
facility: Investigational Site Number : 152001
state: La Araucanía
city: Helsinki
country: Finland
facility: Investigational Site Number : 246001
city: Turku
country: Finland
facility: Investigational Site Number : 246002
city: Nantes Cedex 01
country: France
facility: Investigational Site Number : 250003
city: Pierre Benite
country: France
facility: Investigational Site Number : 250004
city: TOULOUSE Cedex 9
country: France
facility: Investigational Site Number : 250001
city: Athens
country: Greece
facility: Investigational Site Number : 300001
city: Jerusalem
country: Israel
facility: Investigational Site Number : 376004
city: Tel HaShomer
country: Israel
facility: Investigational Site Number : 376002
city: Bologna
country: Italy
facility: Investigational Site Number : 380001
city: Torino
country: Italy
facility: Investigational Site Number : 380002
city: San Luis Potosi
country: Mexico
facility: Investigational Site Number : 484003
state: San Luis Potosí
city: Monterrey
country: Mexico
facility: Investigational Site Number : 484001
city: Arequipa
country: Peru
facility: Investigational Site Number : 604001
city: Lima
country: Peru
facility: Investigational Site Number : 604002
city: Moscow
country: Russian Federation
facility: Investigational Site Number : 643002
city: Novosibirsk
country: Russian Federation
facility: Investigational Site Number : 643003
city: Petrozavodsk
country: Russian Federation
facility: Investigational Site Number : 643001
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number : 643004
city: Barcelona
country: Spain
facility: Investigational Site Number : 724005
state: Barcelona [Barcelona]
city: Badalona
country: Spain
facility: Investigational Site Number : 724007
state: Catalunya [Cataluña]
city: Pamplona
country: Spain
facility: Investigational Site Number : 724002
state: Navarra
city: Valencia
country: Spain
facility: Investigational Site Number : 724006
state: Valenciana, Comunidad
city: Madrid
country: Spain
facility: Investigational Site Number : 724004
city: Salamanca
country: Spain
facility: Investigational Site Number : 724001
city: Sevilla
country: Spain
facility: Investigational Site Number : 724008
city: Ankara
country: Turkey
facility: Investigational Site Number : 792002
city: Ankara
country: Turkey
facility: Investigational Site Number : 792005
city: İstanbul
country: Turkey
facility: Investigational Site Number : 792001
city: Samsun
country: Turkey
facility: Investigational Site Number : 792004
city: Kyiv
country: Ukraine
facility: Investigational Site Number : 804001
city: Vinnytsia
country: Ukraine
facility: Investigational Site Number : 804004
city: Zaporizhzhya
country: Ukraine
facility: Investigational Site Number : 804002
city: Southampton
country: United Kingdom
facility: Investigational Site Number : 826002
state: Hampshire
city: Nottingham
country: United Kingdom
facility: Investigational Site Number : 826001
state: Nottinghamshire
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.