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

NCT ID: NCT01084252

Last Updated: 2024-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 351 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-11
• Study Completion Date: 2023-07-13

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.

Conditions

Hematological Malignancy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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: 414 weeks).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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: 414 weeks).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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: 414 weeks).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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: 92 weeks).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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: 301 weeks).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

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: 301 weeks).

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Dexamethasone

Intervention Type: DRUG

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Dexamethasone

Intervention Type: DRUG

Pharmaceutical form: tablet

Route of administration: oral

Interventions

Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Intervention Type: DRUG

Dexamethasone

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Intervention Type: DRUG

Dexamethasone

Pharmaceutical form: tablet

Route of administration: oral

Intervention Type: DRUG

Other Intervention Names

Sarclisa

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Mayo Clinic Site Number : 840003

Scottsdale, Arizona, United States

UCSF MS Center Site Number : 840005

San Francisco, California, United States

Emory University Site Number : 840009

Atlanta, Georgia, United States

University of Chicago Site Number : 840010

Chicago, Illinois, United States

The University Of Michigan Site Number : 840022

Ann Arbor, Michigan, United States

Karmanos Cancer Center Site Number : 840027

Detroit, Michigan, United States

Mayo Clinic of Rochester Site Number : 840018

Rochester, Minnesota, United States

Washington University School of Medicine Site Number : 840013

St Louis, Missouri, United States

The Cancer Center At Hackensack University Medical Site Number : 840011

Hackensack, New Jersey, United States

Memorial Sloan-Kettering Cancer Center Site Number : 840014

New York, New York, United States

Duke University Medical College Site Number : 840016

Durham, North Carolina, United States

University of Cincinnati Site Number : 840004

Cincinnati, Ohio, United States

Vanderbilt University Site Number : 840001

Nashville, Tennessee, United States

Huntsman Cancer Institute at the University of Utah Site Number : 840002

Salt Lake City, Utah, United States

Fred Hutchinson Cancer Research Center Site Number : 840012

Seattle, Washington, United States

Medical College of Wisconsin Site Number : 840017

Milwaukee, Wisconsin, United States

Investigational Site Number : 032003

Capital Federal, Buenos Aires, Argentina

Investigational Site Number : 032002

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Investigational Site Number : 032001

Ciudad de Buenos Aires, Buenos Aires, Argentina

Investigational Site Number : 056001

Antwerp, , Belgium

Hospital Mae de Deus Site Number : 076003

Porto Alegre, Rio Grande do Sul, Brazil

Hospital de Amor - Hospital do Cancer de Barretos - Fundacao Pio XII Site Number : 076001

Barretos, São Paulo, Brazil

Clínica São Germano Site Number : 076002

São Paulo, São Paulo, Brazil

Instituto COI de Educacao e Pesquisa Site Number : 076004

Rio de Janeiro, , Brazil

Investigational Site Number : 152001

Temuco, La Araucanía, Chile

Investigational Site Number : 246001

Helsinki, , Finland

Investigational Site Number : 246002

Turku, , Finland

Investigational Site Number : 250003

Nantes, , France

Investigational Site Number : 250004

Pierre-Bénite, , France

Investigational Site Number : 250001

Toulouse, , France

Investigational Site Number : 300001

Athens, , Greece

Investigational Site Number : 376004

Jerusalem, , Israel

Investigational Site Number : 376002

Tel Litwinsky, , Israel

Investigational Site Number : 380001

Bologna, , Italy

Investigational Site Number : 380002

Torino, , Italy

Investigational Site Number : 484003

San Luis Potosí City, San Luis Potosí, Mexico

Investigational Site Number : 484001

Monterrey, , Mexico

Investigational Site Number : 604001

Arequipa, , Peru

Investigational Site Number : 604002

Lima, , Peru

Investigational Site Number : 643002

Moscow, , Russia

Investigational Site Number : 643003

Novosibirsk, , Russia

Investigational Site Number : 643001

Petrozavodsk, , Russia

Investigational Site Number : 643004

Saint Petersburg, , Russia

Investigational Site Number : 724005

Barcelona, Barcelona [Barcelona], Spain

Investigational Site Number : 724007

Badalona, Catalunya [Cataluña], Spain

Investigational Site Number : 724002

Pamplona, Navarre, Spain

Investigational Site Number : 724006

Valencia, Valenciana, Comunidad, Spain

Investigational Site Number : 724004

Madrid, , Spain

Investigational Site Number : 724001

Salamanca, , Spain

Investigational Site Number : 724008

Seville, , Spain

Investigational Site Number : 792002

Ankara, , Turkey (Türkiye)

Investigational Site Number : 792005

Ankara, , Turkey (Türkiye)

Investigational Site Number : 792001

Istanbul, , Turkey (Türkiye)

Investigational Site Number : 792004

Samsun, , Turkey (Türkiye)

Investigational Site Number : 804001

Kyiv, , Ukraine

Investigational Site Number : 804004

Vinnytsia, , Ukraine

Investigational Site Number : 804002

Zaporizhzhya, , Ukraine

Investigational Site Number : 826002

Southampton, Hampshire, United Kingdom

Investigational Site Number : 826001

Nottingham, Nottinghamshire, United Kingdom

Countries

United States; Argentina; Belgium; Brazil; Chile; Finland; France; Greece; Israel; Italy; Mexico; Peru; Russia; Spain; Turkey (Türkiye); Ukraine; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 33080623 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32409691 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U1111-1116-5472

Identifier Type: REGISTRY

Identifier Source: secondary_id

2013-001418-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

TED10893

Identifier Type: -

Identifier Source: org_study_id