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Isatuximab in Combination With REGN2810 (Cemiplimab) in Patients With Advanced Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03367819
Recruitment Status : Terminated (The study was stopped after interim analysis indicated that overall result was not sufficient to satisfy per-protocol criteria to move forward in metastatic, castration-resistant prostate cancer (mCRPC) and non-small cell lung cancer (NSCLC) cohorts.)
First Posted : December 11, 2017
Results First Posted : May 16, 2022
Last Update Posted : May 16, 2022
Sponsor:
Information provided by (Responsible Party):
Sanofi

Brief Summary:

Primary Objectives:

  • To characterize the safety and tolerability of isatuximab in combination with REGN2810 in participants with metastatic, castration-resistant prostate cancer (mCRPC) who were naïve to anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1)-containing therapy, or non-small cell lung cancer (NSCLC) who progressed on anti-PD-1/PD-L1-containing therapy, and to confirm the recommended Phase 2 dose (RP2D).
  • To assess the response rate of isatuximab in combination with REGN2810 in participants with either mCRPC who were anti-PD-1/PD-L1 therapy naive, or NSCLC who progressed on anti-PD-1/PD-L1 therapy, or of isatuximab as single agent in participants with mCRPC.

Secondary Objectives:

  • To evaluate the safety of the combination of isatuximab with REGN2810 or isatuximab monotherapy.
  • To evaluate the immunogenicity of isatuximab and REGN2810.
  • To characterize the pharmacokinetic (PK) profile of isatuximab single agent or in combination with REGN2810, and to characterize the PK of REGN2810 in combination with isatuximab.
  • To assess overall efficacy of isatuximab in combination with REGN2810 or as a single agent.

Condition or disease Intervention/treatment Phase
Prostate Cancer Non-small Cell Lung Cancer Drug: Isatuximab SAR650984 Drug: Cemiplimab REGN2810 Phase 1 Phase 2

Detailed Description:
The total study duration per participant was up to 28 months including an up to 28 days screening period, an up to 24 months treatment period, and a 3 months safety follow up period.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Random assignment used only for allocation to Cohort A-1 or A-2
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab (SAR650984) in Combination With REGN2810, or Isatuximab Alone, in Patients With Advanced Malignancies
Actual Study Start Date : January 4, 2018
Actual Primary Completion Date : March 10, 2021
Actual Study Completion Date : March 10, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Isatuximab

Arm Intervention/treatment
Experimental: Phase 1: mCRPC/NSCLC
Isatuximab dose 1 and REGN2810 predefined dose
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Other Name: Sarclisa

Drug: Cemiplimab REGN2810

Pharmaceutical form: solution for infusion

Route of administration: intravenous


Experimental: Cohort A-1: mCRPC, isatuximab and REGN2810 combination
Participants with mCRPC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Other Name: Sarclisa

Drug: Cemiplimab REGN2810

Pharmaceutical form: solution for infusion

Route of administration: intravenous


Experimental: Cohort A-2: mCRPC, isatuximab monotherapy
Participants with mCRPC will be given isatuximab dose 2
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Other Name: Sarclisa

Experimental: Phase 2 Cohort B: NSCLC
Participants with NSCLC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Other Name: Sarclisa

Drug: Cemiplimab REGN2810

Pharmaceutical form: solution for infusion

Route of administration: intravenous


Experimental: Possibly Phase 2 Cohort C: mCRPC
Isatuximab dose 3 will be given in combination with REGN2810 predefined dose or isatuximab dose 3 will be given as monotherapy in participants with mCRPC
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Other Name: Sarclisa

Drug: Cemiplimab REGN2810

Pharmaceutical form: solution for infusion

Route of administration: intravenous


Experimental: Possibly Phase 2 Cohort D: NSCLC
Isatuximab dose 3 will be given in combination with REGN2810 predefined dose
Drug: Isatuximab SAR650984

Pharmaceutical form: solution for infusion

Route of administration: intravenous

Other Name: Sarclisa

Drug: Cemiplimab REGN2810

Pharmaceutical form: solution for infusion

Route of administration: intravenous





Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (21 days) ]
    DLTs: adverse events occurring during 1st treatment cycle, unless due to disease progression/to cause obviously unrelated to investigational medicinal product (IMP) which included:hematological abnormalities: Grade(G) 4 neutropenia(N) for 7/more consecutive days, G3 to G4 N with fever (temperature greater than or equal to [>=] 38.5 degree Celsius on more than 1 occasion) or microbiologically/radiographically documented infection, G3 to G4 thrombocytopenia with clinically significant bleeding. Non-hematological abnormalities: G4 non-hematologic AE, G>=2 uveitis, G3 non-hematological AE lasting greater than (>)3 days (except G3 fatigue, allergic reaction/hypersensitivity attributed to isatuximab or REGN2810 and G3 or G4 clinically non-significant laboratory abnormality), delay in initiation of Cycle 2 >14 days due to treatment related laboratory abnormalities/AE. Any other toxicity that Investigator and Sponsor deemed to be dose-limiting, regardless of grade, was also considered as DLT.

  2. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) ]
    An 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. Serious adverse events (SAEs) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study treatment up to 30 days after the last dose of study treatment). TEAEs included both SAEs and non-SAEs.

  3. Number of Participants With Laboratory Abnormalities: Hematological Parameters [ Time Frame: From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) ]
    Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased and neutrophil count decreased. Abnormality criteria was based on National Cancer Institute Common Terminology Criteria for Adverse Event version 4.03 (NCI-CTCAE v 4.03), where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Only those categories in which at least 1 participant had data were reported.

  4. Number of Participants With Laboratory Abnormalities: Electrolytes [ Time Frame: From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) ]
    Abnormal electrolytes parameters assessed were hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia and hyperglycemia. Abnormality criteria was based on NCI-CTCAE v 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Only those categories in which at least 1 participant had data were reported.

  5. Number of Participants With Laboratory Abnormalities: Renal Parameters [ Time Frame: From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) ]
    Abnormal renal parameters assessed were creatinine clearance (CrCl), creatinine increased and hyperuricemia. Creatinine clearance was assessed in categories: >=60 - less than (<) 90 milliliters per minute per 1.73 square meter (mL/min/1.73m^2), >=30 - <60 mL/min/1.73m^2, >=15 - <30 mL/min/1.73m^2 and <15 mL/min/1.73m^2. Creatinine increased and hyperuricemia abnormality criteria was based on NCI-CTCAE v 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. For all these 3 parameters, only those categories in which at least 1 participant had data were reported.

  6. Number of Participants With Laboratory Abnormalities: Liver Function Parameters [ Time Frame: From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years) ]
    Abnormal liver function parameters assessed were aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Abnormality criteria was based on NCI-CTCAE v 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Only those categories in which at least 1 participant had data were reported.

  7. Overall Response Rate (ORR): Percentage of Participants With Overall Response [ Time Frame: From the date of randomization to the date of first documentation of progression or death due to any cause, whichever occurred first (maximum duration: up to 2 years) ]
    For participants with mCRPC, response was defined as achieving complete response (CR) or partial response (PR) as best overall response (BOR) for soft tissue assessed and confirmed by the Investigators and/or a prostate-specific antigen (PSA) decline of >=50 percent (%) from Baseline that was subsequently confirmed per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. For participants with NSCLC, ORR was defined as the percentage of participants with CR or PR as BOR according to RECIST 1.1. criteria. Per RECIST 1.1. criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in short axis to <10 millimeters (mm) and PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.


Secondary Outcome Measures :
  1. Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab, Post Treatment [ Time Frame: From Baseline up to 2 years ]
    ADA response were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA (including participants without pretreatment samples).

  2. Number of Participants With Anti-drug Antibodies (ADA) Response Against REGN2810, Post Treatment [ Time Frame: From Baseline up to 2 years ]
    ADA response were categorized as treatment boosted ADA and treatment-induced ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA (including participants without pretreatment samples).

  3. Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab [ Time Frame: At start of infusion (SOI), before actual end of infusion (EOI), EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 ]
    Cmax was defined as the maximum observed plasma concentration. Cmax analysis was done separately for isatuximab for participants with mCRPC and NSCLC.

  4. Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) After the First Infusion of REGN2810 [ Time Frame: At SOI, before actual EOI, EOI+4 hours, 72 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1 ]
    Cmax was defined as the maximum observed plasma concentration. Cmax analysis was done separately for REGN2810 for participants with mCRPC and NSCLC.

  5. Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours (AUC0-168 hr) After the First Administration of Isatuximab [ Time Frame: At SOI, before actual EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1 ]
    AUC0-168 hr was defined as the area under the plasma concentration-time curve from time zero to 168h and was calculated using the trapezoidal method over the dosing interval (i.e., 7 days) for isatuximab alone.

  6. Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 504 Hours (AUC0-504 hr) After the First Administration of REGN2810 [ Time Frame: At SOI, before actual EOI, EOI+4 hours, 72 hours, 168 hours, 336 hours and 504 hours post-dose on Day 1 of Cycle 1 ]
    AUC0-504 hr was defined as the area under the plasma concentration-time curve from time zero to 504h and was calculated using the trapezoidal method over the dosing interval (i.e., 21 days) for REGN2810 alone.

  7. Best Percent-change From Baseline in Tumor Burden [ Time Frame: Up to 2 years ]
    Tumor burden change was defined as the best percent-change from Baseline in a sum of the diameters (longest for non-nodal lesion, short axis for nodal lesions) for all target lesions.

  8. Duration of Response (DOR) [ Time Frame: From the date of first response until disease progression or death, whichever occurred first (maximum duration: up to 2 years) ]
    DOR: defined as time (in months) from date of first response (PR or CR in radiographic objective response, or PSA decline >=50% for participants with mCRPC) that was subsequently confirmed to the date of first disease progression (PD) or death, whichever occurred first. PD included radiographic disease progression or unequivocal clinical progression. RECIST 1.1 criteria was used to assess radiographic PD in participants with NSCLC and PCWG3 criteria for participants with mCRPC. Per RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target/non-target) must had reduction in short axis to <10 mm and PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (Baseline sum if that was smallest), sum with an absolute increase of at least 5 mm and appearance of 1 or more new lesions.

  9. Progression-free Survival (PFS) [ Time Frame: From the date of the first study treatment administration to the date of first documented disease progression or death of any cause, whichever occurred first (maximum duration: up to 2 years) ]
    For mCRPC participants, PFS was defined as the time (in months) from first study treatment administration to the date of first documented disease progression or the date of death from any cause, whichever occurred first. Disease progression included radiographic disease progression (per PCWG3 criteria) or unequivocal clinical progression. For NSCLC participants, PFS was defined as the time from first study treatment administration to the date of first documented radiographic progression (PD) (per RECIST 1.1) or the date of death from any cause, whichever occurred first. Per RECIST 1.1 criteria, PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the Baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. Appearance of 1 or more new lesions was also considered as progression. Analysis was performed using Kaplan-Meier method.

  10. Percentage of Participants With Disease Control (DC) >=6 Months [ Time Frame: From the date of first response to the date of first documented disease progression or death (due to any cause) (maximum duration: up to 2 years) ]
    Disease control: defined as percentage of participants with confirmed CR/PR/stable disease (SD), as assessed by Investigator PCWG3 modified RECIST 1.1 criteria relative to total number of participants in analysis population. Per PCWG3 modified RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target/non-target) must had reduction in short axis to <10 mm, PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference Baseline sum diameters and SD: neither sufficient shrinkage from the Baseline to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum diameters while on study. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study, sum with an absolute increase of diameter of at least 5 mm and appearance of 1 or more new lesions.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must had a known diagnosis of either metastatic castration-resistant prostate cancer (mCRPC) or non-small cell lung cancer (NSCLC) with evidence of measurable disease.
  • Failure of, inability to, or refusal to receive standard of care.
  • Greater than or equal to (>=) 18 years of age.

Exclusion Criteria:

  • Prior exposure to isatuximab or participation in clinical studies with isatuximab.
  • For participants with mCRPC, prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1 pathway.
  • Evidence of other immune related disease /conditions.
  • History of non-infectious pneumonitis requiring steroids or current pneumonitis; history of the thoracic radiation.
  • Had received a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus were permitted.
  • Prior solid organ or hematologic transplant.
  • Eastern Cooperative Oncology Group performance status (PS) >=2.
  • Poor bone marrow reserve.
  • Poor organ function.

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03367819


Locations
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United States, Alabama
Investigational Site Number 8400003
Birmingham, Alabama, United States, 35249
United States, Georgia
Investigational Site Number 8400007
Atlanta, Georgia, United States, 30322
United States, New Jersey
Investigational Site Number 8400002
Hackensack, New Jersey, United States, 07601
United States, Tennessee
Investigational Site Number 8400005
Nashville, Tennessee, United States, 37203
United States, Texas
Investigational Site Number 8400004
Houston, Texas, United States, 77030
France
Investigational Site Number 2500002
Bordeaux Cedex, France, 33076
Investigational Site Number 2500001
Villejuif, France, 94800
Italy
Investigational Site Number 3800003
Rozzano, Milano, Italy, 20089
Investigational Site Number 3800001
Orbassano, Torino, Italy, 10043
Investigational Site Number 3800006
Napoli, Italy, 80131
Investigational Site Number 3800004
Padova, Italy, 35128
Investigational Site Number 3800005
Verona, Italy, 37134
Taiwan
Investigational Site Number 1580002
Tainan, Taiwan, 704
Investigational Site Number 1580001
Taipei 100, Taiwan
United Kingdom
Investigational Site Number 8260001
Sutton, Surrey, United Kingdom, SM2 5PT
Investigational Site Number 8260002
Newcastle upon Tyne, United Kingdom, NE7 7DN
Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
  Study Documents (Full-Text)

Documents provided by Sanofi:
Study Protocol  [PDF] June 11, 2019
Statistical Analysis Plan  [PDF] December 17, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03367819    
Other Study ID Numbers: ACT15319
2017-002846-61 ( EudraCT Number )
U1111-1197-7792 ( Registry Identifier: ICTRP )
First Posted: December 11, 2017    Key Record Dates
Results First Posted: May 16, 2022
Last Update Posted: May 16, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sanofi:
Anti-CD38 monoclonal antibody
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Neoplasms by Site
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Cemiplimab
Antineoplastic Agents, Immunological
Antineoplastic Agents