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

NCT03367819 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: ACT153192017-002846-61U1111-1197-7792
• Study Type: interventional
• Target: 44
• Locations: 5 countries
• Sites: 16

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.

Conditions

Prostate Cancer; Non-small Cell Lung Cancer

Keywords

Anti-CD38 monoclonal antibody

Outcome Measures

Primary Outcomes (7)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  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.

  Cycle 1 (21 days)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  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.

  From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years)

• Number of Participants With Laboratory Abnormalities: Hematological Parameters

  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.

  From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years)

• Number of Participants With Laboratory Abnormalities: Electrolytes

  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.

  From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years)

• Number of Participants With Laboratory Abnormalities: Renal Parameters

  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.

  From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years)

• Number of Participants With Laboratory Abnormalities: Liver Function Parameters

  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.

  From Baseline up to 30 days after the last dose of study treatments (maximum duration: up to 2 years)

• Overall Response Rate (ORR): Percentage of Participants With Overall Response

  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.

  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)

Secondary Outcomes (10)

• Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab, Post Treatment

  From Baseline up to 2 years

• Number of Participants With Anti-drug Antibodies (ADA) Response Against REGN2810, Post Treatment

  From Baseline up to 2 years

• Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab

  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

• Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) After the First Infusion of REGN2810

  At SOI, before actual EOI, EOI+4 hours, 72 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1

• Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 168 Hours (AUC0-168 hr) After the First Administration of Isatuximab

  At SOI, before actual EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

Study Arms (6)

Phase 1: mCRPC/NSCLC

EXPERIMENTAL

Isatuximab dose 1 and REGN2810 predefined dose

Drug: Isatuximab SAR650984; Drug: Cemiplimab REGN2810

Cohort A-1: mCRPC, isatuximab and REGN2810 combination

EXPERIMENTAL

Participants with mCRPC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose

Drug: Isatuximab SAR650984; Drug: Cemiplimab REGN2810

Cohort A-2: mCRPC, isatuximab monotherapy

EXPERIMENTAL

Participants with mCRPC will be given isatuximab dose 2

Drug: Isatuximab SAR650984

Phase 2 Cohort B: NSCLC

EXPERIMENTAL

Participants with NSCLC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose

Drug: Isatuximab SAR650984; Drug: Cemiplimab REGN2810

Possibly Phase 2 Cohort C: mCRPC

EXPERIMENTAL

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; Drug: Cemiplimab REGN2810

Possibly Phase 2 Cohort D: NSCLC

EXPERIMENTAL

Isatuximab dose 3 will be given in combination with REGN2810 predefined dose

Drug: Isatuximab SAR650984; Drug: Cemiplimab REGN2810

Interventions

Isatuximab SAR650984 DRUG

Pharmaceutical form: solution for infusion Route of administration: intravenous

Also known as: Sarclisa

Cohort A-1: mCRPC, isatuximab and REGN2810 combination; Cohort A-2: mCRPC, isatuximab monotherapy; Phase 1: mCRPC/NSCLC; Phase 2 Cohort B: NSCLC; Possibly Phase 2 Cohort C: mCRPC; Possibly Phase 2 Cohort D: NSCLC

Cemiplimab REGN2810 DRUG

Pharmaceutical form: solution for infusion Route of administration: intravenous

Cohort A-1: mCRPC, isatuximab and REGN2810 combination; Phase 1: mCRPC/NSCLC; Phase 2 Cohort B: NSCLC; Possibly Phase 2 Cohort C: mCRPC; Possibly Phase 2 Cohort D: NSCLC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (16)

Investigational Site Number 8400003

Birmingham, Alabama, 35249, United States

Location

Investigational Site Number 8400007

Atlanta, Georgia, 30322, United States

Location

Investigational Site Number 8400002

Hackensack, New Jersey, 07601, United States

Location

Investigational Site Number 8400005

Nashville, Tennessee, 37203, United States

Location

Investigational Site Number 8400004

Houston, Texas, 77030, United States

Location

Investigational Site Number 2500002

Bordeaux, 33076, France

Location

Investigational Site Number 2500001

Villejuif, 94800, France

Location

Investigational Site Number 3800003

Rozzano, Milano, 20089, Italy

Location

Investigational Site Number 3800001

Orbassano, Torino, 10043, Italy

Location

Investigational Site Number 3800006

Napoli, 80131, Italy

Location

Investigational Site Number 3800004

Padua, 35128, Italy

Location

Investigational Site Number 3800005

Verona, 37134, Italy

Location

Investigational Site Number 1580002

Tainan, 704, Taiwan

Location

Investigational Site Number 1580001

Taipei, Taiwan

Location

Investigational Site Number 8260001

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Investigational Site Number 8260002

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Zucali PA, Lin CC, Carthon BC, Bauer TM, Tucci M, Italiano A, Iacovelli R, Su WC, Massard C, Saleh M, Daniele G, Greystoke A, Gutierrez M, Pant S, Shen YC, Perrino M, Meng R, Abbadessa G, Lee H, Dong Y, Chiron M, Wang R, Loumagne L, Lepine L, de Bono J. Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study. J Immunother Cancer. 2022 Jan;10(1):e003697. doi: 10.1136/jitc-2021-003697.

  PMID: 35058326 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

isatuximab; cemiplimab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

The study was terminated after the interim analysis of the primary endpoint. Few planned outcome measures per-protocol were not analyzed because overall efficacy results were not sufficient at the time of interim analyses of both the cohorts.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Random assignment used only for allocation to Cohort A-1 or A-2

Study Record Dates

• First Submitted: December 5, 2017
• First Posted: December 11, 2017
• Study Start: January 4, 2018
• Primary Completion: March 10, 2021
• Study Completion: March 10, 2021
• Last Updated: May 16, 2022
• Results First Posted: May 16, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share

Locations

FR (2); IT (5); TW (2); US (5); GB (2)