Safety, Preliminary Efficacy and PK of Isatuximab (SAR650984) Alone or in Combination With Atezolizumab in Patients With Advanced Malignancies

NCT03637764 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: ACT153772018-000390-67U1111-1202-0839
• Study Type: interventional
• Target: 107
• Locations: 8 countries
• Sites: 26

Brief Summary

Primary Objectives:

• Phase 1: To characterize the safety and tolerability of isatuximab in combination with atezolizumab in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC), or recurrent glioblastoma multiforme (GBM), and to determine the recommended Phase 2 dose (RP2D).
• Phase 2: To assess response rate (RR) of isatuximab in combination with atezolizumab in participants with HCC or SCCHN or EOC.
• Phase 2: To assess the progression free survival rate at 6 months (PFS-6) of isatuximab in combination with atezolizumab, or as a single agent in participants with GBM. Secondary Objectives:
• To evaluate the safety profile of isatuximab monotherapy (GBM only), or in combination with atezolizumab in Phase 2.
• To evaluate the immunogenicity of isatuximab and atezolizumab.
• To characterize the pharmacokinetic (PK) profile of isatuximab single agent (GBM only) and atezolizumab in combination with isatuximab.
• To assess the overall efficacy of isatuximab in combination with atezolizumab, or single agent (GBM only).

Conditions

Neoplasm

Keywords

Anti-CD38 monoclonal antibody

Outcome Measures

Primary Outcomes (10)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  DLTs: AEs occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause which included: hematological abnormalities: Grade(G) 4 neutropenia(N) for 7 or 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 thrombocytopenia with clinically significant bleeding/ G4 thrombocytopenia. Non-hematological abnormalities: G \>=2 Aspartate transaminase (AST)/ Alanine transaminase (ALT) elevation simultaneous with G \>=2 total bilirubin elevation without initial findings of cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting greater than (\>)3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE. Any other AE that study committee deemed to be dose-limiting, regardless of grade, was also considered DLT.

  Cycle 1 (21 days)

• Recommended Phase 2 Dose (RP2D)

  RP2D was the starting dose selected for Phase 2 part of the study. RP2D was the selected dose at which no more than 1 out of 6 participants (starting dose or dose level minus -1 \[DL-1\]) or 2 out of 12 participants (starting dose) experienced a DLT related to the investigational medicinal product. DLTs: Adverse Event (AE) occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause included: hematological abnormalities: G4 N for 7/ more consecutive days, G3 to G4 N with fever, G3/G4 thrombocytopenia. Non-hematological abnormalities: G\>=2 AST/ALT elevation simultaneous with G \>=2 total bilirubin elevation without cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting \>3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE.

  Cycle 1 (21 days)

• Maximum Tolerated Dose (MTD)

  MTD was defined as the highest dose level at which no more than 1 out of 6 participants (starting dose or DL-1) or 2 out of 12 participants (starting dose) experienced a DLT related to the investigational medicinal product. DLTs: AE occurring during 1st treatment cycle, unless due to disease progression/obviously unrelated cause included: hematological abnormalities: G4 N for 7 or more consecutive days, G3 to G4 N with fever, G3 or G4 thrombocytopenia. Non-hematological abnormalities: G\>=2 AST/ ALT elevation simultaneous with G \>=2 total bilirubin elevation without cholestasis or any other reason found, G4 non-hematologic AE, G3 to 4 cytokine release syndrome, G3 non-hematological AE lasting \>3 days, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities or AEs.

  Cycle 1 (21 days)

• Percentage of Participants With Overall Response (OR): For HCC/SCCHN/EOC Cohorts

  OR was defined as the percentage of participants with complete response (CR) and partial response (PR) as best overall response, assessed per RECIST 1.1 criteria. Best overall response was derived per RECIST 1.1 criteria using disease assessments performed from the first dose of treatment throughout the study excluding any assessments performed after the cut-off date or following the initiation of a further anticancer treatment. CR was defined as the disappearance of all target lesions, pathological lymph nodes (target/non-target)- reduction in short axis \<10 mm; PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Disease progression was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum, sum with an absolute increase of diameter of at least 5 mm and appearance of \>1 new lesion.

  From randomization until disease progression, or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)

• Probability of Participants With Progression Free Survival at 6 Months (PFS-6): GBM Cohort

  PFS-6 was defined as the probability of participants alive without disease progression at 6 months as assessed by RANO criteria. Participants who didn't experience documented progression or death before analysis cut-off date or date of initiation of new anticancer treatment, PFS was censored at date of last valid disease assessment not showing progression performed prior to initiation of further anticancer treatment or analysis cut-off date, whichever was 1st. Per RANO criteria, progressive disease was defined as \>=25% increase size of T1- gadolinium enhancing disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status. PFS-6 was evaluated by Kaplan-Meier method.

  From randomization until 6 months after the last participant's first treatment in the GBM Cohort D-1

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

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

• Number of Participants With Hematological Abnormalities

  Hematological parameters assessed were anemia, white blood cell (WBC) decreased, platelet count decreased, lymphocyte count decreased, and neutrophil count decreased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

• Number of Participants With Abnormal Electrolyte Parameters

  Electrolyte parameters assessed were hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoalbuminemia, hypoglycemia and hyperglycemia. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

• Number of Participants With Renal Function Abnormalities

  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. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

• Number of Participants With Liver Abnormalities

  Abnormal liver function parameters assessed were AST increased, ALT increased, alkaline phosphatase (ALP) increased, blood bilirubin (BB) increased. Parameters were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life Threatening. Grade refers to the severity of the AEs.

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

Secondary Outcomes (16)

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

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure:106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

• Number of Participants With Anti-drug Antibodies (ADA) Response Against Atezolizumab

  From Baseline up to 30 days after last study treatment administration (maximum duration of exposure: 106 weeks for Cohort A, 108 weeks for Cohort B, 61 weeks for Cohort C and 54 weeks for Cohort D-1)

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

  At start of infusion (SOI), end of infusion (EOI), EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1

• Pharmacokinetics (PK): Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab

  At end of infusion on Cycle 1 Day 1

• Pharmacokinetics (PK): Time to Reach Cmax (Tmax) After First Infusion of Isatuximab

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

Study Arms (4)

Cohort A: HCC: Isatuximab + Atezolizumab

EXPERIMENTAL

Participants with hepatocellular carcinoma (HCC) received atezolizumab 1200 milligrams, every 3 weeks (Q3W), intravenous (IV) infusion along with isatuximab 10 milligrams per kilogram (mg/kg), IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable adverse events (AE), participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 106 weeks).

Drug: Isatuximab SAR650984; Drug: Atezolizumab

Cohort B: SCCHN: Isatuximab + Atezolizumab

EXPERIMENTAL

Participants with squamous cell carcinoma of the head and neck (SCCHN) received atezolizumab 1200 milligrams,Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 108 weeks).

Drug: Isatuximab SAR650984; Drug: Atezolizumab

Cohort C: EOC: Isatuximab + Atezolizumab

EXPERIMENTAL

Participants with epithelial ovarian cancer (EOC) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 61 weeks).

Drug: Isatuximab SAR650984; Drug: Atezolizumab

Cohort D-1: GBM: Isatuximab + Atezolizumab

EXPERIMENTAL

Participants with glioblastoma multiforme (GBM) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks).

Drug: Isatuximab SAR650984; Drug: Atezolizumab

Interventions

Isatuximab SAR650984 DRUG

Pharmaceutical form: solution for infusion Route of administration: intravenous

Also known as: Sarclisa

Cohort A: HCC: Isatuximab + Atezolizumab; Cohort B: SCCHN: Isatuximab + Atezolizumab; Cohort C: EOC: Isatuximab + Atezolizumab; Cohort D-1: GBM: Isatuximab + Atezolizumab

Atezolizumab DRUG

Pharmaceutical form: solution for infusion Route of administration: intravenous

Also known as: Tecentriq®

Cohort A: HCC: Isatuximab + Atezolizumab; Cohort B: SCCHN: Isatuximab + Atezolizumab; Cohort C: EOC: Isatuximab + Atezolizumab; Cohort D-1: GBM: Isatuximab + Atezolizumab

Eligibility Criteria

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

You may qualify if:

• Participants must have a known diagnosis of either unresectable HCC, platinum-refractory recurrent/metastatic SCCHN, platinum-resistant/refractory EOC with evidence of measurable disease or recurrent GBM.
• Greater than or equal to (\>=)18 years of age.
• For participants with HCC: Documentation of progressive disease (PD) during or after treatment with either sorafenib or lenvatinib, or intolerance to the therapy.
• For participants with SCCHN: Received and failed up to 2 lines of prior systemic anti-cancer therapy with documentation of tumor recurrence or PD within 6 months of last platinum-based therapy in primary, recurrent, or metastatic setting.
• For participants with EOC: Received up to 3 lines of prior platinum-containing therapy when the disease was platinum-sensitive, and the participants should not have received any systemic therapy for platinum-resistant/refractory disease. Specific to France only: Documentation of PD on or after 1 line of anti-cancer therapy for platinum resistant/refractory disease (unless participants are ineligible or intolerant to standard of care for platinum-resistant/refractory disease).
• For participants with GBM: Documentation of PD or first recurrence during or after temozolomide maintenance therapy for newly diagnosed GBM treated with 1st line radiotherapy plus concurrent temozolomide.

You may not qualify if:

• Prior exposure to agent that blocks CD38 or participation in clinical studies with isatuximab.
• For participants with HCC, SCCHN, EOC or GBM 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.
• Received a live-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
• Prior solid organ or bone marrow transplantation.
• Eastern Cooperative Oncology Group performance status \>=2 for participants with HCC, SCCHN or EOC or Karnofsky performance score less than or equal to (\<=) 70 for participants with GBM.
• 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 (26)

Investigational Site Number :8400004

Santa Monica, California, 90404, United States

Location

Investigational Site Number :8400007

Boston, Massachusetts, 02115, United States

Location

Investigational Site Number :8400002

Houston, Texas, 77030, United States

Location

Investigational Site Number :0560001

Brussels, 1200, Belgium

Location

Investigational Site Number :0560002

Ghent, 9000, Belgium

Location

Investigational Site Number :1240001

Toronto, Ontario, M5G 2M9, Canada

Location

Investigational Site Number :2030001

Brno, 65653, Czechia

Location

Investigational Site Number :2030003

Olomouc, 77900, Czechia

Location

Investigational Site Number :2030002

Prague, 12808, Czechia

Location

Investigational Site Number :3800007

Meldola, Forlì-Cesena, 47014, Italy

Location

Investigational Site Number :3800003

Rozzano, Milano, 20089, Italy

Location

Investigational Site Number :3800009

Milan, 20141, Italy

Location

Investigational Site Number :3800004

Padua, 35128, Italy

Location

Investigational Site Number :5280001

Rotterdam, 3015 CE, Netherlands

Location

Investigational Site Number :7240001

Barcelona, Barcelona [Barcelona], 08035, Spain

Location

Investigational Site Number :7240006

Hospitalet de Llobregat, Castille and León, 08908, Spain

Location

Investigational Site Number :7240004

Madrid, Madrid, Comunidad de, 28050, Spain

Location

Investigational Site Number :7240003

Madrid / Madrid, Madrid, Comunidad de, 28040, Spain

Location

Investigational Site Number :7240008

Pamplona, Navarre, 31008, Spain

Location

Investigational Site Number :7240007

Madrid, 28041, Spain

Location

Investigational Site Number :1580005

Kaohsiung City, 807, Taiwan

Location

Investigational Site Number :1580002

Tainan, 704, Taiwan

Location

Investigational Site Number :1580003

Taipei, 104, Taiwan

Location

Investigational Site Number :1580006

Taipei, 112, Taiwan

Location

Investigational Site Number :1580004

Taipei, 114, Taiwan

Location

Investigational Site Number :1580001

Taipei, Taiwan

Location

Related Publications (1)

• Simonelli M, Garralda E, Eskens F, Gil-Martin M, Yen CJ, Obermannova R, Chao Y, Lonardi S, Melichar B, Moreno V, Yu ML, Bongiovanni A, Calvo E, Rottey S, Machiels JP, Gonzalez-Martin A, Paz-Ares L, Chang CL, Mason W, Lin CC, Reardon DA, Vieito M, Santoro A, Meng R, Abbadessa G, Menas F, Lee H, Liu Q, Combeau C, Ternes N, Ziti-Ljajic S, Massard C. Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study. ESMO Open. 2022 Oct;7(5):100562. doi: 10.1016/j.esmoop.2022.100562. Epub 2022 Aug 18.

  PMID: 35987165 BACKGROUND

MeSH Terms

Conditions

Neoplasms

Interventions

isatuximab; atezolizumab

Limitations and Caveats

Study was stopped after performance of interim analysis for 4 cohorts (Cohort A \[HCC\], Cohort B \[SCCHN\], Cohort C \[EOC\] \& Cohort D-1 \[GBM\]) as the efficacy results observed in each cohort did not fulfill the pre-planned interim analysis criteria allowing the study to move to Phase 2 Stage 2 in these 4 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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2018
• First Posted: August 20, 2018
• Study Start: August 6, 2018
• Primary Completion: May 11, 2022
• Study Completion: May 11, 2022
• Last Updated: July 10, 2023
• Results First Posted: June 8, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share

Locations

BE (2); CA (1); NL (1); CZ (3); ES (6); TW (6); IT (4); US (3)