Clinical trial NCT03637764: Safety, Preliminary Efficacy and PK of Isatuximab (SAR650984) Alone or in Combination With Atezolizumab in Patients With Advanced Malignancies
Official title: A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab (SAR650984) in Combination With Atezolizumab or Isatuximab Alone in Patients With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Neoplasm
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-08-20
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Eligibility criteria: Inclusion criteria:

* 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.

Exclusion criteria:

* 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.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (21 days)
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Cycle 1 (21 days)
measure: Maximum Tolerated Dose (MTD)
timeFrame: Cycle 1 (21 days)
measure: Percentage of Participants With Overall Response (OR): For HCC/SCCHN/EOC Cohorts
timeFrame: From randomization until disease progression, or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)
measure: Probability of Participants With Progression Free Survival at 6 Months (PFS-6): GBM Cohort
timeFrame: From randomization until 6 months after the last participant's first treatment in the GBM Cohort D-1
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (TESAEs)
timeFrame: 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)
measure: Number of Participants With Hematological Abnormalities
timeFrame: 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)
measure: Number of Participants With Abnormal Electrolyte Parameters
timeFrame: 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)
measure: Number of Participants With Renal Function Abnormalities
timeFrame: 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)
measure: Number of Participants With Liver Abnormalities
timeFrame: 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:
measure: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab
timeFrame: 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)
measure: Number of Participants With Anti-drug Antibodies (ADA) Response Against Atezolizumab
timeFrame: 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)
measure: Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) After the First Infusion of Isatuximab
timeFrame: 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
measure: Pharmacokinetics (PK): Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab
timeFrame: At end of infusion on Cycle 1 Day 1
measure: Pharmacokinetics (PK): Time to Reach Cmax (Tmax) After First Infusion of Isatuximab
timeFrame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
measure: Pharmacokinetics (PK): Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab
timeFrame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
measure: Pharmacokinetics (PK): Time of Clast (Tlast) After First Infusion of Isatuximab
timeFrame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
measure: Pharmacokinetics (PK): Area Under the Plasma Concentration Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) After First Infusion of Isatuximab
timeFrame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
measure: Pharmacokinetics (PK): Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUC0-168h) After First Infusion of Isatuximab
timeFrame: At SOI, EOI, EOI+4 hours, 72 hours and 168 hours post-dose on Day 1 of Cycle 1
measure: Pharmacokinetics (PK): Trough Plasma Concentrations (Ctrough) of Isatuximab
timeFrame: Pre-infusion on Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 1 Day 15
measure: Plasma Concentration of Atezolizumab
timeFrame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1 and Cycle 16 Day 1
measure: Best Percent Change From Baseline in Tumor Burden
timeFrame: From randomization until progression or death or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks)
measure: Percentage of Participants With Disease Control (DC) >=6 Months
timeFrame: From the date of first response to disease progression or death, or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)
measure: Duration of Response (DOR)
timeFrame: From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration of exposure: up to 108 weeks)
measure: Progression-free Survival (PFS)
timeFrame: From date of first study treatment administration until disease progression or death or study cut-off whichever occurred first (maximum duration of exposure: up to 108 weeks)
measure: Percentage of Participants With Response as Per Response Assessment for Neuro-Oncology (RANO) Criteria: GBM Cohort
timeFrame: From randomization until progression, or death, or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks for Cohort D-1)
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Investigational Site Number :8400004
state: California
city: Boston
country: United States
facility: Investigational Site Number :8400007
state: Massachusetts
city: Houston
country: United States
facility: Investigational Site Number :8400002
state: Texas
city: Bruxelles
country: Belgium
facility: Investigational Site Number :0560001
city: Gent
country: Belgium
facility: Investigational Site Number :0560002
city: Toronto
country: Canada
facility: Investigational Site Number :1240001
state: Ontario
city: Brno
country: Czechia
facility: Investigational Site Number :2030001
city: Olomouc
country: Czechia
facility: Investigational Site Number :2030003
city: Praha 2
country: Czechia
facility: Investigational Site Number :2030002
city: Meldola
country: Italy
facility: Investigational Site Number :3800007
state: Forlì-Cesena
city: Rozzano
country: Italy
facility: Investigational Site Number :3800003
state: Milano
city: Milano
country: Italy
facility: Investigational Site Number :3800009
city: Padova
country: Italy
facility: Investigational Site Number :3800004
city: Rotterdam
country: Netherlands
facility: Investigational Site Number :5280001
city: Barcelona
country: Spain
facility: Investigational Site Number :7240001
state: Barcelona [Barcelona]
city: Hospitalet de Llobregat
country: Spain
facility: Investigational Site Number :7240006
state: Castilla Y León
city: Madrid / Madrid
country: Spain
facility: Investigational Site Number :7240003
state: Madrid, Comunidad De
city: Madrid
country: Spain
facility: Investigational Site Number :7240004
state: Madrid, Comunidad De
city: Pamplona
country: Spain
facility: Investigational Site Number :7240008
state: Navarra
city: Madrid
country: Spain
facility: Investigational Site Number :7240007
city: Kaohsiung
country: Taiwan
facility: Investigational Site Number :1580005
city: Tainan
country: Taiwan
facility: Investigational Site Number :1580002
city: Taipei 100
country: Taiwan
facility: Investigational Site Number :1580001
city: Taipei
country: Taiwan
facility: Investigational Site Number :1580003
city: Taipei
country: Taiwan
facility: Investigational Site Number :1580006
city: Taipei
country: Taiwan
facility: Investigational Site Number :1580004
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.