A Phase 2 Non-randomized, Open-label, Multi-cohort, Multi-center Study Assessing the Clinical Benefit of SAR444245 (THOR-707) Combined With Other Anticancer Therapies for the Treatment of Participants With Advanced and Metastatic Gastrointestinal Cancer
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Sanofi
- Enrollment
- 138
- Locations
- 29
- Primary Endpoint
- Cohort A: Objective Response Rate (ORR)
Study Overview
Brief Summary
The study is a phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical benefit of SAR444245 (THOR-707) combined with other anticancer therapies for the treatment of participants aged 18 years and older with advanced and metastatic gastrointestinal cancer. This study is structured as a master protocol for the investigation of SAR444245 with other anticancer therapies.
Sub study 01 - Cohort A aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC).
Sub study 02 - Cohort B1, B2 and B3 would focus on non MSI-H tumors with a large unmet need to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), especially with low PD-L1 expression or after progression on prior PD1/PD-L1-based regimens.
Sub study 03 - Cohort C aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in participants with advanced unresectable or metastatic HCC who relapsed on prior PD1/PD-L1-based regimens.
Sub study 04 - Cohort D1 and D2 aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 antibody cetuximab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic colorectal cancer (mCRC).
Detailed Description
The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 28 days, a treatment period [max 35 cycles {cohort A; B1,B2, B3, C and D1} = 735 days or until PD {cohort D2}], an end-of-treatment visit at least 30 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or death, whichever is earlier.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participant must be ≥18 years of age (or country's legal age of majority if >18 years), at the time of signing the informed consent.
- •Participants with:
- •Sub-study01: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic esophageal cancer of the squamous cell carcinoma subtype.
- •Sub-study02: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ.
- •Sub-study03: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic hepatocellular carcinoma (HCC), or clinically by AASLD criteria in cirrhotic patients.
- •Sub-study04: Histologically or cytologically confirmed diagnosis of advanced unresectable or mCRC. Only patients with non-MSI-H disease are eligible.
- •Participants (all sub-studies) must have at least one measurable lesion.
- •Mandatory baseline biopsy for the first 20 participants to enroll in sub-study01, sub-study02 and sub-study
- •On-treatment biopsy for at least 20 participants in sub-study
- •On-treatment biopsies are otherwise optional per Investigator's discretion for the other cohorts.
- •Females are eligible to participate if they are not pregnant or breastfeeding, not a woman of childbearing potential (WOCBP) or are a WOCBP that agrees:
- •to use approved contraception method and submit to regular pregnancy testing prior to treatment and for at least 120 days (for Cohort A, B1, B2, B3, C, and D1) or 60 days (for Cohort D2) [corresponding to the time needed to eliminate any study intervention(s)].
- •and to refrain from donating or cryopreserving eggs for 120 days after discontinuing study treatment.
- •Males are eligible to participate if they agree to refrain from donating or cryopreserving sperm, and either abstain from heterosexual intercourse OR use approved contraception during study treatment and for at least 3 days [corresponding to time needed to eliminate SAR444245] after the last dose of SAR
- •Capable of giving signed informed consent.
Exclusion Criteria
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≥
- •Poor organ function.
- •Active brain metastases or leptomeningeal disease.
- •History of allogenic or solid organ transplant.
- •Last administration of prior antitumor therapy or any investigational treatment within 28 days or less than 5 times the half-life, whichever is shorter; major surgery within 28 days prior to first IMP administration.
- •Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 2 weeks of IMP initiation. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder. Participants who require a brief course of steroids (eg, as prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not excluded).
- •Antibiotic use (excluding topical antibiotics) ≤14 days prior to first dose of IMP.
- •Severe or unstable cardiac condition within 6 months prior to starting study treatment.
- •Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years.
- •Participants with baseline SpO2 ≤92% (without oxygen therapy). - Participant has received prior IL2-based anticancer treatment.
- •Participants on sub-study02 cohort B1 and B2 or sub-study 04 - cohort D1 with prior treatment with an agent that blocks the PD-1/PD-L1 pathway.
- •Receipt of a live-virus or live attenuated-virus vaccination within 28 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
- •The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Arms & Interventions
Cohort A: ESCC Post PD-1/PD-L1; SAR444245 24 mcg/kg + Pembrolizumab as 2/3L Therapy
Participants with advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC), regardless of programmed cell death-ligand 1 (PD-L1) expression (any combined positive score [CPS]), who had received at least 1 but no more than 2 prior lines of treatment and had progressed after primary or secondary resistance to an anti-programmed cell death-1 (PD-1)/PD-L1 based regimen were included in this cohort. Participants received SAR444245 24 microgram per kilogram (mcg/kg) along with pembrolizumab 200 milligram (mg) via intravenous (IV) infusion every 3 weeks (q3w) on Day 1 of each cycle (each cycle is 21 days) (as second-line or third-line [2/3L] therapy), until disease progression (PD), unacceptable adverse event (AE) or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: THOR-707 (Drug)
Cohort A: ESCC Post PD-1/PD-L1; SAR444245 24 mcg/kg + Pembrolizumab as 2/3L Therapy
Participants with advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC), regardless of programmed cell death-ligand 1 (PD-L1) expression (any combined positive score [CPS]), who had received at least 1 but no more than 2 prior lines of treatment and had progressed after primary or secondary resistance to an anti-programmed cell death-1 (PD-1)/PD-L1 based regimen were included in this cohort. Participants received SAR444245 24 microgram per kilogram (mcg/kg) along with pembrolizumab 200 milligram (mg) via intravenous (IV) infusion every 3 weeks (q3w) on Day 1 of each cycle (each cycle is 21 days) (as second-line or third-line [2/3L] therapy), until disease progression (PD), unacceptable adverse event (AE) or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: Pembrolizumab (Drug)
Cohort B1: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS >=1
Cohort B1: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS >=1; SAR444245 24mcg/kg+Pembrolizumab as 1-3L Therapy. Participants with advanced unresectable or metastatic gastric cancer (GC) or Siewert Type 2 & 3 gastro-esophageal junction adenocarcinoma (GEJ) and for whom standard of care (SOC) was not in best interest or where no SOC was established, non-high-level microsatellite instability (MSI-H) disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS >=1 GC/GEJ were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as first to [1-]3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: THOR-707 (Drug)
Cohort B1: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS >=1
Cohort B1: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS >=1; SAR444245 24mcg/kg+Pembrolizumab as 1-3L Therapy. Participants with advanced unresectable or metastatic gastric cancer (GC) or Siewert Type 2 & 3 gastro-esophageal junction adenocarcinoma (GEJ) and for whom standard of care (SOC) was not in best interest or where no SOC was established, non-high-level microsatellite instability (MSI-H) disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS >=1 GC/GEJ were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as first to [1-]3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: Pembrolizumab (Drug)
Cohort B2: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS <1
Cohort B2: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS <1; SAR444245 24 mcg/kg+Pembrolizumab as 1-3L Therapy. Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS <1 GC/GEJ were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 1-3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: THOR-707 (Drug)
Cohort B2: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS <1
Cohort B2: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS <1; SAR444245 24 mcg/kg+Pembrolizumab as 1-3L Therapy. Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS <1 GC/GEJ were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 1-3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: Pembrolizumab (Drug)
Cohort B3: GC/GEJ Post PD-1/PD-L1 non-MSI-H; SAR444245 24 mcg/kg + Pembrolizumab as 2-4L Therapy
Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had received atleast 1 and no more than 3 prior lines of treatment and had progressed after primary or secondary resistance to an anti-PD-1/PD-L1-based regimen (regardless of the disease CPS status) were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2-fourth [4]L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: THOR-707 (Drug)
Cohort B3: GC/GEJ Post PD-1/PD-L1 non-MSI-H; SAR444245 24 mcg/kg + Pembrolizumab as 2-4L Therapy
Participants with advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had received atleast 1 and no more than 3 prior lines of treatment and had progressed after primary or secondary resistance to an anti-PD-1/PD-L1-based regimen (regardless of the disease CPS status) were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2-fourth [4]L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: Pembrolizumab (Drug)
Cohort C: HCC Post PD-1/PD-L1; SAR444245 24 mcg/kg + Pembrolizumab as 2/3L Therapy
Participants with advanced unresectable or metastatic hepatocellular carcinoma (HCC), regardless of any CPS, who relapsed on prior PD-1/PD-L1-based regimens, with at least stable disease (SD) as best response and with no more than 2 prior lines of treatment were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2/3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: THOR-707 (Drug)
Cohort C: HCC Post PD-1/PD-L1; SAR444245 24 mcg/kg + Pembrolizumab as 2/3L Therapy
Participants with advanced unresectable or metastatic hepatocellular carcinoma (HCC), regardless of any CPS, who relapsed on prior PD-1/PD-L1-based regimens, with at least stable disease (SD) as best response and with no more than 2 prior lines of treatment were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2/3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: Pembrolizumab (Drug)
Cohort D1: CRC non-MSI-H any RAS; SAR444245 24 mcg/kg + Pembrolizumab as 3-6L Therapy
Participants with advanced unresectable or metastatic colorectal cancer (CRC), regardless of any CPS, non-MSI-H disease, any RAS type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 3-sixth [6]L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: THOR-707 (Drug)
Cohort D1: CRC non-MSI-H any RAS; SAR444245 24 mcg/kg + Pembrolizumab as 3-6L Therapy
Participants with advanced unresectable or metastatic colorectal cancer (CRC), regardless of any CPS, non-MSI-H disease, any RAS type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 3-sixth [6]L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Intervention: Pembrolizumab (Drug)
Cohort D2: CRC non-MSI-H RAS Wild Type; SAR444245 24 mcg/kg + Cetuximab as 3-6L Therapy
Participants with advanced unresectable or metastatic CRC, regardless of any CPS, non-MSI-H disease, RAS wild type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received SAR444245 24 mcg/kg q3w on Day 1 of each cycle along with cetuximab as an initial loading dose of 400 mg/square meter (m^2) on Cycle 1 Day 1 followed by 250 mg/m^2 starting via IV infusion once weekly from Cycle 1 Day 8 (each cycle is 21 days) (as 3-6L therapy) until PD.
Intervention: THOR-707 (Drug)
Cohort D2: CRC non-MSI-H RAS Wild Type; SAR444245 24 mcg/kg + Cetuximab as 3-6L Therapy
Participants with advanced unresectable or metastatic CRC, regardless of any CPS, non-MSI-H disease, RAS wild type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received SAR444245 24 mcg/kg q3w on Day 1 of each cycle along with cetuximab as an initial loading dose of 400 mg/square meter (m^2) on Cycle 1 Day 1 followed by 250 mg/m^2 starting via IV infusion once weekly from Cycle 1 Day 8 (each cycle is 21 days) (as 3-6L therapy) until PD.
Intervention: Cetuximab (Drug)
Outcomes
Primary Outcomes
Cohort A: Objective Response Rate (ORR)
Time Frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months
ORR was defined as the percentage of participants who had a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 millimeter (mm) (\<1 centimeter \[cm\]). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Cohorts B1, B2 and B3: Objective Response Rate
Time Frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 25 months
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Cohort C: Objective Response Rate
Time Frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 20 months
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Cohorts D1 and D2: Objective Response Rate
Time Frame: From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months
ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v 1.1. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Secondary Outcomes
- All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)(From first dose of study treatment administration (Day 1) up to 30 days post last dose of study treatment administration, up to approximately 9 months (Cohorts A, D1 and D2), 26 months (Cohorts B1, B2 and B3) and 21 months (Cohort C))
- All Cohorts: Time to Response (TTR)(From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C))
- All Cohorts: Duration of Response (DOR)(From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C))
- All Cohorts: Clinical Benefit Rate (CBR)(From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C))
- All Cohorts: Progression-Free Survival (PFS)(From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 8 months (Cohort A, D1 and D2), 25 months (Cohort B1, B2 and B3), 20 months (Cohort C))
- Maximum Concentration Observed (Cmax) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Last Concentration Observed Above the Lower Limit of Quantification (Clast) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Time of the Last Concentration Observed Above the Lower Limit of Quantification (Tlast) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Tlast (AUClast) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Area Under the Concentration Versus Time Curve Extrapolated to Infinity (AUC) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Observed Accumulation Ratio (Rac) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Observed Accumulation Ratio Based on Cmax (Rac,Cmax) of Pegenzileukin(Day 1 Cycle 1 and Day 1 Cycle 4 (each cycle is 21 days))
- Cohort D2: Concentration Observed Just Before Intervention Administration During Repeated Dosing (Ctrough) of Cetuximab(Cycles 1, 2, 3, 4, 6 and 8 (each cycle is 21 days))
- Cohort D2: Concentration at End of Infusion (Ceoi) of Cetuximab(Cycles 1, 2, 3, 4, 6 and 8 (each cycle is 21 days))
- All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin(From first dose of study treatment administration (Day 1) up to 30 days post last dose of study treatment administration, up to approximately 9 months (Cohorts A, D1 and D2), 26 months (Cohorts B1, B2 and B3) and 21 months (Cohort C))