A Study of SAR444245 Combined With Other Anticancer Therapies for the Treatment of Participants With Lung Cancer or Mesothelioma (Pegathor Lung 202)

Phase 2

Terminated

Conditions: Pleural Mesothelioma
Non-small Cell Lung Cancer

Interventions: Drug: THOR-707
Drug: Pembrolizumab

Registration Number: NCT04914897

Lead Sponsor: Sanofi

Brief Summary: The Primary Objective was:

-To determine the antitumor activity of SAR444245 in combination with other anticancer therapies.

The Secondary Objectives were:

* To confirm the dose and to assess the safety profile of SAR444245 when combined with other anticancer therapies.

* To assess other indicators of antitumor activity.

* To assess the pharmacokinetic (PK) profile of SAR444245 when given in combination with pembrolizumab.

* To assess the immunogenicity of SAR444245.

Detailed Description: The duration of the study for an individual participant started from the signature of the main informed consent and included a screening period of up to 28 days, a treatment period \[max 35 cycles {cohorts A1, A2, and B1} = 735 days or until PD {cohort C1}\], an end-of-treatment visit at least 30 days following the last administration of study drug (or until the participant 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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 106

Inclusion Criteria

Participant must have been ≥18 years of age (or country's legal age of majority if >18 years), at the time of signing the informed consent.
Histologically or cytologically confirmed diagnosis of Stage IV NSCLC (cohorts A1, A2, and B1), or unresectable malignant pleural mesothelioma (cohort C1).
Cohort A1: PD-L1 expression TPS ≥ 50%
Cohort A2: PD-L1 expression TPS 1 - 49%
Prior anticancer therapy
Cohorts A1 and A2: No prior systemic therapy for advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease.
Cohort B1: One prior anti-PD1/PD-L1 regimen (may include chemotherapy) plus one additional chemotherapy regimen
Cohort C1: One or two prior systemic treatments that include pemetrexed-based regimen in combination with platinum agent.
All cohorts must have had a measurable disease
Mandatory baseline biopsy for the first 20 participants to enroll in cohorts A1, A2
Cohort B1: Based on the Investigator's judgment, either docetaxel or pemetrexed is not the best treatment option for the participant.
Females were eligible to participate if they were 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 150 days after discontinuing study treatment
- to refrain from donating or cryopreserving eggs for 150 days after discontinuing study treatment.
Males were 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 210 days after discontinuing study treatment.
Capable of giving signed informed consent.

Exclusion Criteria

Participants were excluded from the study if any of the following criteria applied:

Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2.
Poor bone marrow reserve
Poor organ function
Participants with baseline SpO2 ≤ 92%.
Active brain metastases or leptomeningeal disease.
History of allogenic tissue/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 or local intervention within 28 days.
Has received prior IL-2-based anticancer treatment.
Comorbidity requiring corticosteroid therapy
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
Known second malignancy either progressing or requiring active treatment within the last 3 years
Cohorts A1, A2, and C1: Prior treatment with an agent (approved or investigational) that blocks the PD1/PD-L1 pathway (participants who joined a study with an anti-PD1/PD-L1 but have written confirmation they were on control arm are allowed).
Receipt of a live-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 the potential participation in a clinical trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A1: NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy	THOR-707	Participants with previously untreated Stage IV non-small cell lung cancer (NSCLC) and programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) of \>=50% were included in this cohort. Participants received pegenzileukin 24 microgram per kilogram (μg/kg) along with pembrolizumab 200 milligram (mg) via intravenous (IV) infusion over 30 minutes every 3 weeks (q3w) on Day 1 of each cycle (each cycle is 21 days) (as first-line \[1L\] therapy), until disease progression (PD), unacceptable adverse event (AE) or other full permanent discontinuation criteria was met or completion of Cycle 35.
Cohort A1: NSCLC, PD-L1 TPS >=50%:Pegenzileukin 24 μg/kg + Pembrolizumab as 1L Therapy	Pembrolizumab	Participants with previously untreated Stage IV non-small cell lung cancer (NSCLC) and programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) of \>=50% were included in this cohort. Participants received pegenzileukin 24 microgram per kilogram (μg/kg) along with pembrolizumab 200 milligram (mg) via intravenous (IV) infusion over 30 minutes every 3 weeks (q3w) on Day 1 of each cycle (each cycle is 21 days) (as first-line \[1L\] therapy), until disease progression (PD), unacceptable adverse event (AE) or other full permanent discontinuation criteria was met or completion of Cycle 35.
Cohort A2: NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy	THOR-707	Participants with previously untreated Stage IV NSCLC and PD-L1 TPS of 1%-49% were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as 1L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Cohort A2: NSCLC, PD-L1 TPS 1%-49%:Pegenzileukin 24 μg/kg+Pembrolizumab as 1L Therapy	Pembrolizumab	Participants with previously untreated Stage IV NSCLC and PD-L1 TPS of 1%-49% were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as 1L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy	THOR-707	Participants with NSCLC for whom standard of care (SOC) was not in their best interest or where no SOC was established were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as second-line or third-line \[2/3L\] therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Cohort B1: NSCLC:Pegenzileukin 24 μg/kg+Pembrolizumab as 2/3L Therapy	Pembrolizumab	Participants with NSCLC for whom standard of care (SOC) was not in their best interest or where no SOC was established were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes q3w on Day 1 of each cycle (each cycle is 21 days) (as second-line or third-line \[2/3L\] therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35.
Cohort C1: Mesothelioma: Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy	THOR-707	Participants with mesothelioma who had no SOC established and had experienced PD during or after at least one but no more than 2 prior regimens were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes 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.
Cohort C1: Mesothelioma: Pegenzileukin 24 μg /kg+Pembrolizumab as 2/3L Therapy	Pembrolizumab	Participants with mesothelioma who had no SOC established and had experienced PD during or after at least one but no more than 2 prior regimens were included in this cohort. Participants received pegenzileukin 24 μg/kg along with pembrolizumab 200 mg via IV infusion over 30 minutes 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.

Primary Outcome Measures

Name	Time	Method
Cohorts A1 and A2: Objective Response Rate (ORR)	From first dose of study treatment administration (Day 1) up to approximately 21 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. 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: Objective Response Rate	From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 14 months	ORR was defined as the percentage of participants who had a confirmed CR or PR as per RECIST v1.1. 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 C1: Objective Response Rate	From first dose of study treatment administration (Day 1) up to approximately 21 months	ORR was defined as the percentage of participants who had a confirmed CR or PR assessed by the investigator as per modified RECIST (mRECIST) v1.1. CR. 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 Outcome Measures

Name	Time	Method
All Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 28 months (Cohorts A1 and A2), 15 months (Cohort B1), and 25 months (Cohort C1)	An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any AE 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 or was an important medical event. TEAEs were defined as AEs that developed, worsened (according to the investigator's opinion) or became serious during the TE period.
All Cohorts: Number of Participants With Dose Limiting Toxicities (DLTs)	From Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)	Selected events that occurred during DLT observation period were considered as DLT unless due to PD or to a cause obviously unrelated to pegenzileukin. Selected events included: grade (G) 4 neutropenia for \>=7 consecutive days, G3 or 4 neutropenia complicated by fever or microbiologically or radiographically documented infection, G3 or 4 thrombocytopenia associated with clinically significant bleeding that required clinical intervention; G3 or above alanine aminotransferase or aspartate aminotransferase in combination with a bilirubin \>2 times upper limit of normal with no evidence of cholestasis or another cause such as viral infection or other drugs;G3 or above vascular leak syndrome, hypotension, and cytokine release syndrome;any other G3; G3 or 4 non-hematologic laboratory value; any death not clearly due to the underlying disease or extraneous causes;any toxicity that required permanent discontinuation of the study treatment(s).
All Cohorts: Time to Response (TTR)	From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)	TTR was defined as the time from the date of first study treatment administration to the first tumor assessment at which the overall response was recorded as PR or CR that was subsequently confirmed as per RECIST v 1.1 (NSCLC) and assessed by the investigator as per mRECIST v1.1 (mesothelioma). 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.
All Cohorts: Duration of Response (DOR)	From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)	DOR was defined as time from date of first tumor assessment at which overall response was recorded as CR or PR that was subsequently confirmed to date of first documentation of objective PD before initiation of any post-treatment anti-cancer therapy or death due to any cause, whichever occurred first, as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). CR: 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: 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 the smallest sum on study (this included baseline sum if that was smallest on study), in addition to relative increase of 20%, sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm).
All Cohorts: Clinical Benefit Rate (CBR)	From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)	The CBR was defined as the percentage of participants with clinical benefit: confirmed CR or PR as best overall response (BOR), or stable disease (SD) that lasted at least 6 months as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). CR: 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: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. BOR was the best response observed from start of the study treatment until PD, death, cut-off date or initiation of post-treatment anticancer therapy, whichever occurred first. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
All Cohorts: Progression Free Survival (PFS)	From first dose of study treatment administration (Day 1) up to maximum exposure of study treatment; approximately 27 months (Cohorts A1 and A2), 14 months (Cohort B1), and 24 months (Cohort C1)	The PFS was defined as the time from the date of first study treatment to the date of the first documentation of objective PD, or death due to any cause, whichever occurred first as per RECIST v 1.1 (NSCLS) and assessed by investigator as per mRECIST v1.1 (mesothelioma). PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study), in addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm (0.5 cm).
All Cohorts: Plasma Concentrations of Pegenzileukin	Days 2 and 3 of Cycle 1 (each cycle is 21 days)	Blood samples were collected at specified timepoints for the assessment of plasma concentrations of pegenzileukin. The pharmacokinetic (PK) parameters were calculated using non-compartmental method.
All Cohorts: Concentration at End of Infusion (Ceoi) of Pegenzileukin	Cycles 1, 2, 4, 7, 10, and 15 (each cycle is 21 days)	Blood samples were collected at specified timepoints for the assessment of Ceoi of pegenzileukin.
All Cohorts: Number of Participants With Anti-Drug Antibodies (ADAs) Against Pegenzileukin	From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment; approximately 28 months (Cohorts A1 and A2), 15 months (Cohort B1), and 25 months (Cohort C1)	Blood samples were collected at specified timepoints to assess the presence of ADAs against pegenzileukin. Treatment-emergent ADA was defined as at least one treatment-induced or treatment-boosted ADA. Treatment-induced ADA was defined as ADA that developed during the TE period and without pre-existing ADA (including participants without pre-treatment samples). Treatment-boosted ADA was defined as pre-existing ADA that was boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADA is presented.

Trial Locations

Locations (35): Thomas Jefferson University Hospital Site Number : 8400009
🇺🇸
Philadelphia, Pennsylvania, United States
Thomas Jefferson University - North East Site Number : 8401009
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Philadelphia, Pennsylvania, United States
Investigational Site Number : 0320002
🇦🇷
CABA, Buenos Aires, Argentina
Investigational Site Number : 0360002
🇦🇺
Richmond, Victoria, Australia
Investigational Site Number : 1520005
🇨🇱
Santaigo, Reg Metropolitana de Santiago, Chile
Investigational Site Number : 1520004
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Santiago, Reg Metropolitana de Santiago, Chile
Investigational Site Number : 1520002
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Santiago, Reg Metropolitana de Santiago, Chile
Investigational Site Number : 1520001
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Santiago, Reg Metropolitana de Santiago, Chile
Investigational Site Number : 1520003
🇨🇱
Temuco, Chile
Investigational Site Number : 2500006
🇫🇷
Bordeaux, France
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Thomas Jefferson University Hospital Site Number : 8400009
🇺🇸Philadelphia, Pennsylvania, United States