Safety and Efficacy Study of Vociprotafib (SAR442720) in Combination With Other Agents in Advanced Malignancies

Sanofi

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Metastatic Neoplasm

Treatments: Drug: Adagrasib; Drug: Pembrolizumab; Drug: Vociprotafib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04418661

TCD16210

U1111-1244-2555 (Other Identifier)

2020-000436-22 (EudraCT Number)

Details and patient eligibility

About

Primary Objectives:

• Part 1
• To characterize the safety and tolerability of SAR442720 in combination with pembrolizumab in participants with advanced solid tumors.
• To define the MTD and RP2D for the combination of SAR442720 and pembrolizumab in participants with solid tumors.
• Part 2
• To determine the anti-tumor activity of SAR442720 in combination with pembrolizumab.
• Part 3A
• To define the MTD and RP2D for the combination of SAR442720 and adagrasib in participants with KRAS G12C NSCLC
• To characterize the safety and tolerability of SAR442720 in combination with adagrasib in participants with KRAS G12C NSCLC
• Part 3B
• To determine the anti-tumor activity of SAR442720 in combination with adagrasib in participants with KRAS G12C NSCLC
• Part 4
• To evaluate the impact of food on the PK of SAR442720 when dosed with pembrolizumab.
• To evaluate the impact of the formulations (formulation 1 and formulation 2) on the PK of SAR442720 when dosed with pembrolizumab.

Secondary Objectives:

• Part 1
• To assess the PK of SAR442720 with pembrolizumab, and the PK of pembrolizumab with SAR442720.
• To estimate the anti-tumor effects of SAR442720 with pembrolizumab.
• Part 2
• To assess the safety profile of SAR442720 combined with pembrolizumab.
• To assess other indicators of anti-tumor activity.
• To assess the PK of SAR442720 with pembrolizumab, and the PK of pembrolizumab with SAR442720.
• Part 3A
• To characterize the PK of SAR442720 with adagrasib, and the PK of adagrasib with SAR442720.
• To estimate the anti-tumor effects of SAR442720 with adagrasib
• Part 3B
• To assess the safety profile of SAR442720 with adagrasib in participants with KRAS G12C NSCLC.
• To assess other indicators of anti-tumor activity.
• To assess the PK of SAR442720 with adagrasib, and the PK of adagrasib with SAR442720.
• Part 4
• To assess the safety and tolerability of SAR442720 formulations with pembrolizumab
• To estimate the anti-tumor effects of SAR442720 with pembrolizumab.

Full description

This open label Phase 1 multicenter study was designed to evaluate the safety and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of SAR442720 in combination with pembrolizumab in participants with solid tumors in Part 1.

In Part 2, in the expansion cohort (Cohort A) we assessed the antitumor activity and safety of SAR442720 combined with pembrolizumab in participants with metastatic 1L lung cancer.

In Part 3, we evaluated the safety, MTD, RP2D and antitumor activity of SAR442720 in combination with adagrasib in participants with lung cancer and KRAS G12C mutation.

In Part 4, we evaluated the impact of the formulations (formulation 1 and formulation 2) and of the food on the PK of SAR442720 when dosed in combination with pembrolizumab. The expected duration of study intervention for participants may vary, based on progression date; median expected duration of study per participant was estimated to be about 10 months in Part 1, Part 3 and Part 4 (up to 1 month for screening, a median of 6 months for treatment, and a median of 3 months for long term follow-up) and in Part 2 16 months (up to 1 month for screening, a median of 12 months for treatment and a median of 3 months for long term follow up.)

Enrollment: 65 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Participants must be ≥ 18 years of age.
• Histologically proven diagnosis of advanced solid tumors.
• Participants must have one or more of the following molecular aberrations (Part 1): KRAS mutations and amplifications, BRAF Class 3 mutations, or NF1 LOF mutations.
• Participants must have following molecular aberration (Part 3A and 3B): - KRAS G12C mutation.
• At least 1 measurable disease per RECIST 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Woman of childbearing potential must agree to follow contraceptive guidance.
• Capable of giving signed informed consent.

Exclusion criteria

• Predicted life expectancy <3 months.
• Primary central nervous system (CNS) tumors.
• Symptomatic or impending cord compression. Stable CNS disease was allowed.
• History of cerebrovascular stroke or transient ischemic attack within previous 6 months.
• Prior solid organ or hematologic transplant.
• History or current retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vascular occlusion (RVO), neovascular macular degeneration.
• Any clinically significant cardiac disease.
• Active, known or suspected autoimmune disease.
• History of or current interstitial lung disease or pneumonitis.
• Receipt of a live-virus vaccination within 28 days, viral vaccine that do not contain live virus within 7 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
• Known infection with human immunodeficiency virus (HIV), known uncontrolled hepatitis B infection, active tuberculosis, or severe infection requiring parenteral antibiotic treatment.
• Inadequate hematologic, hepatic and renal function.
• Known second malignancy.
• Impairment of gastrointestinal function.
• Any unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol.
• History of severe allergic reaction to any of the study intervention components.

The above information was not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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65 participants in 6 patient groups

Part 1- SAR442720 140 mg BIW + Pembrolizumab

Experimental group

Description:

Participants were administered SAR442720 140 milligram (mg) orally twice a week (BIW) on Days 1 and 4 along with pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks (Q3W) in 21-day cycles until disease progression, unacceptable adverse events (AEs), or the participant's or investigator's decision to stop the treatment.

Treatment:

Drug: Vociprotafib

Drug: Pembrolizumab

Part 1- SAR442720 200mg BIW + Pembrolizumab

Experimental group

Description:

Participants were administered SAR442720 200 mg orally BIW on Days 1 and 2 along with pembrolizumab 200 mg via IV infusion Q3W in 21-day cycles until disease progression, unacceptable AEs, or the participant's or investigator's decision to stop the treatment.

Treatment:

Drug: Vociprotafib

Drug: Pembrolizumab

Part 2- SAR442720 200mg + Pembrolizumab - Cohort A1 (PDL1 TPS >=50%)

Experimental group

Description:

Participants with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS)\>=50% non-small cell lung cancer (NSCLC) were administered SAR442720 200 mg orally BIW on Days 1 and 2 in 21-day cycles along with an IV infusion of pembrolizumab 200 mg on Q3W (21 days cycle) or 400 mg once in every 6 weeks (Q6W) (42 days cycle) until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment.

Treatment:

Drug: Vociprotafib

Drug: Pembrolizumab

Part 2- SAR442720 200mg + Pembrolizumab - Cohort A2 (PDL1 TPS 1% - 49%)

Experimental group

Description:

Participants with PDL1 TPS 1% - 49% NSCLC were administered SAR442720 200 mg orally BIW on Days 1 and 2 in 21-day cycles along with an IV infusion of pembrolizumab 200 mg on Q3W (21 days cycle) or 400 mg Q6W (42 days cycle) until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment.

Treatment:

Drug: Vociprotafib

Drug: Pembrolizumab

Part 3A- SAR442720 100mg BIW + Adagrasib

Experimental group

Description:

Participants were administered SAR442720 100 mg orally BIW on Days 1 and 2 along with adagrasib 400 mg orally twice daily (BID) in 21-day cycles until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment.

Treatment:

Drug: Vociprotafib

Drug: Adagrasib

Part 4- SAR442720 200mg + Pembrolizumab

Experimental group

Description:

Participants were administered SAR442720 200 mg orally BIW on Days 1 and 2 in 21-day cycles (as tablet during the first cycle and as capsule from Cycle 2) along with an IV infusion of pembrolizumab 200 mg Q3W (21-day cycle)or 400 mg Q6W (42-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment.

Treatment:

Drug: Vociprotafib

Drug: Pembrolizumab