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

Primary Purpose

Metastatic Neoplasm

Status

Active

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

SAR442720

Pembrolizumab

Adagrasib

About this trial

This is an interventional treatment trial for Metastatic Neoplasm

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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 is 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 is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Sites / Locations

University of California Irvine Medical Center-Site Number:8400002
~University of Texas - MD Anderson Cancer Center-Site Number:8400001
Investigational Site Number :0320001
Investigational Site Number :0320004
Investigational Site Number :0320003
Investigational Site Number :0320002
Investigational Site Number :0360002
Investigational Site Number :0360001
Investigational Site Number :0360003
Investigational Site Number :1520004
Investigational Site Number :1520001
Investigational Site Number :1520003
Investigational Site Number :1520002
Investigational Site Number :4100003
Investigational Site Number :4100001
Investigational Site Number :4100002
Investigational Site Number :5280001
Investigational Site Number :7020001
Investigational Site Number :7240001
Investigational Site Number :7240002
Investigational Site Number :7240003
Investigational Site Number :1580002
Investigational Site Number :1580001

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

SAR442720 + Pembrolizumab

SAR442720 + Pembrolizumab: Non-small cell lung cancer with Tumor proportion score > 50%

SAR442720 + Pembrolizumab: Non-small cell lung cancer with Tumor proportion score 1-49%

SAR444270 + adagrasib: Dose Escalation

SAR444270 + adagrasib: Dose Expansion

SAR442720 + Pembrolizumab continuous

Arm Description

Part 1: SAR442720 (also known as RMC-4630) will be administered orally twice a week (BIW) followed by pembrolizumab which is given intravenously (IV) once every 3 weeks (Q3W). The dose of SAR442720 will be escalated or de-escalated depending on the emerging safety data of the combination.

Part 2: SAR442720 dose will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W)

Part 3A; SAR442720 and adagrasib will be administered orally on a continuous basis.

Part 3B: Once SAR442720 dose is confirmed in Part 3A SAR442720 and adagrasib will be administered orally on a continuous basis.

Part 4: SAR442720 will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W)

Outcomes

Primary Outcome Measures

Incidence of Adverse Events (AEs) SAR442720 and pembrolizumab

Part 1: Incidence, nature, and severity of treatment emergent AEs and serious adverse events (SAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 for the combination of SAR442720 and pembrolizumab.

Incidence of study-drug related Dose Limiting Toxicities (DLTs)

Part 1 and 3A: Incidence of study drug-related dose-limiting toxicities (DLTs) in Cycle 1.

Objective Response Rate (ORR)

Part 2 and 3B: Objective response rate defined as the proportion of participants who have a confirmed CR or partial response (PR) determined by investigator, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Incidence of Adverse Events (AEs) SAR442720 and adagrasib

Part 3A: Incidence, nature, and severity of TEAEs and SAEs, graded according to NCI CTCAEv5.0 for the combination of SAR442720 and adagrasib.

Part 4: Plasma concentrations of SAR442720 in combination with pembrolizumab under impact of food

Secondary Outcome Measures

Part 1 and 2: Plasma concentrations of SAR442720

Part 1 and 2: Serum concentration of pembrolizumab

Objective response rate (ORR) Part 1 and Part 4

Part 1 and Part 4: Objective response rate of SAR442720 and pembrolizumab in all participants. ORR of combination therapy with SAR442720 and pembrolizumab will be based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.

Duration of response (DoR)

Part 1 and Part 2 and 3B: Duration of response per RECIST v1.1 is defined as the interval from the first documentation of CR (complete response) or PR (partial response) to the earlier of the first documentation of definitive disease progression or death due to any cause, whichever occurs first.

Incidence of Adverse Events

Part 2 and 3B and Part 4: Incidence, nature, and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) graded according to the NCI CTCAE v5 for the combination of SAR442720 and pembrolizumab.

Time to Response (TTR)

Part 2 and 3B: Time to response (TTR) defined as the time from the first administration of investigational medicinal product (IMP) to the first documented evidence of PR or CR determined by the Investigator per RECIST v1.1 (for NSCLC).

Clinical Benefit Rate (CBR)

Part 2 and 3B: Clinical benefit rate (CBR) including confirmed CR or PR at any time or stable disease (SD) of at least 6 months (determined by the Investigator per RECIST v1.1.

Disease Control Rate (DCR)

Part 2 and 3B: Disease control rate (DCR) including confirmed CR or PR or stable disease (SD) as determined by the Investigator per RECIST v1.1.

Progression free survival (PFS)

Part 2 and 3B: Progression free survival (PFS), defined as the time from the date of first IMP administration to the date of the first documented disease progression determined by the Investigator as per RECIST v1.1 or death due to any cause, whichever occurs first.

Part 3A: Plasma concentrations of SAR442720

Part 3A: Plasma concentrations of adagrasib

Objective Response Rate (ORR) of SAR442720 and adagrasib

Part 3A: ORR of SAR442720 and adagrasib in all participants. ORR of combination therapy with SAR442720 and adagrasib will be based on RECIST v1.1.

Duration of Response (DOR) of SAR442720 and adagrasib

Part 3: DOR of SAR442720 and adagrasib in all participants. ORR of combination therapy with SAR442720 and adagrasib will be based on RECIST v1.1.

Part 3B: Plasma concentrations of SAR442720 and adagrasib

Full Information

NCT ID

NCT04418661

First Posted

May 29, 2020

Last Updated

May 12, 2023

Sponsor

Sanofi

Collaborators

Revolution Medicines, Inc., Mirati Therapeutics Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04418661

Brief Title

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

Official Title

A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of SAR442720 in Combination With Other Agents in Participants With Advanced Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

May 12, 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

June 9, 2020 (Actual)

Primary Completion Date

July 15, 2024 (Anticipated)

Study Completion Date

July 15, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

Collaborators

Revolution Medicines, Inc., Mirati Therapeutics Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

Detailed Description

This open label Phase 1 multicenter study is 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 will assess the antitumor activity and safety of SAR442720 combined with pembrolizumab in participants with metastatic 1L lung cancer. In Part 3, we will evaluate 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 will evaluate 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 is 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.)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Neoplasm

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

65 (Actual)

8. Arms, Groups, and Interventions

Arm Title

SAR442720 + Pembrolizumab

Arm Type

Experimental

Arm Description

Arm Title

SAR442720 + Pembrolizumab: Non-small cell lung cancer with Tumor proportion score > 50%

Arm Type

Experimental

Arm Description

Part 2: SAR442720 dose will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W)

Arm Title

SAR442720 + Pembrolizumab: Non-small cell lung cancer with Tumor proportion score 1-49%

Arm Type

Experimental

Arm Description

Part 2: SAR442720 dose will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W)

Arm Title

SAR444270 + adagrasib: Dose Escalation

Arm Type

Experimental

Arm Description

Part 3A; SAR442720 and adagrasib will be administered orally on a continuous basis.

Arm Title

SAR444270 + adagrasib: Dose Expansion

Arm Type

Experimental

Arm Description

Part 3B: Once SAR442720 dose is confirmed in Part 3A SAR442720 and adagrasib will be administered orally on a continuous basis.

Arm Title

SAR442720 + Pembrolizumab continuous

Arm Type

Experimental

Arm Description

Part 4: SAR442720 will be administered orally in combination with Pembrolizumab which is given by IV infusion once every 3 weeks (Q3W) or once every 6 weeks (Q6W)

Intervention Type

Drug

Intervention Name(s)

SAR442720

Intervention Description

Pharmaceutical form: Varies Route of administration: Varies

Intervention Type

Drug

Intervention Name(s)

Pembrolizumab

Intervention Description

Pharmaceutical form:Sterile Lyophilized powder for reconstitution Route of administration: Infusion

Intervention Type

Drug

Intervention Name(s)

Adagrasib

Intervention Description

Pharmaceutical form:Sterile Tablet Route of administration: Oral

Primary Outcome Measure Information:

Title

Incidence of Adverse Events (AEs) SAR442720 and pembrolizumab

Description

Time Frame

21 days

Title

Incidence of study-drug related Dose Limiting Toxicities (DLTs)

Description

Part 1 and 3A: Incidence of study drug-related dose-limiting toxicities (DLTs) in Cycle 1.

Time Frame

up to 2 years

Title

Objective Response Rate (ORR)

Description

Time Frame

up to 2 years

Title

Incidence of Adverse Events (AEs) SAR442720 and adagrasib

Description

Part 3A: Incidence, nature, and severity of TEAEs and SAEs, graded according to NCI CTCAEv5.0 for the combination of SAR442720 and adagrasib.

Time Frame

up to 2 years

Title

Part 4: Plasma concentrations of SAR442720 in combination with pembrolizumab under impact of food

Time Frame

up to 2 years

Secondary Outcome Measure Information:

Title

Part 1 and 2: Plasma concentrations of SAR442720

Time Frame

up to 2 years

Title

Part 1 and 2: Serum concentration of pembrolizumab

Time Frame

up to 2 years

Title

Objective response rate (ORR) Part 1 and Part 4

Description

Time Frame

up to 2 years

Title

Duration of response (DoR)

Description

Time Frame

up to 2 years

Title

Incidence of Adverse Events

Description

Time Frame

up to 2 years

Title

Time to Response (TTR)

Description

Time Frame

up to 2 years

Title

Clinical Benefit Rate (CBR)

Description

Part 2 and 3B: Clinical benefit rate (CBR) including confirmed CR or PR at any time or stable disease (SD) of at least 6 months (determined by the Investigator per RECIST v1.1.

Time Frame

up to 2 years

Title

Disease Control Rate (DCR)

Description

Part 2 and 3B: Disease control rate (DCR) including confirmed CR or PR or stable disease (SD) as determined by the Investigator per RECIST v1.1.

Time Frame

up to 2 years

Title

Progression free survival (PFS)

Description

Time Frame

up to 2 years

Title

Part 3A: Plasma concentrations of SAR442720

Time Frame

up to 2 years

Title

Part 3A: Plasma concentrations of adagrasib

Time Frame

up to 2 years

Title

Objective Response Rate (ORR) of SAR442720 and adagrasib

Description

Part 3A: ORR of SAR442720 and adagrasib in all participants. ORR of combination therapy with SAR442720 and adagrasib will be based on RECIST v1.1.

Time Frame

up to 2 years

Title

Duration of Response (DOR) of SAR442720 and adagrasib

Description

Part 3: DOR of SAR442720 and adagrasib in all participants. ORR of combination therapy with SAR442720 and adagrasib will be based on RECIST v1.1.

Time Frame

up to 2 years

Title

Part 3B: Plasma concentrations of SAR442720 and adagrasib

Time Frame

up to 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 is 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 is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

University of California Irvine Medical Center-Site Number:8400002

City

Orange

State/Province

California

ZIP/Postal Code

92868

Country

United States

Facility Name

~University of Texas - MD Anderson Cancer Center-Site Number:8400001

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Investigational Site Number :0320001

City

Caba

State/Province

Buenos Aires

ZIP/Postal Code

C1019ABS

Country

Argentina

Facility Name

Investigational Site Number :0320004

City

Caba

State/Province

Ciudad De Buenos Aires

ZIP/Postal Code

C1078AAI

Country

Argentina

Facility Name

Investigational Site Number :0320003

City

Rosario

State/Province

Santa Fe

ZIP/Postal Code

2000

Country

Argentina

Facility Name

Investigational Site Number :0320002

City

Buenos Aires

ZIP/Postal Code

C1125ABD

Country

Argentina

Facility Name

Investigational Site Number :0360002

City

Randwick

State/Province

New South Wales

ZIP/Postal Code

2031

Country

Australia

Facility Name

Investigational Site Number :0360001

City

Woolloongabba

State/Province

Queensland

ZIP/Postal Code

4102

Country

Australia

Facility Name

Investigational Site Number :0360003

City

Heidelberg West

State/Province

Victoria

ZIP/Postal Code

3081

Country

Australia

Facility Name

Investigational Site Number :1520004

City

Santiago

State/Province

Reg Metropolitana De Santiago

ZIP/Postal Code

7500713

Country

Chile

Facility Name

Investigational Site Number :1520001

City

Santiago

State/Province

Reg Metropolitana De Santiago

ZIP/Postal Code

8420383

Country

Chile

Facility Name

Investigational Site Number :1520003

City

Viña del Mar

State/Province

Valparaíso

ZIP/Postal Code

2520598

Country

Chile

Facility Name

Investigational Site Number :1520002

City

Temuco

ZIP/Postal Code

4800827

Country

Chile

Facility Name

Investigational Site Number :4100003

City

Cheongju-si

State/Province

Chungcheongbuk-do

ZIP/Postal Code

28644

Country

Korea, Republic of

Facility Name

Investigational Site Number :4100001

City

Seoul

State/Province

Seoul-teukbyeolsi

ZIP/Postal Code

03722

Country

Korea, Republic of

Facility Name

Investigational Site Number :4100002

City

Seongnam-si, Gyeonggi-do

ZIP/Postal Code

13496

Country

Korea, Republic of

Facility Name

Investigational Site Number :5280001

City

Leiden

ZIP/Postal Code

2333 ZA

Country

Netherlands

Facility Name

Investigational Site Number :7020001

City

Singapore

Country

Singapore

Facility Name

Investigational Site Number :7240001

City

Madrid / Madrid

State/Province

Madrid, Comunidad De

ZIP/Postal Code

28040

Country

Spain

Facility Name

Investigational Site Number :7240002

City

Madrid / Madrid

State/Province

Madrid, Comunidad De

ZIP/Postal Code

28050

Country

Spain

Facility Name

Investigational Site Number :7240003

City

Valencia / Valencia

State/Province

Valenciana, Comunidad

ZIP/Postal Code

46010

Country

Spain

Facility Name

Investigational Site Number :1580002

City

Tainan

ZIP/Postal Code

704

Country

Taiwan

Facility Name

Investigational Site Number :1580001

City

Taipei

ZIP/Postal Code

100

Country

Taiwan

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

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

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