Clinical trial NCT04418661: Safety and Efficacy Study of Vociprotafib (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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Metastatic Neoplasm
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Revolution Medicines, Inc.
name: Mirati Therapeutics Inc.
First posted: 2020-06-05
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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 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.)

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 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.

Primary outcomes:
measure: Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of IMP up to 30 days after the last dose; approximately 27 weeks
measure: Parts 1 and 3A: Number of Participants With Treatment Related Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (21 days)
measure: Part 2: Percentage of Participants With Objective Response Rate (ORR)
timeFrame: Tumor assessments performed every 9 weeks (56 ±7 days) after the date of first IMP up to end of treatment, approximately 107 weeks
measure: Part 3A: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events
timeFrame: From first dose of IMP up to 30 days after the last dose; approximately 7 weeks
measure: Part 4: Plasma Concentration of SAR442720 in Combination With Pembrolizumab
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours post-dose on C1 D1, C1 D15, C2 D1; Pre-dose on C1 D8 and C6 D1; end of treatment (Week 45)
measure: Part 4: Area Under Curve From Zero to Last Concentration Timepoint (AUClast) for SAR442720 Tablets and Capsules
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours on C1 D1, C1 D15 and C2D1
measure: Part 4: Maximum Observed Plasma Concentration (Cmax) for SAR442720 Tablets and Capsules
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours on C1 D1, C1 D15 and C2 D1
measure: Part 4: Time to Reach Maximum Plasma Concentration (Tmax) for SAR442720 Tablets and Capsules
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, 24 hours on C1 D1, C1 D15 and C2 D1
Secondary outcomes:
measure: Part 1: Plasma Concentration of SAR442720
timeFrame: Pre-dose, 2, 8, hours post-dose on C1 D1 and C2D1; pre-dose C1D8, C1D15, and C6D1; 2 hours C2D2; and end of treatment (Week 22)
measure: Part 2: Plasma Concentration of SAR442720
timeFrame: Pre-dose and 2 hours post-dose C1D1 and C2D1; pre-dose on C1D8, C1D15, C6D1; and end of treatment (Week 104)
measure: Parts 1 and 2: Serum Concentration of Pembrolizumab
timeFrame: Pre-dose and post-dose C1D1; pre-dose on C2D1 and C6D1
measure: Parts 1 and 4: Percentage of Participants With Objective Response Rate
timeFrame: Tumor assessments performed on C3 D1 (± 7 days) and every 2 cycles up to C7 D1 (± 7 days), and then every 3 cycles thereafter, approximately 23.7 weeks (Part 1), 46 weeks (Part 4)
measure: Part 1: Duration of Response (DoR)
timeFrame: Tumor assessments performed on C3 D1 (± 7 days) and every 2 cycles up to C7 D1 (± 7 days), and then every 3 cycles thereafter, approximately 23.7 weeks
measure: Part 2: Duration of Response
timeFrame: Tumor assessments performed every 9 weeks (56 ±7 days) after the date of first IMP up to end of treatment, approximately 107 weeks
measure: Part 2: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events
timeFrame: From first dose of IMP up to 30 days after the last dose; approximately 111 weeks
measure: Part 4: Number of Participants With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events
timeFrame: From first dose of IMP up to 30 days after the last dose; approximately 50 weeks
measure: Part 2: Time to Response (TTR)
timeFrame: Tumor assessments performed every 9 weeks (56 ±7 days) after the date of first IMP up to end of treatment, approximately 107 weeks
measure: Part 2: Percentage of Participants With Clinical Benefit Rate
timeFrame: Tumor assessments performed every 9 weeks (56 ±7 days) after the date of first IMP up to end of treatment, approximately 107 weeks
measure: Part 2: Percentage of Participants With Disease Control Rate
timeFrame: Tumor assessments performed every 9 weeks (56 ±7 days) after the date of first IMP up to end of treatment, approximately 107 weeks
measure: Part 2: Progression Free Survival (PFS)
timeFrame: Tumor assessments performed every 9 weeks (56 ±7 days) after the date of first IMP up to end of treatment, approximately 107 weeks
measure: Part 3A: Plasma Concentration of SAR442720
timeFrame: Pre-dose, 0.5, 1, 2, 4, 6, 24 hours post-dose C1D1; pre-dose C1D8; pre-dose, 0.5, 1, 2, 4, 6 post-dose C1D15, and end of treatment (Week 3)
measure: Part 3A: Plasma Concentration of Adagrasib
timeFrame: Pre-dose, 1, 2, 4, 6, 8 post-dose C1D1 and C1D15; pre-dose C1D8
measure: Part 3A: Percentage of Participants With Objective Response Rate
timeFrame: Tumor assessments performed till end of treatment, approximately 3 weeks
measure: Part 3A: Duration of Response
timeFrame: Tumor assessments performed till end of treatment, approximately 3 weeks
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California Irvine Medical Center- Site Number : 8400002
state: California
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center- Site Number : 8400001
state: Texas
city: Rosario
country: Argentina
facility: Investigational Site Number : 0320003
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320001
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320004
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320002
city: Sydney
country: Australia
facility: Investigational Site Number : 0360002
state: New South Wales
city: Woolloongabba
country: Australia
facility: Investigational Site Number : 0360001
state: Queensland
city: Melbourne
country: Australia
facility: Investigational Site Number : 0360003
state: Victoria
city: Temuco
country: Chile
facility: Investigational Site Number : 1520002
state: La Araucanía
city: Santiago
country: Chile
facility: Investigational Site Number : 1520001
state: Reg Metropolitana De Santiago
city: Viña Del Mar
country: Chile
facility: Investigational Site Number : 1520003
state: Valparaíso
city: Cheongju-si
country: Korea, Republic of
facility: Investigational Site Number : 4100003
state: Chungcheongbuk-do
city: Seongnam-si
country: Korea, Republic of
facility: Investigational Site Number : 4100002
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100001
state: Seoul-teukbyeolsi
city: Madrid
country: Spain
facility: Investigational Site Number : 7240001
city: Madrid
country: Spain
facility: Investigational Site Number : 7240002
city: Valencia
country: Spain
facility: Investigational Site Number : 7240003
city: Tainan City
country: Taiwan
facility: Investigational Site Number : 1580002
city: Taipei City
country: Taiwan
facility: Investigational Site Number : 1580001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: