Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination in Patients With a KRAS G12C Mutation KRYSTAL-7
- Conditions
- Advanced Non-Small Cell Lung CancerMetastatic Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT04613596
- Lead Sponsor
- Mirati Therapeutics Inc.
- Brief Summary
The Phase 2 portion of this study evaluates the efficacy and safety of MRTX849 monotherapy and in combination with pembrolizumab in cohorts of patients with advanced NSCLC with KRAS G12C mutation and any PD-L1 TPS and who are candidates for first-line treatment.
The Phase 3 portion of the study compares the efficacy of adagrasib in combination with pembrolizumab versus pembrolizumab in patients with unresectable, locally advanced or metastatic squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS \>=50% and who are candidates for first line treatment.
- Detailed Description
The Phase 2 portion of this study will evaluate the efficacy and safety of MRTX849 as monotherapy and in combination with pembrolizumab. There will be 3 cohorts of patients, all of whom have KRAS G12C mutation, have advanced or metastatic NSCLC, and are candidates for first-line treatment. 2 cohorts have PD-L1 TPS score \<1% and are randomized to MRTX849 monotherapy or MRTX849 in combination with pembrolizumab. The 3rd cohort has PD-L1 TPS score of 1% or higher and is treated with MRTX849 and pembrolizumab
The Phase 3 portion of the study will randomize patients with squamous or nonsquamous NSCLC with KRAS G12C mutation and TPS \>=50% in the first-line setting to adagrasib plus pembrolizumab or pembrolizumab. Primary efficacy objective is to compare efficacy between experimental and comparator arms. Secondary and exploratory objectives include evaluation of secondary efficacy endpoints, safety and tolerability, adagrasib PK, PROs, and correlative genomic biomarkers for the combination regimen in the study population.
MRTX849 is an orally available small molecule inhibitor of KRAS G12C, and Pembrolizumab (KEYTRUDA®) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 806
-
Phase 2: Histologically confirmed diagnosis of unresectable or metastatic NSCLC with KRAS G12C mutation and any PD-L1 TPS
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Phase 3: Histologically confirmed diagnosis of unresectable or metastatic squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS >=50%
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Phase 3: Presence of evaluable or measurable disease per RECIST
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Phase 3: CNS Inclusion - Based on screening brain imaging, patients must have one of the following:
- No evidence of brain metastases
- Untreated brain metastases not needing immediate local therapy
- Previously treated brain metastases not needing immediate local therapy
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Phase 2 and Phase 3: Prior systemic treatment for locally advanced or metastatic NSCLC including chemotherapy, immune checkpoint inhibitor therapy, or a therapy targeting KRAS G12C mutation (e.g., AMG 510).
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Phase 2: Active brain metastases
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Phase 3: Patients with known central nervous system (CNS) lesions must not have any of the following:
- Any untreated brain lesions > 1.0 cm in size
- Any brainstem lesions
- Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a total daily dose of > 10 mg of prednisone (or equivalent) prior to randomization.
- Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain lesions notwithstanding CNS-directed therapy
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Phase 3: Radiation to the lung > 30 Gy within 6 months prior to the first dose of study treatment
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2 Cohort 1a: PD-L1 TPS <1% Adagrasib Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab Phase 2 Cohort 2: PD-L1 TPS ≥1% Adagrasib Cohort 2: Adagrasib BID in combination with pembrolizumab Phase 2 Cohort 1b: PD-L1 TPS <1% Adagrasib Cohort 1b: Adagrasib BID monotherapy Phase 3 Cohort 3 Investigational Arm Adagrasib Adagrasib BID in combination with pembrolizumab Phase 3 Cohort 4 Comparator Arm Pembrolizumab Pembrolizumab
- Primary Outcome Measures
Name Time Method Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC. 22 months Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab 36 months Progression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival
- Secondary Outcome Measures
Name Time Method Phase 2: To characterize the safety and tolerability of study treatments in selected populations 22 months Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.
Phase 2: Duration of Response 22 months Defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of either Progression of Disease (PD) or death due to any cause, whichever occurs first.
Phase 2: Progression Free Survival 22 months Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first.
Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations 22 months Overall Survival (OS)
Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations. 22 months Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations
Phase 3: To evaluate the PK of adagrasib administered in the study population 36 months Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations
Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population 36 months Patient Reported Outcomes to measure quality of life
Phase 3: Progression Free Survival per RECIST 1.1 by Investigator 36 months Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first.
Phase 3: Objective Response Rate (ORR) per RECIST 1.1 by Investigator and BICR 36 months Defined as the percent of patients documented to have a confirmed CR or PR.
Phase 3: To evaluate the safety and tolerability in the study population 36 months Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.
Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR 36 months Defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of either Progression of Disease (PD) or death due to any cause, whichever occurs first.
Trial Locations
- Locations (715)
Local Institution - 007-556-A
🇺🇸Goodyear, Arizona, United States
USOR - Arizona Oncology - Prescott Valley
🇺🇸Prescott Valley, Arizona, United States
Local Institution - 007-568-A
🇺🇸Safford, Arizona, United States
Local Institution - 007-568-B
🇺🇸Safford, Arizona, United States
Local Institution - 007-568-C
🇺🇸Safford, Arizona, United States
Local Institution - 007-568-D
🇺🇸Safford, Arizona, United States
Local Institution - 007-568-E
🇺🇸Safford, Arizona, United States
Arizona Clinical Research Center
🇺🇸Tucson, Arizona, United States
Highlands Oncology Group - Springdale
🇺🇸Springdale, Arkansas, United States
Providence - Saint Joseph Home Health - Anaheim
🇺🇸Anaheim, California, United States
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