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
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.
Study details:
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Phase 2: Histologically confirmed diagnosis of unresectable or metastatic NSCLC with KRAS G12C mutation and any PD-L1 TPS
- Phase 3: Histologically confirmed diagnosis of unresectable or metastatic squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS >=50%
- Phase 3: Presence of evaluable or measurable disease per RECIST
- Phase 3: CNS Inclusion - Based on screening brain imaging, patients must have one of the following:
- 1. No evidence of brain metastases
- 2. Untreated brain metastases not needing immediate local therapy
- 3. Previously treated brain metastases not needing immediate local therapy
Exclusion criteria
- 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).
- Phase 2: Active brain metastases
- Phase 3: Patients with known central nervous system (CNS) lesions must not have any of the following:
- 1. Any untreated brain lesions > 1.0 cm in size
- 2. Any brainstem lesions
- 3. 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.
- 4. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain lesions notwithstanding CNS-directed therapy
- Phase 3: Radiation to the lung > 30 Gy within 6 months prior to the first dose of study treatment
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2PHASE3
Study ID
NCT04613596
Intervention or treatment
DRUG: Adagrasib
DRUG: Adagrasib
DRUG: Adagrasib
DRUG: Adagrasib
DRUG: Pembrolizumab
Conditions
- Advanced Non-Small Cell Lung Cancer
- Metastatic Non-Small Cell Lung Cancer
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Research sites nearby
Closest Location:
Ballarat Regional Integrated Cancer Center
Select from list below to view details:
Ballarat Regional Integrated Cancer Center
Ballarat, Australia
Flinders Medical Centre
Bedford Park, Australia
Local Institution - 007-004
Clayton, Australia
Canberra Hospital
Garran, Australia
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Who is running the clinical trial?
Mirati Therapeutics Inc.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Phase 2 Cohort 1a: PD-L1 TPS <1%
| Drug: Adagrasib |
EXPERIMENTAL: Phase 2 Cohort 1b: PD-L1 TPS <1%
| Drug: Adagrasib |
EXPERIMENTAL: Phase 2 Cohort 2: PD-L1 TPS ≥1%
| Drug: Adagrasib |
EXPERIMENTAL: Phase 3 Cohort 3 Investigational Arm
| Drug: Adagrasib |
ACTIVE_COMPARATOR: Phase 3 Cohort 4 Comparator Arm
| Drug: Pembrolizumab |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC. | Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) | 22 months |
| Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab | Progression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival | 36 months |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Phase 2: To characterize the safety and tolerability of study treatments in selected populations | Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities. | 22 months |
| Phase 2: Duration of Response | 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. | 22 months |
| Phase 2: Progression Free Survival | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. | 22 months |
| Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations | 1-Year Survival rate | 12 months |
| Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations | Overall Survival (OS) | 22 months |
| Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations. | Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations | 22 months |
| Phase 3: To evaluate the safety and tolerability in the study population | Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities. | 36 months |
| Phase 3: To evaluate the PK of adagrasib administered in the study population | Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations | 36 months |
| Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population | Patient Reported Outcomes to measure quality of life | 36 months |
| Phase 3: Progression Free Survival per RECIST 1.1 by Investigator | Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first. | 36 months |
| Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR | 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. | 36 months |
| Phase 3: Objective Response Rate (ORR) per RECIST 1.1 by Investigator and BICR | Defined as the percent of patients documented to have a confirmed CR or PR. | 36 months |
References
Clinical Trials Gov: 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-7Other trials to consider
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