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

Phase 3RecruitingNCT04613596

Mirati Therapeutics Inc.626 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Interventions

AdagrasibDRUG

Adagrasib 400 mg twice daily (BID) in combination with pembrolizumab (Cohort 1a)

AdagrasibDRUG

Adagrasib 600 mg BID monotherapy (Cohort 1b)

AdagrasibDRUG

adagrasib 400 mg BID in combination with pembrolizumab

AdagrasibDRUG

Adagrasib 400 mg BID + pembrolizumab 200 mg every Q3W

PembrolizumabDRUG

Pembrolizumab 200 mg IV Q3W

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 measurable disease per RECIST1.1 * 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 \> 2.0 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

Locations (770)

Local Institution - 007-556-A

Goodyear, Arizona, United States

NOT_YET_RECRUITING

USOR - Arizona Oncology - Prescott Valley

Prescott Valley, Arizona, United States

RECRUITING

Local Institution - 007-568-A

Safford, Arizona, United States

NOT_YET_RECRUITING

Local Institution - 007-568-B

Safford, Arizona, United States

Outcomes

Primary Outcomes

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)

Time frame: 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

Time frame: 36 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 22 months

Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations

1-Year Survival rate

Time frame: 12 months

Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations

Overall Survival (OS)

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 36 months

Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR

Time frame: 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.

Time frame: 36 months

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

Overview

Conditions

Interventions

Eligibility

Locations (770)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts