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

PHASE2PHASE3RECRUITING

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 nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS \>=50% and who are candidates for first line treatment.

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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.

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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
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2020-12-02

    Primary completion: 2028-10-31

    Study completion finish: 2029-10-31

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE2

      PHASE3

    trial

    Trial 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
    Image related to Advanced Non-Small Cell Lung Cancer
    • Condition: Advanced Non-Small Cell Lung Cancer, Metastatic Non-Small Cell Lung Cancer

    • DRUG: Adagrasib and other drugs

    • Woolloongabba, Not Specified, Australia and more

    • Sponsor: Mirati Therapeutics Inc.

    Find a site

    Closest Location:

    Princess Alexandra Hospital

    Research sites nearby

    Select from list below to view details:

    • Princess Alexandra Hospital

      Woolloongabba, Not Specified, Australia

    • Ballarat Regional Integrated Cancer Center

      Ballarat, Not Specified, Australia

    • Flinders Medical Centre

      Bedford Park, Not Specified, Australia

    • Local Institution - 007-004

      Clayton, Not Specified, Australia

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    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/ArmIntervention/Treatment
    EXPERIMENTAL: Phase 2 Cohort 1a: PD-L1 TPS <1%
    • Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab
    DRUG: Adagrasib
    • Adagrasib 400 mg twice daily (BID) in combination with pembrolizumab (Cohort 1a)
    EXPERIMENTAL: Phase 2 Cohort 1b: PD-L1 TPS <1%
    • Cohort 1b: Adagrasib BID monotherapy
    DRUG: Adagrasib
    • Adagrasib 600 mg BID monotherapy (Cohort 1b)
    EXPERIMENTAL: Phase 2 Cohort 2: PD-L1 TPS ≥1%
    • Cohort 2: Adagrasib BID in combination with pembrolizumab
    DRUG: Adagrasib
    • adagrasib 400 mg BID in combination with pembrolizumab
    EXPERIMENTAL: Phase 3 Cohort 3 Investigational Arm
    • Adagrasib BID in combination with pembrolizumab
    DRUG: Adagrasib
    • Adagrasib 400 mg BID + pembrolizumab 200 mg every Q3W
    ACTIVE_COMPARATOR: Phase 3 Cohort 4 Comparator Arm
    • Pembrolizumab
    DRUG: Pembrolizumab
    • Pembrolizumab 200 mg IV Q3W

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome 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 pembrolizumabProgression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival36 months

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Phase 2: To characterize the safety and tolerability of study treatments in selected populationsSafety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.22 months
    Phase 2: Duration of ResponseDefined 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 SurvivalDefined 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 populations1-Year Survival rate12 months
    Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populationsOverall 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 concentrations22 months
    Phase 3: To evaluate the safety and tolerability in the study populationSafety 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 populationPharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations36 months
    Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study populationPatient Reported Outcomes to measure quality of life36 months
    Phase 3: Progression Free Survival per RECIST 1.1 by InvestigatorDefined 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 BICRDefined 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 BICRDefined as the percent of patients documented to have a confirmed CR or PR.36 months

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    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-7

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