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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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ClinicalTrials.gov Identifier: NCT04613596
Recruitment Status : Recruiting
First Posted : November 3, 2020
Last Update Posted : April 24, 2024
Sponsor:
Information provided by (Responsible Party):
Mirati Therapeutics Inc.

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


Condition or disease Intervention/treatment Phase
Advanced Non-Small Cell Lung Cancer Metastatic Non-Small Cell Lung Cancer Drug: Adagrasib Drug: Pembrolizumab Phase 2 Phase 3

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 806 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: MRTX849 Monotherapy, MRTX849 in Combination with Pembrolizumab and Pembrolizumab alone
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination With Pembrolizumab Versus Pembrolizumab in Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation
Actual Study Start Date : December 2, 2020
Estimated Primary Completion Date : October 31, 2028
Estimated Study Completion Date : October 31, 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/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)
Other Name: Pembrolizumab
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
Other Name: 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
Other Name: Pemrolizumab
Active Comparator: Phase 3 Cohort 4 Comparator Arm
Pembrolizumab
 Drug: Pembrolizumab
Pembrolizumab 200 mg IV Q3W


Outcome Measures
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Primary Outcome Measures :
  1. Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC. [ Time Frame: 22 months ]
    Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)

  2. Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab [ Time Frame: 36 months ]
    Progression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival


Secondary Outcome Measures :
  1. Phase 2: To characterize the safety and tolerability of study treatments in selected populations [ Time Frame: 22 months ]
    Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.

  2. Phase 2: Duration of Response [ Time Frame: 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.

  3. Phase 2: Progression Free Survival [ Time Frame: 22 months ]
    Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first.

  4. Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations [ Time Frame: 12 months ]
    1-Year Survival rate

  5. Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations [ Time Frame: 22 months ]
    Overall Survival (OS)

  6. Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations. [ Time Frame: 22 months ]
    Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations

  7. Phase 3: To evaluate the safety and tolerability in the study population [ Time Frame: 36 months ]
    Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.

  8. Phase 3: To evaluate the PK of adagrasib administered in the study population [ Time Frame: 36 months ]
    Pharmacokinetics (PK) Blood plasma Adagrasib and potential metabolite concentrations

  9. Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population [ Time Frame: 36 months ]
    Patient Reported Outcomes to measure quality of life

  10. Phase 3: Progression Free Survival per RECIST 1.1 by Investigator [ Time Frame: 36 months ]
    Defined as time from first study treatment until disease progression or death from any cause, whichever occurs first.

  11. Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR [ Time Frame: 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.

  12. Phase 3: Objective Response Rate (ORR) per RECIST 1.1 by Investigator and BICR [ Time Frame: 36 months ]
    Defined as the percent of patients documented to have a confirmed CR or PR.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04613596


Contacts
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Contact: Mirati Therapeutics Study Locator Services 18448935530 miratistudylocator@careboxhealth.com

Locations
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Sponsors and Collaborators
Mirati Therapeutics Inc.
Investigators
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Study Director: Barbara Wamil, MD Mirati Therapeutics Inc.
More Information
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Responsible Party: Mirati Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT04613596    
Other Study ID Numbers: 849-007
First Posted: November 3, 2020    Key Record Dates
Last Update Posted: April 24, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mirati Therapeutics Inc.:
KRAS G12C
Non-small cell lung cancer
NSCLC
Metastatic Non-Small Cell Lung Cancer
 Adagrasib
Krazati
TPS
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
 Carcinoma, Bronchogenic
Bronchial Neoplasms
Pembrolizumab
Adagrasib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action