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

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

Tracking Information

• First Submitted Date: October 28, 2020
• First Posted Date: November 3, 2020
• Last Update Posted Date: April 24, 2024
• Actual Study Start Date: December 2, 2020
• Estimated Primary Completion Date: October 31, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 22, 2024)

• 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)
• 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

Original Primary Outcome Measures (submitted: October 30, 2020)

Evaluate the clinical activity of MRTX849 in combination with pembrolizumab [ Time Frame: 11 months ]

Objective Response Rate (ORR) RECIST 1.1

Current Secondary Outcome Measures (submitted: January 22, 2024)

• 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.
• 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.
• 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.
• Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations [ Time Frame: 12 months ]
  1-Year Survival rate
• Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations [ Time Frame: 22 months ]
  Overall Survival (OS)
• 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
• 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.
• 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
• 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
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: October 30, 2020)

• To characterize the safety and tolerability of the combination regimen in the selected population. [ Time Frame: 11 months ]
  • Safety characterized by type, incidence, severity, timing, seriousness and relationship to study treatment of adverse events and laboratory abnormalities.
• Duration of Response (DOR) [ Time Frame: 11 months ]
  MRTX849 in combination with pembrolizumab

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

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.

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 Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

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

Condition

• Advanced Non-Small Cell Lung Cancer
• Metastatic Non-Small Cell Lung Cancer

Intervention

• Drug: Adagrasib
  Adagrasib 400 mg twice daily (BID) in combination with pembrolizumab (Cohort 1a)
  Other Name: Pembrolizumab
• Drug: Adagrasib
  Adagrasib 600 mg BID monotherapy (Cohort 1b)
• Drug: Adagrasib
  adagrasib 400 mg BID in combination with pembrolizumab
  Other Name: Pembrolizumab
• Drug: Adagrasib
  Adagrasib 400 mg BID + pembrolizumab 200 mg every Q3W
  Other Name: Pemrolizumab
• Drug: Pembrolizumab
  Pembrolizumab 200 mg IV Q3W

Study Arms

• Experimental: Phase 2 Cohort 1a: PD-L1 TPS <1%
  Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab
  Intervention: Drug: Adagrasib
• Experimental: Phase 2 Cohort 1b: PD-L1 TPS <1%
  Cohort 1b: Adagrasib BID monotherapy
  Intervention: Drug: Adagrasib
• Experimental: Phase 2 Cohort 2: PD-L1 TPS ≥1%
  Cohort 2: Adagrasib BID in combination with pembrolizumab
  Intervention: Drug: Adagrasib
• Experimental: Phase 3 Cohort 3 Investigational Arm
  Adagrasib BID in combination with pembrolizumab
  Intervention: Drug: Adagrasib
• Active Comparator: Phase 3 Cohort 4 Comparator Arm
  Pembrolizumab
  Intervention: Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 11, 2024): 806
• Original Estimated Enrollment (submitted: October 30, 2020): 120
• Estimated Study Completion Date: October 31, 2029
• Estimated Primary Completion Date: October 31, 2028 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, Germany, Hungary, Ireland, Israel, Italy, Korea, Republic of, Netherlands, Poland, Portugal, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04613596
• Other Study ID Numbers: 849-007
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Mirati Therapeutics Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Mirati Therapeutics Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Barbara Wamil, MD; Mirati Therapeutics Inc.

• PRS Account: Mirati Therapeutics Inc.
• Verification Date: April 2024