Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1

Phase 1

Recruiting

• Conditions: Advanced Cancer; Metastatic Cancer; Malignant Neoplastic Disease
• Interventions: Drug: MRTX849; Drug: Pembrolizumab; Drug: Cetuximab; Drug: Afatinib

• Registration Number: NCT03785249
• Lead Sponsor: Mirati Therapeutics Inc.

Brief Summary

This study will evaluate the safety, tolerability, drug levels, molecular effects, and clinical activity of MRTX849 (adagrasib) in patients with advanced solid tumors that have a KRAS G12C mutation.

Detailed Description

This study will evaluate the safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of MRTX849 (adagrasib) in patients with advanced solid tumors with a KRAS G12C mutation. MRTX849 (adagrasib) is an orally-available small molecule inhibitor of KRAS G12C.

Study Timeline

• Study First Submitted: 2018-12-18
• Study First Submitted QC: 2018-12-19
• Study First Posted: 2018-12-24
• Study Start: 2019-01-15
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-14
• Last Update Posted: 2025-07-17
• Primary Completion: 2026-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 822

Inclusion Criteria

• Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation
• Unresectable or metastatic disease
• Standard treatment is not available or patient declines; first-line treatment for NSCLC for certain cohorts
• Adequate organ function

Exclusion Criteria

• History of intestinal disease or major gastric surgery or inability to swallow oral medications
• Other active cancer

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1b Expansion	MRTX849	Expansion cohort to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of MRTX849 to recommend Phase 2 regimens
Pilot Phase 1b Combination with Pembrolizumab	Pembrolizumab	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with pembrolizumab in patients with NSCLC
Pilot Phase 1b Combination with Cetuximab	MRTX849	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with CRC
Pilot Phase 1b Combination with Cetuximab	Cetuximab	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with CRC
Pilot Phase 1b Combination with Afatinib	MRTX849	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with afatinib in patients with NSCLC
Pilot Phase 1b Combination with Afatinib	Afatinib	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with afatinib in patients with NSCLC
Phase 2 Combination with Cetuximab	Cetuximab	Phase 2 evaluation of the clinical activity of MRTX849 in combination with cetuximab in patients with CRC
Pilot Phase 1b Combination with Cetuximab in NSCLC	MRTX849	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with NSCLC
Pilot Phase 1b Combination with Cetuximab in NSCLC	Cetuximab	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with NSCLC
Pilot Phase 1b Combination with Cetuximab in PDAC	Cetuximab	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with pancreatic adenocarcinoma (PDAC)
Phase 2	MRTX849	Separate cohorts of patients stratified by histological diagnosis, prior treatment history or co-mutation status (e.g., STK11) for evaluation of clinical activity of MRTX849
Phase 2 Combination with Cetuximab	MRTX849	Phase 2 evaluation of the clinical activity of MRTX849 in combination with cetuximab in patients with CRC
Phase 1 Dose Exploration	MRTX849	Dose escalation of MRTX849 to determine maximum tolerated dose
Pilot Phase 1b Combination with Pembrolizumab	MRTX849	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with pembrolizumab in patients with NSCLC
Pilot Phase 1b Combination with Cetuximab in PDAC	MRTX849	Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with pancreatic adenocarcinoma (PDAC)

Primary Outcome Measures

Name	Time	Method
Characterize the safety of MRTX849 in patients having advanced solid tumor malignancies with KRAS G12C mutation	20 months	Number of participants with treatment related adverse events
Evaluate the pharmacokinetics of MRTX849	20 months	Blood plasma concentration
Evaluate clinical activity/efficacy of MRTX849	20 months	Objective response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST)

Secondary Outcome Measures

Name	Time	Method
Establish maximum tolerated dose	12 months	Number of participants with dose limiting toxicity
Characterize safety and tolerability of MRTX849 in combination with selected therapeutic agents	12 months	Number of participants with dose limiting toxicity
Evaluate the pharmacokinetics of new MRTX849 oral formulations	6 months	Blood plasma concentration
Evaluate the pharmacokinetics of MRTX849 administered with food	6 months	Blood plasma concentration

Trial Locations

Locations (228)

ONeal Comprehensive Cancer Center at the University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Alaska Oncology and Hematology; 🇺🇸 Anchorage, Alaska, United States

Mayo Clinic Arizona - Phoenix Campus; 🇺🇸 Phoenix, Arizona, United States

Local Institution - 001-807; 🇺🇸 Scottsdale, Arizona, United States

Local Institution - 001-873-A; 🇺🇸 Tucson, Arizona, United States

USOR - Arizona Oncology - Tucson - Rudasill; 🇺🇸 Tucson, Arizona, United States

Local Institution - 001-840-B; 🇺🇸 Bellflower, California, United States

Beverly Hills Cancer Center; 🇺🇸 Beverly Hills, California, United States

City of Hope - Duarte (Main Campus); 🇺🇸 Duarte, California, United States

Local Institution - 001-850-K; 🇺🇸 Dublin, California, United States

Scroll for more (218 remaining)