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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1

Conditions
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Advanced Cancer, Metastatic Cancer, Malignant Neoplastic Disease

Intervention / Treatment
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* Drug: MRTX849
* Drug: Pembrolizumab
* Drug: Cetuximab
* Drug: Afatinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Exploration<br>Dose escalation of MRTX849 to determine maximum tolerated dose | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>|
| Experimental: Phase 1b Expansion<br>Expansion cohort to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of MRTX849 to recommend Phase 2 regimens | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>|
| Experimental: Phase 2<br>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 | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>|
| Experimental: Pilot Phase 1b Combination with Pembrolizumab<br>Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with pembrolizumab in patients with NSCLC | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>Drug: Pembrolizumab<br>* Pembrolizumab is administered as an intravenous infusion once every 3 weeks<br>|
| Experimental: Pilot Phase 1b Combination with Cetuximab<br>Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with CRC | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>Drug: Cetuximab<br>* Cetuximab will be administered as an intravenous infusion once per week or once every 2 weeks<br>|
| Experimental: Pilot Phase 1b Combination with Afatinib<br>Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with afatinib in patients with NSCLC | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>Drug: Afatinib<br>* Afatinib will be administered orally once a day in a continuous regimen<br>|
| Experimental: Phase 2 Combination with Cetuximab<br>Phase 2 evaluation of the clinical activity of MRTX849 in combination with cetuximab in patients with CRC | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>Drug: Cetuximab<br>* Cetuximab will be administered as an intravenous infusion once per week or once every 2 weeks<br>|
| Experimental: Pilot Phase 1b Combination with Cetuximab in NSCLC<br>Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with NSCLC | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>Drug: Cetuximab<br>* Cetuximab will be administered as an intravenous infusion once per week or once every 2 weeks<br>|
| Experimental: Pilot Phase 1b Combination with Cetuximab in PDAC<br>Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with pancreatic adenocarcinoma (PDAC) | Drug: MRTX849<br>* MRTX849 will be administered orally once or twice daily in a continuous regimen<br>Drug: Cetuximab<br>* Cetuximab will be administered as an intravenous infusion once per week or once every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS, NSCLC, Colorectal Cancer, Colon Cancer, Metastatic Cancer, Pancreatic Cancer, Adagrasib, STK11 mutation, KRAS G12C