Adagrasib in Combination With TNO155 in Patients With Cancer (KRYSTAL 2)

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 in combination with TNO155 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 in combination with TNO155 in patients with advanced solid tumors with a KRAS G12C mutation. MRTX849 is an orally available small molecule inhibitor of KRAS G12C and TNO155 is a selective, orally bioavailable allosteric inhibitor of wild-type SHP2.

Official Title
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A Phase 1/2 Trial of MRTX849 in Combination With TNO155 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL 2

Conditions
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Advanced Cancer, Metastatic Cancer, Malignant Neoplastic Disease

Intervention / Treatment
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* Drug: MRTX849
* Drug: TNO155


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 (phase 2 must be either Non-Small Cell Lung Cancer or Colorectal Cancer) Unresectable or metastatic disease No available treatment with curative intent Adequate organ function Exclusion Criteria: History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions likely to alter absorption of study treatment or result in inability to swallow Other active cancer Cardiac abnormalities

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 TNO155 to determine maximum tolerated dose of TNO155 in combination with MRTX849 | Drug: MRTX849<br>* KRAS G12C Inhibitor<br>* Other names: adagrasib;Drug: TNO155<br>* SHP2 Inhibitor<br>|
| Experimental: Phase 1b Expansion<br>Expansion cohort to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of MRTX849 in combination with TNO155 to recommend Phase 2 regimens | Drug: MRTX849<br>* KRAS G12C Inhibitor<br>* Other names: adagrasib;Drug: TNO155<br>* SHP2 Inhibitor<br>|
| Experimental: Phase 2<br>Separate cohorts of patients stratified by histological diagnosis for evaluation of clinical activity to evaluate clinical activity of MRTX849 and TNO155 in combination | Drug: MRTX849<br>* KRAS G12C Inhibitor<br>* Other names: adagrasib;Drug: TNO155<br>* SHP2 Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the safety of MRTX849 and TNO155 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 and TNO155 | Blood plasma concentration | 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish maximum tolerated dose | Number of participants with dose limiting toxicity | 12 months | 
| Evaluate clinical activity of MRTX849 | Objective response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) | 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, KRAS G12C, Non-small cell lung cancer, Colorectal Cancer, Colon Cancer, Metastatic Cancer, Pancreatic Cancer, SHP2, Advanced Solid Tumors