Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101)

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of sotorasib administered in investigational regimens in adult participants with KRAS p.G12C mutant advanced solid tumors.

Official Title
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A Phase 1b/2, Protocol Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Sotorasib Monotherapy and in Combination With Other Anti-cancer Therapies in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101)

Conditions
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Advanced Solid Tumors, Kirsten Rat Sarcoma (KRAS) pG12C Mutation

Intervention / Treatment
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* Drug: Sotorasib
* Drug: trametinib
* Drug: RMC-4630
* Drug: afatinib
* Drug: pembrolizumab
* Drug: panitumumab
* Drug: carboplatin, pemetrexed, docetaxel, paclitaxel
* Drug: atezolizumab
* Drug: palbociclib
* Drug: MVASI® (bevacizumab-awwb)
* Drug: TNO155
* Drug: FOLFIRI
* Drug: FOLFOX
* Drug: BI 1701963
* Drug: AMG 404
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women greater than or equal to 18 years old. Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Exclusion Criteria: Primary brain tumor. Spinal cord compression, or untreated, or symptomatic, or active brain metastases, or leptomeningeal disease from non-brain tumors. Myocardial infarction within 6 months of study day 1. Gastrointestinal (GI) tract disease causing the inability to take oral medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Sotorasib + atezolizumab<br>Experimental: Sotorasib + atezolizumab Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C advanced non-small cell lung cancer. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced non-small cell lung cancer. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: atezolizumab<br>* atezolizumab administered as an intravenous (IV) injection.<br>|
| Experimental: Sotorasib + MVASI® (bevacizumab-awwb)+ FOLFIRI or FOLFOX<br>Experimental: Sotorasib + MVASI® (bevacizumab-awwb)+ FOLFIRI or FOLFOX Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced colorectal cancer. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced colorectal cancer. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: MVASI® (bevacizumab-awwb)<br>* MVASI® (bevacizumab-awwb) administered as an intravenous (IV) infusion.<br>Drug: FOLFIRI<br>* FOLFIRI chemotherapy combination of leucovorin administered as an intravenous (IV) injection, 5-fluorouracil (5-FU) administered as IV bolus injection or IV continuous infusion (depending on dose), and irinotecan administered as IV injection.<br>Drug: FOLFOX<br>* FOLFOX chemotherapy combination of leucovorin administered as intravenous (IV) injection, 5-fluorouracil (5-FU) administered as IV bolus injection or IV continuous infusion (depending on dose), and oxaliplatin administered as IV injection.<br>|
| Experimental: Sotorasib + TNO155<br>Experimental: Sotorasib + TNO155 Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced solid tumors. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced solid tumors. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: TNO155<br>* TNO155 administered orally as a capsule.<br>|
| Experimental: Sotorasib + BI 1701963<br>Experimental: Sotorasib + BI 1701963 Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced solid tumors. Upon completion of dose exploration part of the study the dose expansion cohort is for eligible participants with KRAS P.G12C mutant advanced non-small cell lung cancer and advanced colorectal cancer. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: BI 1701963<br>* BI 1701963 administered orally<br>|
| Experimental: Sotorasib + AMG 404<br>Experimental: Sotorasib + AMG 404 Dose Exploration and Dose Expansion • Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced solid tumors. • Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced solid tumors | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: AMG 404<br>* AMG 404 administered as an intravenous (IV) infusion.<br>|
| Experimental: Sotorasib + carboplatin, pemetrexed, docetaxel, paclitaxel, pembrolizumab<br>Experimental: Sotorasib + carboplatin, pemetrexed, docetaxel, paclitaxel, pembrolizumab Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C advanced non-small cell lung cancer. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced non-small cell lung cancer. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: pembrolizumab<br>* pembrolizumab administered as an intravenous (IV) infusion.<br>Drug: carboplatin, pemetrexed, docetaxel, paclitaxel<br>* carboplatin, pemetrexed, docetaxel administered as an intravenous (IV) infusion.<br>|
| Experimental: Sotorasib + everolimus<br>Experimental: Sotorasib + everolimus Dose Exploration and Dose Expansion • Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C advanced solid tumor. • Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced solid tumor. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: everolimus<br>* everolimus administered orally.<br>|
| Experimental: Sotorasib Monotherapy<br>Experimental: Sotorasib only Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C advanced non-small cell lung cancer with brain metastases. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced non-small cell lung cancer with brain metastases. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>|
| Experimental: Sotorasib + palbociclib<br>Experimental: Sotorasib + palbociclib Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C advanced solid tumor. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced solid tumor. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: palbociclib<br>* palbociclib administered orally as a tablet.<br>|
| Experimental: Sotorasib + pembrolizumab<br>Experimental: Sotorasib + pembrolizumab Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant non small cell lung cancer. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS P.G12C mutant non small cell lung cancer. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: pembrolizumab<br>* pembrolizumab administered as an intravenous (IV) infusion.<br>|
| Experimental: Sotorasib + trametinib + panitumumab<br>Experimental: Sotorasib + trametinib + panitumumab Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced solid tumors. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced solid tumors. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: trametinib<br>* trametinib administered orally as a tablet.<br>Drug: panitumumab<br>* panitumumab administered as an intravenous (IV) infusion.<br>|
| Experimental: Sotorasib + RMC-4630<br>Experimental: Sotorasib + RMC-4630 Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced solid tumors. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants, with KRAS p.G12C mutant advanced solid tumors. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: RMC-4630<br>* RMC-4630 administered orally as a capsule.<br>|
| Experimental: Sotorasib + afatinib<br>Experimental: Sotorasib + afatinib Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C advanced non-small cell lung cancer. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced non-small cell lung cancer. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: afatinib<br>* afatinib administered orally as a tablet.<br>|
| Experimental: Sotorasib + panitumumab +/- FOLFIRI<br>Experimental: Sotorasib + panitumumab +/- FOLFIRI Dose Exploration and Dose Expansion Enrollment into the dose exploration cohort is for eligible participants with KRAS P.G12C mutant advanced colorectal cancer. Upon completing the dose exploration part of the study, dose expansion may proceed consisting of participants with KRAS p.G12C mutant advanced solid tumors. | Drug: Sotorasib<br>* Sotorasib administered orally as a tablet.<br>Drug: panitumumab<br>* panitumumab administered as an intravenous (IV) infusion.<br>Drug: FOLFIRI<br>* FOLFIRI chemotherapy combination of leucovorin administered as an intravenous (IV) injection, 5-fluorouracil (5-FU) administered as IV bolus injection or IV continuous infusion (depending on dose), and irinotecan administered as IV injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants with Dose Limiting Toxicities (DLTs) |  | 12 Months | 
| Phase 1b: Number of Participants with Treatment-emergent Adverse Events (TEAEs) |  | 12 Months | 
| Phase 1b: Number of Participants with Treatment-related Adverse Events |  | 12 Months | 
| Phase 1b: Number of Participants with Clinically Significant Changes in Vital Signs |  | 12 Months | 
| Phase 1b: Number of Participants with Clinically Significant Changes in ECG Measurements |  | 12 Months | 
| Phase 1b: Number of Participants with Clinically Significant Changes in Laboratory Test Values |  | 12 Months | 
| Phase 2: Objective Response Rate |  | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Maximum Plasma Concentration (Cmax) |  | 12 Months | 
| Phase 1b: Time to Maximum Plasma Concentration (Tmax) |  | 12 Months | 
| Phase 1b: Area Under the Plasma Concentration-time Curve (AUC) |  | 12 Months | 
| Phase 1b: Objective Response Rate |  | 12 Months | 
| Phase 1b: Disease Control Rate |  | 12 Months | 
| Phase 1b: Duration of Response |  | 12 Months | 
| Phase 1b: Progression-free Survival |  | 12 Months | 
| Phase 1b: Duration of Stable Disease |  | 12 Months | 
| Phase 1b: Time to Response |  | 12 Months | 
| Phase 1b: Overall Survival |  | 12 Months | 
| Phase 1b: Sotorasib + EGFR Inhibitor +/- Chemotherapeutic Regimen Only: Quantification of Plasma Levels |  | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Intracranial Objective Response Rate | Intracranial objective response rate assessed per Response Assessment in Neuro-oncology Brain Metastases (RANO-BM). | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Intracranial Disease Control Rate | Intracranial disease control rate assessed per Response Assessment in Neuro-oncology Brain Metastases (RANO-BM). | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Intracranial Duration of Response | Intracranial duration of response assessed per Response Assessment in Neuro-oncology Brain Metastases (RANO-BM). | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Time to Intracranial Radiation Therapy |  | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Intracranial Progression-free Survival (PFS) | Intracranial PFS assessed per Response Assessment in Neuro-oncology Brain Metastases (RANO-BM) | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Non-intracranial Progression-free Survival (PFS) | Non-intracranial PFS assessed per RECIST 1.1. | 12 Months | 
| Phase 1b: Sotorasib Monotherapy Only: Overall Progression-free Survival (PFS) | Overall PFS assessed per RECIST 1.1 and RANO-BM. | 12 Months | 
| Phase 1b: Sotorasib + TNO155 Only: Best Overall Response |  | 12 Months | 
| Phase 2: Number of Participants with Treatment-emergent Adverse Events (TEAEs) |  | 12 Months | 
| Phase 2: Number of Participants with Grade ≥3 Treatment-emergent Adverse Events (TEAEs) |  | 12 Months | 
| Phase 2: Maximum Plasma Concentration (Cmax) |  | 12 Months | 
| Phase 2: Time to Maximum Plasma Concentration (Tmax) |  | 12 Months | 
| Phase 2: Area Under the Plasma Concentration-time Curve (AUC) |  | 12 Months | 
| Phase 2: Disease Control Rate |  | 12 Months | 
| Phase 2: Duration of Response |  | 12 Months | 
| Phase 2: Progression-free Survival |  | 12 Months | 
| Phase 2: Time to Response |  | 12 Months | 
| Phase 2: Overall Survival |  | 12 Months | 
| Phase 1b: Sotorasib + Afatinib + Loperamide Only: Number of Participants with Dose Limiting Toxicities (DLTs) |  | 12 Months | 
| Phase 1b: Sotorasib + Afatinib + Loperamide Only: Number of Participants with Treatment-emergent Adverse Events (TEAEs) |  | 12 Months | 
| Phase 1b: Sotorasib + Afatinib + Loperamide Only: Number of Participants with Treatment-related Adverse Events |  | 12 Months | 
| Phase 1b: Sotorasib + Afatinib + Loperamide Only: Number of Participants with Clinically Significant Changes in Vital Signs |  | 12 Months | 
| Phase 1b: Sotorasib + Afatinib + Loperamide Only: Number of Participants with Clinically Significant Changes in ECG Measurements |  | 12 Months | 
| Phase 1b: Sotorasib + Afatinib + Loperamide Only: Number of Participants with Clinically Significant Changes in Laboratory Test Values |  | 12 Months |