A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)

Study Overview
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Brief Summary
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Evaluate the safety and tolerability of sotorasib in adult subjects with KRAS p.G12C mutant advanced solid tumors. Estimate the maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) in adult subjects with KRAS p.G12C mutant advanced solid tumors.

Official Title
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A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Sotorasib (AMG 510) Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and Sotorasib (AMG 510) Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100)

Conditions
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KRAS p.G12C Mutant Advanced Solid Tumors

Intervention / Treatment
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* Drug: sotorasib
* Drug: Anti PD-1/L1
* Drug: Midazolam


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. Exclusion Criteria Active brain metastases 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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Exploration Part 1 monotherapy<br>Cohorts with food effect and alternative dosing regimens Enrollment into the dose exploration cohorts may be from any eligible solid tumor type. Dose escalation will begin with 2-4 subjects treated at the lowest planned dose level of 180 mg. If no DLT is observed, dose escalation will continue to the next planned dose cohort | Drug: sotorasib<br>* Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation<br>|
| Experimental: Phase 1 Dose Expansion Part 2 monotherapy<br>Upon completing the dose exploration part of the study, dose expansion may proceed with 3 groups consisting of subjects with KRAS p.G12C mutant advanced solid tumors. Dose expansion in these 3 groups may be done concurrently | Drug: sotorasib<br>* Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation<br>|
| Experimental: Phase 1 combination arm with sotorasib and anti PD-1/L1<br>Additional subjects will be enrolled into the combination arm with sotorasib in combination with an anti (PD-1/L1) | Drug: sotorasib<br>* Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation<br>Drug: Anti PD-1/L1<br>* Administered as an intravenous (IV) infusion<br>|
| Experimental: Phase 1 monotherapy treatment naive advanced NSCLC<br>Separate cohort of part 1 dose expansion subjects to evaluate the safety and clinical activity of sotorasib administered orally once daily in subjects with previously untreated advanced non-small cell lung cancer (NSCLC). Drug-drug interaction will be evaluated in 6 of the subjects enrolled in the treatment naive cohort by adding Midazolam alone on Day -1 and in combination with sotorasib on Day 15 of Cycle 1, where each cycle is 21 days. | Drug: sotorasib<br>* Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation<br>Drug: Midazolam<br>* Administered as an oral hydrochloride (HCI) syrup<br>|
| Experimental: Phase 2 monotherapy dose comparison<br>Subjects with NSCLC will be enrolled in a dose comparison study evaluating safety and efficacy | Drug: sotorasib<br>* Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation<br>|
| Experimental: Phase 1 Does escalation and Expansion monotherapy BID<br>BID 2L+solid tumors (fed state) | Drug: sotorasib<br>* Characterize the pharmacokinetics (PK) of sotorasib following administration as an oral Tablet formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary: Number of subjects with treatment-emergent adverse events | Treatment-emergent adverse events will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC Phase 2 monotherapy dose comparison | 24 Months | 
| Primary: Number of subjects with treatment-related adverse events | Treatment-related adverse events will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 
| Primary: Number of subjects with grade ≥3 treatment-emergent adverse events | Grade ≥3 treatment-emergent adverse events will be a primary outcome measure in the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Primary: Number of subjects with serious adverse events | Serious adverse events will be a primary outcome measure in the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Primary: Number of subjects with adverse events of interest | Adverse events of interest will be a primary outcome measure in the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Primary: Number of subjects with clinically significant changes in vital signs | Vital signs will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC | Baseline to 24 Months | 
| Primary: Number of subjects with clinically significant changes in physical examination results | Physical examinations will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 | Baseline to 24 Months | 
| Primary: Number of subjects with clinically significant changes on electrocardiograms (ECGs) | ECGs will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC | Baseline to 24 Months | 
| Primary: Number of subjects with clinically significant changes in clinical laboratory values | Abnormal clinical laboratory values will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC | Baseline to 24 Months | 
| Primary: Number of subjects with dose-limiting toxicities (DLTs) | DLTs will be a primary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC | 21 Days | 
| Primary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria | ORR will be a primary outcome measure in the following group: Phase 1 monotherapy treatment naïve advanced NSCLC Phase 2 monotherapy Phase 2 monotherapy dose comparison | 24 Months | 
| Primary: Duration of response (DOR) as assessed by RECIST 1.1 criteria | DOR will be a primary outcome measure in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 
| Primary: Disease control as assessed by RECIST 1.1 criteria | Disease control will be a primary outcome measure in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 
| Primary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria | Duration of SD will be a primary outcome measure in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 
| Primary: Time to response (TTR) as assessed by RECIST 1.1 criteria | TTR will be a primary outcome measure in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary: Plasma concentration (Cmax) of sotorasib | Cmax will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC Phase 2 monotherapy dose comparison | 15 Weeks | 
| Secondary: Plasma concentration (Cmax) of midazolam | Cmax of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 16 Days | 
| Secondary: Time to achieve Cmax (Tmax) of sotorasib | Tmax will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC | 15 Weeks | 
| Secondary: Area under the plasma concentration-time curve (AUC) of sotorasib | AUC will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 1 monotherapy treatment naïve advanced NSCLC Phase 2 monotherapy dose comparison | 15 Weeks | 
| Secondary: Area under the plasma concentration-time curve (AUC) of midazolam | AUC of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 16 Days | 
| Secondary: Clearance of midazolam from the plasma | Clearance of midazolam from the plasma will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 16 Days | 
| Secondary: Terminal half-life (t1/2) of midazolam | t1/2 of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group: - Phase 1 monotherapy treatment naïve advanced NSCLC | 16 Days | 
| Secondary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria | ORR will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 | 24 Months | 
| Secondary: Duration of response (DOR) as assessed by RECIST 1.1 criteria | DOR will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Disease control as assessed by RECIST 1.1 criteria | DOR will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Progression-free survival (PFS) as assessed by RECIST 1.1 criteria | PFS will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 2 monotherapy dose comparison Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 
| Secondary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria | Duration of SD will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 | 24 Months | 
| Secondary: Depth of response (best percentage change from baseline in lesion sum diameters) as assessed by RECIST 1.1 criteria | Depth of response will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | Baseline to 24 Months | 
| Secondary: Time to response (TTR) as assessed by RECIST 1.1 criteria | DOR will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Overall survival (OS) | OS will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy Phase 2 monotherapy Phase 1 combination arm with sotorasib and anti PD-1/L1 Phase 2 monotherapy dose comparison Phase 1 monotherapy treatment naïve advanced NSCLC | 24 Months | 
| Secondary: sotorasib exposure and QTc interval relationship | sotorasib exposure and QTc interval relationship will be a secondary outcome measure for the following groups: Phase 1 Dose Exploration Part 1 monotherapy Phase 1 Dose Expansion Part 2 monotherapy | 24 Months | 
| Secondary: Progression-free survival (PFS) at 6 months | PFS at 6 months will be a secondary outcome measure for the following group: - Phase 2 monotherapy | 6 Months | 
| Secondary: Progression-free survival (PFS) at 12 months | PFS at 12 months will be a secondary outcome measure for the following group: - Phase 2 monotherapy | 12 Months | 
| Secondary: Overall survival (OS) at 12 months | OS at 12 months will be a secondary outcome measure for the following group: - Phase 2 monotherapy | 12 Months | 
| Secondary: Number of subjects with treatment-emergent adverse events | Treatment-emergent adverse events will be a secondary outcome measure for the following group: - Phase 2 monotherapy | 24 Months | 
| Secondary: Number of subjects with grade ≥3 treatment-emergent adverse events | Grade ≥3 treatment-emergent adverse events will be a secondary outcome measure for the following group: - Phase 2 monotherapy | 24 Months | 
| Secondary: Impact of treatment on disease-related symptoms and health related quality of life (HRQOL) as assessed by EORTC QLQ-C30 | Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by disease-specific modules Quality-of-Life Questionnaire Lung Cancer Module (QLQ LC13) | Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by non-small cell lung cancer symptom assessment questionnaire (NSCLC SAQ) for NSCLC | Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Severity (PGIS) | Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Change (PGIC) in cough, dyspnea and chest pain for NSCLC | Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Treatment-related symptoms and impact on the subject as assessed by EORTC QLQ-C30 | Treament related symptoms and impact on the subject will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Treatment-related symptoms and impact on the subject as assessed by selected questions from the Patient-reported Outcome of the Common Terminology Criteria for Adverse Events (PRO-CTCAE library) | Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Treatment-related symptoms and impact on the subject as assessed by a single item about symptom bother, item GP5 of the Functional Assessment of Cancer Therapy - General (FACT-G) | Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | 24 Months | 
| Secondary: Change from baseline in physical function as assessed by EORTC QLQ-C30 | Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group: - Phase 2 monotherapy dose comparison | Baseline to 24 Months |