A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation

Study Overview
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Brief Summary
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The reason for this study is to see if the study drug LY3499446 is safe and effective in participants with solid tumors with KRAS G12C mutation.

Official Title
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A Phase 1/2 Study of LY3499446 Administered to Patients With Advanced Solid Tumors With KRAS G12C Mutation

Conditions
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Advanced Solid Tumor, Non-Small Cell Lung Cancer, Colorectal Cancer

Intervention / Treatment
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* Drug: LY3499446
* Drug: Abemaciclib
* Drug: Cetuximab
* Drug: Erlotinib
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have diagnosis of a solid tumor with KRAS G12C mutation that did not respond to at least 1 line of standard therapy and has spread to other part(s) of the body For phase II, participants must be willing to have new tumor tissue biopsies (doctor removes a small amount of tissue) during the study if it does not cause undue risks to health Participants must be willing to use highly effective birth control Participants must have adequate organ function Participants must be able to swallow capsules Exclusion Criteria: Participants must not have certain infections such as hepatitis or tuberculosis or HIV that is not well controlled Participants must not have another serious medical condition including a serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last three months Participants must not have cancer of the central nervous system that is not stable Participants must not be pregnant or breastfeeding Participants must not use herbal supplements

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3499446 Phase 1 Cohort A1 High Dose<br>Participants received high dose LY3499446 as oral monotherapy twice daily (BID) in 21-day cycles. | Drug: LY3499446<br>* Administered orally<br>|
| Experimental: LY3499446 Phase 1 Cohort AO Mid Dose<br>Participant received mid dose LY3499446 as oral monotherapy once every other day (QOD) in 21-day cycles. | Drug: LY3499446<br>* Administered orally<br>|
| Experimental: LY3499446 Phase 1 Cohort A-2 Low Dose<br>Participants received low dose LY3499446 as oral monotherapy once daily (QD) in 21-Day cycles. | Drug: LY3499446<br>* Administered orally<br>|
| Experimental: LY3499446 + Combination Drugs Phase 1<br>LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts. | Drug: LY3499446<br>* Administered orally<br>Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Cetuximab<br>* Administered IV<br>Drug: Erlotinib<br>* Administered orally<br>|
| Experimental: LY3499446 Monotherapy + Combination Drugs Phase 2<br>LY3499446 as oral monotherapy and LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). The trial was terminated prior to initiation of Phase 2 of this study. | Drug: LY3499446<br>* Administered orally<br>Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Cetuximab<br>* Administered IV<br>Drug: Erlotinib<br>* Administered orally<br>|
| Active Comparator: Docetaxel Phase 2<br>Docetaxel IV infusion. The trial was terminated prior to initiation of Phase 2 of this study. | Drug: Docetaxel<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs) | DLT is defined as an event that is clinically significant and not clearly related to disease progression or intercurrent illness that occurred within the DLT observation period of the Cycle 1 timeframe. | Cycle 1 (21 Day Cycle) | 
| Phase 2: Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) in Colorectal Cancer (CRC) Cohorts and Other Tumors Cohort | ORR is defined as percentage of participants who achieved a CR or PR out of all the participants treated. Tumor responses were measured and record using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST) v1.1 guidelines. CR is defined as the disappearance of all targeted and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions and no appearance of new lesions. | Baseline through Measured Progressive Disease | 
| Phase 2: Progression-Free Survival (PFS) Non-Small Lung Cancer (NSCLC Cohorts) | PFS was defined as the time from study enrollment (for non-randomized cohorts)/ the time from randomization (for randomized cohorts) to the first observation of progressive disease (PD) or death without documented disease progression per RECIST V1.1 criteria. | Baseline to Objective Progression or Death Due to Any Cause | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446 | Average concentration after the first dose of LY3499446. | Cycle 1 Day 1: Predose, 0.5, 1, 1.5, 2, 3, 4, 8, 24 hours post-dose | 
| Phase 1: PK: Average Concentration at Steady State of LY3499446 in Combination With Abemaciclib | PK: Average Concentration at Steady State of LY3499446 in Combination with Abemaciclib | Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles) | 
| Phase 1: PK: Average Concentration at Steady State of LY3499446 in Combination With Cetuximab | PK: Average Concentration at Steady State of LY3499446 in Combination with Cetuximab | Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles) | 
| Phase 1: PK: Average Concentration at Steady State of LY3499446 in Combination With Erlotinib | PK: Average Concentration at Steady State of LY3499446 in Combination with Erlotinib | Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles) | 
| Phase 1: ORR: Percentage of Participants Who Achieve CR or PR | ORR is defined as percentage of participants who achieved a CR or PR out of all the participants treated. Tumor responses were measured and record using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST) v1.1 guidelines. CR is defined as the disappearance of all targeted and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions and no appearance of new lesions. | Baseline through Measured Progressive Disease (Up to 11 Months) | 
| Phase 1: PFS | PFS was defined as the time from study enrollment (for non-randomized cohorts)/ the time from randomization (for randomized cohorts) to the first observation of progressive disease (PD) overall response or death without documented disease progression per RECIST V1.1 criteria. | Baseline to Objective Progression or Death Due to Any Cause (Up to 11 Months) | 
| Phase 1: Duration of Response (DoR) | DoR was defined as the time from the date measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or objective progression is observed, per RECIST v1.1 criteria, or the date of death from any cause in the absence of objectively determined disease progression or recurrence. | Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Up to 11 Months) | 
| Phase 1: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, and SD | DCR was defined as the percentage of participants who achieved a best overall response (BOR) of confirmed CR, confirmed PR, or SD out of all participants treatment. Best response is determined from a sequence of responses assessed. Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. CR is defined as the disappearance of all targeted and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions and no appearance of new lesions. | Baseline through Measured Progressive Disease (Up to 11 Months) |