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

Phase 1

Terminated

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

Interventions: Drug: LY3499446
Drug: Docetaxel
Drug: Abemaciclib
Drug: Cetuximab
Drug: Erlotinib

Registration Number: NCT04165031

Lead Sponsor: Eli Lilly and Company

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LY3499446 + Combination Drugs Phase 1	LY3499446	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts.
LY3499446 Phase 1 Cohort A1 High Dose	LY3499446	Participants received high dose LY3499446 as oral monotherapy twice daily (BID) in 21-day cycles.
LY3499446 Monotherapy + Combination Drugs Phase 2	LY3499446	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.
LY3499446 Phase 1 Cohort AO Mid Dose	LY3499446	Participant received mid dose LY3499446 as oral monotherapy once every other day (QOD) in 21-day cycles.
LY3499446 Phase 1 Cohort A-2 Low Dose	LY3499446	Participants received low dose LY3499446 as oral monotherapy once daily (QD) in 21-Day cycles.
LY3499446 + Combination Drugs Phase 1	Erlotinib	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts.
LY3499446 + Combination Drugs Phase 1	Abemaciclib	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts.
LY3499446 + Combination Drugs Phase 1	Cetuximab	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts.
LY3499446 Monotherapy + Combination Drugs Phase 2	Cetuximab	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.
Docetaxel Phase 2	Docetaxel	Docetaxel IV infusion. The trial was terminated prior to initiation of Phase 2 of this study.
LY3499446 Monotherapy + Combination Drugs Phase 2	Abemaciclib	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.
LY3499446 Monotherapy + Combination Drugs Phase 2	Erlotinib	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.

Primary Outcome Measures

Name	Time	Method
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	Baseline through Measured Progressive Disease	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.
Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs)	Cycle 1 (21 Day Cycle)	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.
Phase 2: Progression-Free Survival (PFS) Non-Small Lung Cancer (NSCLC Cohorts)	Baseline to Objective Progression or Death Due to Any Cause	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.

Secondary Outcome Measures

Name	Time	Method
Phase 1: PFS	Baseline to Objective Progression or Death Due to Any Cause (Up to 11 Months)	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.
Phase 1: 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)	PK: Average Concentration at Steady State of LY3499446 in Combination with Abemaciclib
Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446	Cycle 1 Day 1: Predose, 0.5, 1, 1.5, 2, 3, 4, 8, 24 hours post-dose	Average concentration after the first dose of LY3499446.
Phase 1: 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)	PK: Average Concentration at Steady State of LY3499446 in Combination with Cetuximab
Phase 1: 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)	PK: Average Concentration at Steady State of LY3499446 in Combination with Erlotinib
Phase 1: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, and SD	Baseline through Measured Progressive Disease (Up to 11 Months)	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.
Phase 1: ORR: Percentage of Participants Who Achieve CR or PR	Baseline through Measured Progressive Disease (Up to 11 Months)	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.
Phase 1: Duration of Response (DoR)	Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Up to 11 Months)	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.

Trial Locations

Locations (4): Linear Clinical Research Ltd
🇦🇺
Nedlands, Western Australia, Australia
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Indiana Univ Melvin & Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
St Vincent's Hospital
🇦🇺
Darlinghurst, New South Wales, Australia