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

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

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.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer; Non-Small Cell Lung Cancer; Advanced Solid Tumor
• Intervention / Treatment: Drug: Abemaciclib; Drug: Docetaxel; Drug: LY3499446; Drug: Cetuximab; Drug: Erlotinib

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Linear Clinical Research Ltd
• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Univ Melvin & Bren Simon Cancer Center
  • New Jersey
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Cancer Center
  • New York
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10022
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2019
• Primary Completion (Actual): October 30, 2020
• Study Completion (Actual): October 30, 2020

Study Registration Dates

• First Submitted: November 14, 2019
• First Submitted That Met QC Criteria: November 14, 2019
• First Posted (Actual): November 15, 2019

Study Record Updates

• Last Update Posted (Actual): November 24, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Docetaxel; Erlotinib Hydrochloride; Cetuximab
• Other Study ID Numbers: 17501 (Other Identifier: City of Hope Comprehensive Cancer Center); J2K-MC-JZKA (Other Identifier: Eli Lilly and Company); 2019-003070-53 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No