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

• ClinicalTrials.gov Identifier: NCT04165031
• Recruitment Status: Terminated
• First Posted: November 15, 2019
• Results First Posted: November 24, 2021
• Last Update Posted: November 24, 2021
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: November 14, 2019
• First Posted Date: November 15, 2019
• Results First Submitted Date: October 27, 2021
• Results First Posted Date: November 24, 2021
• Last Update Posted Date: November 24, 2021
• Actual Study Start Date: November 28, 2019
• Actual Primary Completion Date: October 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2021)

• Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: 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: 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 [ Time Frame: 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 2: Progression-Free Survival (PFS) Non-Small Lung Cancer (NSCLC Cohorts) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 14, 2019)

• Phase 1: Number or Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (21 Day Cycle) ]
  Phase 1: Number or Participants with DLTs
• Phase 2: Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) (CRC Cohorts and Other Tumors Cohort) [ Time Frame: Baseline through Measured Progressive Disease (Estimated up to 24 Months) ]
  Phase 2: ORR: Percentage of Participants Who Achieve CR or PR (CRC Cohorts and Other Tumors Cohort)
• Phase 2: Progression-Free Survival (PFS) (NSCLC Cohorts) [ Time Frame: Baseline to Objective Progression or Death Due to Any Cause (Estimated up to 24 Months) ]
  Phase 2: PFS (NSCLC Cohorts)

Current Secondary Outcome Measures (submitted: October 27, 2021)

• Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446 [ Time Frame: 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 Abemaciclib [ Time Frame: 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: PK: Average Concentration at Steady State of LY3499446 in Combination With Cetuximab [ Time Frame: 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 [ Time Frame: 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: ORR: Percentage of Participants Who Achieve CR or PR [ Time Frame: 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: PFS [ Time Frame: 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: Duration of Response (DoR) [ Time Frame: 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.
• Phase 1: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, and SD [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: November 14, 2019)

• Pharmacokinetics (PK): Average Concentration at Steady State of LY3499446 [ Time Frame: Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles) ]
  PK: Average Concentration at Steady State of LY3499446
• PK: Average Concentration at Steady State of LY3499446 in Combination with Abemaciclib [ Time Frame: 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
• PK: Average Concentration at Steady State of LY3499446 in Combination with Cetuximab [ Time Frame: 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
• PK: Average Concentration at Steady State of LY3499446 in Combination with Erlotinib [ Time Frame: 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: ORR: Percentage of Participants Who Achieve CR or PR [ Time Frame: Baseline through Measured Progressive Disease (Estimated up to 24 Months) ]
  Phase 1: ORR: Percentage of Participants Who Achieve CR or PR
• Phase 1: PFS [ Time Frame: Baseline to Objective Progression or Death Due to Any Cause (Estimated up to 24 Months) ]
  Phase 1: PFS
• Duration of Response (DoR) [ Time Frame: Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Estimated up to 24 Months) ]
  DoR
• Disease Control Rate (DCR): Percentage of Participants with a Best Overall Response of CR, PR, and SD [ Time Frame: Baseline through Measured Progressive Disease (Estimated up to 24 Months) ]
  Disease Control Rate (DCR): Percentage of Participants with a Best Overall Response of CR, PR, and SD

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation
• Official Title: A Phase 1/2 Study of LY3499446 Administered to Patients With Advanced Solid Tumors With KRAS G12C Mutation
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Solid Tumor
• Non-Small Cell Lung Cancer
• Colorectal Cancer

Intervention

• Drug: LY3499446
  Administered orally
• Drug: Abemaciclib
  Administered orally
  Other Name: LY2835219
• Drug: Cetuximab
  Administered IV
• Drug: Erlotinib
  Administered orally
• Drug: Docetaxel
  Administered IV

Study Arms

• Experimental: LY3499446 Phase 1 Cohort A1 High Dose
  Participants received high dose LY3499446 as oral monotherapy twice daily (BID) in 21-day cycles.
  Intervention: Drug: LY3499446
• 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.
  Intervention: Drug: LY3499446
• Experimental: LY3499446 Phase 1 Cohort A-2 Low Dose
  Participants received low dose LY3499446 as oral monotherapy once daily (QD) in 21-Day cycles.
  Intervention: Drug: LY3499446
• 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.

  Interventions:

  • Drug: LY3499446
  • Drug: Abemaciclib
  • Drug: Cetuximab
  • Drug: Erlotinib
• 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.

  Interventions:

  • Drug: LY3499446
  • Drug: Abemaciclib
  • Drug: Cetuximab
  • Drug: Erlotinib
• Active Comparator: Docetaxel Phase 2

  Docetaxel IV infusion.

  The trial was terminated prior to initiation of Phase 2 of this study.

  Intervention: Drug: Docetaxel

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 7, 2020): 5
• Original Estimated Enrollment (submitted: November 14, 2019): 230
• Actual Study Completion Date: October 30, 2020
• Actual Primary Completion Date: October 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, United States
• Removed Location Countries: Canada, Italy, Japan, Spain

Administrative Information

• NCT Number: NCT04165031
• Other Study ID Numbers: 17501; J2K-MC-JZKA ( Other Identifier: Eli Lilly and Company ); 2019-003070-53 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: October 2021