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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04165031
Recruitment Status : Terminated (The study was terminated due to an unexpected toxicity finding.)
First Posted : November 15, 2019
Results First Posted : November 24, 2021
Last Update Posted : November 24, 2021
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Non-Small Cell Lung Cancer Colorectal Cancer Drug: LY3499446 Drug: Abemaciclib Drug: Cetuximab Drug: Erlotinib Drug: Docetaxel Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of LY3499446 Administered to Patients With Advanced Solid Tumors With KRAS G12C Mutation
Actual Study Start Date : November 28, 2019
Actual Primary Completion Date : October 30, 2020
Actual Study Completion Date : October 30, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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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: LY3499446
Administered orally

Drug: Abemaciclib
Administered orally
Other Name: LY2835219

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: LY3499446
Administered orally

Drug: Abemaciclib
Administered orally
Other Name: LY2835219

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


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04165031


Locations
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United States, Indiana
Indiana Univ Melvin & Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, New Jersey
Memorial Sloan Kettering Cancer Center
Middletown, New Jersey, United States, 07748
United States, New York
Memorial Sloan Kettering Cancer Center
Harrison, New York, United States, 10604
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10022
Australia, New South Wales
St Vincent's Hospital
Darlinghurst, New South Wales, Australia, 2010
Australia, Western Australia
Linear Clinical Research Ltd
Nedlands, Western Australia, Australia, 6009
Sponsors and Collaborators
Eli Lilly and Company
Investigators
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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
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol  [PDF] January 21, 2020
Statistical Analysis Plan  [PDF] February 4, 2020

More Information
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Additional Information:

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT04165031    
Other Study ID Numbers: 17501
J2K-MC-JZKA ( Other Identifier: Eli Lilly and Company )
2019-003070-53 ( EudraCT Number )
First Posted: November 15, 2019    Key Record Dates
Results First Posted: November 24, 2021
Last Update Posted: November 24, 2021
Last Verified: October 2021
Individual Participant Data (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
Statistical Analysis Plan (SAP)
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/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
 Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Docetaxel
Cetuximab
Erlotinib Hydrochloride
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors
Enzyme Inhibitors