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

Primary Purpose

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

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LY3499446
Abemaciclib
Cetuximab
Erlotinib
Docetaxel
Sponsored by
Eli Lilly and Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Solid Tumor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Indiana Univ Melvin & Bren Simon Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • St Vincent's Hospital
  • Linear Clinical Research Ltd

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Active Comparator

Arm Label

LY3499446 Phase 1 Cohort A1 High Dose

LY3499446 Phase 1 Cohort AO Mid Dose

LY3499446 Phase 1 Cohort A-2 Low Dose

LY3499446 + Combination Drugs Phase 1

LY3499446 Monotherapy + Combination Drugs Phase 2

Docetaxel Phase 2

Arm Description

Participants received high dose LY3499446 as oral monotherapy twice daily (BID) in 21-day cycles.

Participant received mid dose LY3499446 as oral monotherapy once every other day (QOD) in 21-day cycles.

Participants received low dose LY3499446 as oral monotherapy once daily (QD) in 21-Day cycles.

LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts.

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

Outcomes

Primary Outcome Measures

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.
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.
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.

Secondary Outcome Measures

Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446
Average concentration after the first dose of LY3499446.
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
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
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
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.
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.
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.
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.

Full Information

First Posted
November 14, 2019
Last Updated
October 27, 2021
Sponsor
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT04165031
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated due to an unexpected toxicity finding.
Study Start Date
November 28, 2019 (Actual)
Primary Completion Date
October 30, 2020 (Actual)
Study Completion Date
October 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eli Lilly and Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Solid Tumor, Non-Small Cell Lung Cancer, Colorectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LY3499446 Phase 1 Cohort A1 High Dose
Arm Type
Experimental
Arm Description
Participants received high dose LY3499446 as oral monotherapy twice daily (BID) in 21-day cycles.
Arm Title
LY3499446 Phase 1 Cohort AO Mid Dose
Arm Type
Experimental
Arm Description
Participant received mid dose LY3499446 as oral monotherapy once every other day (QOD) in 21-day cycles.
Arm Title
LY3499446 Phase 1 Cohort A-2 Low Dose
Arm Type
Experimental
Arm Description
Participants received low dose LY3499446 as oral monotherapy once daily (QD) in 21-Day cycles.
Arm Title
LY3499446 + Combination Drugs Phase 1
Arm Type
Experimental
Arm Description
LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). This trial was terminated prior to initiation of combination therapy cohorts.
Arm Title
LY3499446 Monotherapy + Combination Drugs Phase 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Docetaxel Phase 2
Arm Type
Active Comparator
Arm Description
Docetaxel IV infusion. The trial was terminated prior to initiation of Phase 2 of this study.
Intervention Type
Drug
Intervention Name(s)
LY3499446
Intervention Description
Administered orally
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Other Intervention Name(s)
LY2835219
Intervention Description
Administered orally
Intervention Type
Drug
Intervention Name(s)
Cetuximab
Intervention Description
Administered IV
Intervention Type
Drug
Intervention Name(s)
Erlotinib
Intervention Description
Administered orally
Intervention Type
Drug
Intervention Name(s)
Docetaxel
Intervention Description
Administered IV
Primary Outcome Measure Information:
Title
Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs)
Description
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.
Time Frame
Cycle 1 (21 Day Cycle)
Title
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
Description
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.
Time Frame
Baseline through Measured Progressive Disease
Title
Phase 2: Progression-Free Survival (PFS) Non-Small Lung Cancer (NSCLC Cohorts)
Description
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.
Time Frame
Baseline to Objective Progression or Death Due to Any Cause
Secondary Outcome Measure Information:
Title
Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446
Description
Average concentration after the first dose of LY3499446.
Time Frame
Cycle 1 Day 1: Predose, 0.5, 1, 1.5, 2, 3, 4, 8, 24 hours post-dose
Title
Phase 1: PK: Average Concentration at Steady State of LY3499446 in Combination With Abemaciclib
Description
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)
Title
Phase 1: PK: Average Concentration at Steady State of LY3499446 in Combination With Cetuximab
Description
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)
Title
Phase 1: PK: Average Concentration at Steady State of LY3499446 in Combination With Erlotinib
Description
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)
Title
Phase 1: ORR: Percentage of Participants Who Achieve CR or PR
Description
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.
Time Frame
Baseline through Measured Progressive Disease (Up to 11 Months)
Title
Phase 1: PFS
Description
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.
Time Frame
Baseline to Objective Progression or Death Due to Any Cause (Up to 11 Months)
Title
Phase 1: Duration of Response (DoR)
Description
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.
Time Frame
Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Up to 11 Months)
Title
Phase 1: Disease Control Rate (DCR): Percentage of Participants With a Best Overall Response of CR, PR, and SD
Description
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.
Time Frame
Baseline through Measured Progressive Disease (Up to 11 Months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
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)
Organizational Affiliation
Eli Lilly and Company
Official's Role
Study Director
Facility Information:
Facility Name
Indiana Univ Melvin & Bren Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
Middletown
State/Province
New Jersey
ZIP/Postal Code
07748
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
Harrison
State/Province
New York
ZIP/Postal Code
10604
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10022
Country
United States
Facility Name
St Vincent's Hospital
City
Darlinghurst
State/Province
New South Wales
ZIP/Postal Code
2010
Country
Australia
Facility Name
Linear Clinical Research Ltd
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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 URL
https://vivli.org/
Links:
URL
https://www.lillytrialguide.com/en-US/studies/solid-tumor/JZKA#?postal=
Description
A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation

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

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