Advanced Solid Tumor, Colorectal Cancer, Non-Small Cell Lung Cancer
Conditions
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.
Interventions
DRUGLY3499446
Administered orally
DRUGAbemaciclib
Administered orally
DRUGCetuximab
Administered IV
DRUGErlotinib
Administered orally
DRUGDocetaxel
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 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 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 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: 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: 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. |
| 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: 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: 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 |
Countries
Australia, United States
Participant flow
Pre-assignment details
A participant was identified as having completed the study if the participant was observed until event of progressive disease (PD) or death, or the participant had discontinued study treatment and is in follow up at the time of the final analysis. The study was terminated due to an unexpected toxicity finding.
Participants by arm
| Arm | Count |
|---|---|
| LY3499446 Phase 1 Cohort A1 (High Dose) Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles. | 2 |
| LY3499446 Phase 1 Cohort AO (Mid Dose) Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles. | 1 |
| LY3499446 Phase 1 Cohort A-2 (Low Dose) Participants received low dose LY 3499446 as oral monotherapy once QD in 21-day cycles. | 2 |
| LY3499446 + Combination Drug Phase 1 LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV).
The trial was terminated prior to initiation of this portion. | 0 |
| LY3499446 Monotherapy + Combination Drug Phase 2 LY3499446 monotherapy orally. LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV).
The trial was terminated prior to initiation of this portion. | 0 |
| Docetaxel Phase 2 Docetaxel IV infusion.
The trial was terminated prior to initiation of this portion. | 0 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | LY3499446 Phase 1 Cohort AO (Mid Dose) | LY3499446 Phase 1 Cohort A-2 (Low Dose) | LY3499446 + Combination Drug Phase 1 | LY3499446 Phase 1 Cohort A1 (High Dose) | LY3499446 Monotherapy + Combination Drug Phase 2 | Docetaxel Phase 2 |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Australia | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 0 / 1 | 1 / 2 |
| other Total, other adverse events | 2 / 2 | 1 / 1 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 | 1 / 2 |
Outcome results
Primary
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.
Time frame: Cycle 1 (21 Day Cycle)
Population: All participants who received at least one dose of study drug and had a dose limiting toxicity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY3499446 Phase 1 Cohort A1 (High Dose) | Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| LY3499446 Phase 1 Cohort AO (Mid Dose) | Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| LY3499446 Phase 1 Cohort A-2 (Low Dose) | Phase 1: Number or Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
Primary
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.
Time frame: Baseline through Measured Progressive Disease
Population: Zero participants were analyzed due to early termination of study.
Primary
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.
Time frame: Baseline to Objective Progression or Death Due to Any Cause
Population: Zero participants were analyzed due to early termination of study.
Secondary
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.
Time frame: Baseline through Measured Progressive Disease (Up to 11 Months)
Population: Zero participants were analyzed due to early termination of study.
Secondary
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.
Time frame: Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Up to 11 Months)
Population: Zero participants were analyzed due to early termination of study.
Secondary
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.
Time frame: Baseline through Measured Progressive Disease (Up to 11 Months)
Population: Zero participants were analyzed due to early termination of study.
Secondary
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.
Time frame: Baseline to Objective Progression or Death Due to Any Cause (Up to 11 Months)
Population: Zero participants were analyzed due to early termination of study.
Secondary
Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446
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
Population: All participants who have received at least one dose of study drug and had evaluable PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LY3499446 Phase 1 Cohort A1 (High Dose) | Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446 | NA nanograms per milliliter (ng/mL) |
| LY3499446 Phase 1 Cohort AO (Mid Dose) | Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446 | NA nanograms per milliliter (ng/mL) |
| LY3499446 Phase 1 Cohort A-2 (Low Dose) | Phase 1: Pharmacokinetics (PK): Average Concentration of LY3499446 | NA nanograms per milliliter (ng/mL) |
Secondary
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
Time frame: Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles)
Population: Zero participants were analyzed due to early termination of study.
Secondary
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
Time frame: Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles)
Population: Zero participants were analyzed due to early termination of study.
Secondary
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
Time frame: Predose Cycle 1 Day 1 through Cycle 3 Day 1 (21 Day Cycles)
Population: Zero participants were analyzed due to early termination of study.