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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Advanced Solid Tumor; Non-Small Cell Lung Cancer; Colorectal Cancer
• Interventions: Drug: LY3499446; Drug: Abemaciclib; Drug: Cetuximab; Drug: Erlotinib; Drug: Docetaxel
• Enrollment: 5

Participant Flow

Recruitment Details
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.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)	LY3499446 + Combination Drug Phase 1	LY3499446 Monotherapy + Combination Drug Phase 2	Docetaxel Phase 2
Arm/Group 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 LY 3499446 as oral monotherapy once daily (QD) in 21-day cycles.	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). The trial was terminated prior to initiation of this portion.	LY3499446 monotherapy orally. LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). The trial was terminated prior to initiation of this portion.	Docetaxel IV infusion. The trial was terminated prior to initiation of this portion.
Period Title: Overall Study
Started	2	1	2	0	0	0
Received at Least One Dose of Study Drug	2	1	2	0	0	0
Completed	1	0	1	0	0	0
Not Completed	1	1	1	0	0	0
Reason Not Completed
Adverse Event	1	1	0	0	0	0
Withdrawal by Subject	0	0	1	0	0	0

Baseline Characteristics

Arm/Group Title		LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)	LY3499446 + Combination Drug Phase 1	LY3499446 Monotherapy + Combination Drug Phase 2	Docetaxel Phase 2	Total
Arm/Group Description		Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles.	Participants received low dose LY 3499446 as oral monotherapy once QD in 21-day cycles.	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). The trial was terminated prior to initiation of this portion.	LY3499446 monotherapy orally. LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV). The trial was terminated prior to initiation of this portion.	Docetaxel IV infusion. The trial was terminated prior to initiation of this portion.	Total of all reporting groups
Overall Number of Baseline Participants		2	1	2	0	0	0	5
Baseline Analysis Population Description		All participants who received at least one dose of study drug
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants	1 participants	2 participants	0 participants	0 participants	0 participants	5 participants
	<=18 years	0	0	0	0	0	0	0
	Between 18 and 65 years	1	0	0	0	0	0	1
	>=65 years	1	1	2	0	0	0	4
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants	1 participants	2 participants	0 participants	0 participants	0 participants	5 participants
	Female	1	1	2	0	0	0	4
	Male	1	0	0	0	0	0	1
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants	1 participants	2 participants	0 participants	0 participants	0 participants	5 participants
	Hispanic or Latino	0	0	0	0	0	0	0
	Not Hispanic or Latino	2	1	2	0	0	0	5
	Unknown or Not Reported	0	0	0	0	0	0	0
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2 participants	1 participants	2 participants	0 participants	0 participants	0 participants	5 participants
	American Indian or Alaska Native	0	0	0	0	0	0	0
	Asian	0	0	0	0	0	0	0
	Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
	Black or African American	0	0	0	0	0	0	0
	White	2	1	2	0	0	0	5
	More than one race	0	0	0	0	0	0	0
	Unknown or Not Reported	0	0	0	0	0	0	0
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	2 participants	1 participants	2 participants	0 participants	0 participants	0 participants	5 participants
United States		0	1	2	0	0	0	3
Australia		2	0	0	0	0	0	2

Outcome Measures

1. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug and had a dose limiting toxicity.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group Description:	Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles.	Participants received low dose LY3499446 as oral monotherapy once QD in 21-day cycles.
Overall Number of Participants Analyzed	2	1	2
Measure Type: Count of Participants; Unit of Measure: Participants
	2	1	1

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Monotherapy + Combination Drugs Phase 2	Docetaxel Phase 2
Arm/Group Description:	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV).	Docetaxel IV infusion.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Monotherapy + Combination Drugs Phase 2	Docetaxel Phase 2
Arm/Group Description:	LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV).	Docetaxel IV infusion.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who have received at least one dose of study drug and had evaluable PK.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group Description:	Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles.	Participants received low dose LY3499446 as oral monotherapy once QD in 21-day cycles.
Overall Number of Participants Analyzed	2	1	2
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanograms per milliliter (ng/mL)
	NA [1]; (NA%)	NA [2]; (NA%)	NA [3]; (NA%)

[1]

N=2: Geometric mean and Geometric Coefficient of Variation were not calculated, individual values reported:1056 ng/mL and 570 ng/mL.

[2]

N=1: Geometric mean and Geometric Coefficient of Variation were not calculated, individual values reported: 865 ng/mL.

[3]

N=2: Geometric mean and Geometric Coefficient of Variation were not calculated, individual values reported: 225 ng/mL and 116 ng/mL.

5. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 and Abemaciclib Phase 1
Arm/Group Description:	LY3499446 in combination with abemaciclib orally.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 and Cetuximab Phase 1
Arm/Group Description:	LY3499446 in combination with cetuximab intravenously (IV).
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

7. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Monotherapy and Erlotinib Phase 1
Arm/Group Description:	LY3499446 in combination with erlotinib orally.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

8. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group Description:	Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles.	Participants received low dose LY3499446 as oral monotherapy once QD in 21-day cycles.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

9. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group Description:	Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy QOD in 21-day cycles.	Participants received low dose LY3499446 as oral monotherapy QD in 21-day cycles in 21-day cycles.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

10. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group Description:	Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles.	Participants received low dose LY3499446 as oral monotherapy once QD in 21-day cycles.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

11. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to early termination of study.

Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)	LY3499446 Phase 1 Cohort AO (Mid Dose)	LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group Description:	Participants received high dose LY3499446 as oral monotherapy BID in 21-day cycles.	Participant received mid dose LY3499446 as oral monotherapy once QOD in 21-day cycles.	Participants received low dose LY3499446 as oral monotherapy once QD in 21-day cycles.
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	Baseline up to 11 months
Adverse Event Reporting Description	All participants who received at least one dose of study drug.
Arm/Group Title	LY3499446 Phase 1 Cohort A1 (High Dose)		LY3499446 Phase 1 Cohort AO (Mid Dose)		LY3499446 Phase 1 Cohort A-2 (Low Dose)
Arm/Group 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 monotherapy orally once QD in 21-day cycles.
All-Cause Mortality
	LY3499446 Phase 1 Cohort A1 (High Dose)		LY3499446 Phase 1 Cohort AO (Mid Dose)		LY3499446 Phase 1 Cohort A-2 (Low Dose)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/2 (50.00%)		0/1 (0.00%)		1/2 (50.00%)
Serious Adverse Events
	LY3499446 Phase 1 Cohort A1 (High Dose)		LY3499446 Phase 1 Cohort AO (Mid Dose)		LY3499446 Phase 1 Cohort A-2 (Low Dose)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0.00%)		0/1 (0.00%)		1/2 (50.00%)
General disorders
Pyrexia † 1	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Hypoxia † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Pleural effusion † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Respiratory failure † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
1 Term from vocabulary, MedDRA 23.0; 2 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	LY3499446 Phase 1 Cohort A1 (High Dose)		LY3499446 Phase 1 Cohort AO (Mid Dose)		LY3499446 Phase 1 Cohort A-2 (Low Dose)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100.00%)		1/1 (100.00%)		2/2 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	0/2 (0.00%)	0	1/1 (100.00%)	1	0/2 (0.00%)	0
Haemolysis † 2	2/2 (100.00%)	2	1/1 (100.00%)	1	1/2 (50.00%)	1
Leukocytosis † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Cardiac disorders
Cardiac arrest † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Palpitations † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	2
Gastrointestinal disorders
Constipation † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Nausea † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	2/2 (100.00%)	4
General disorders
Fatigue † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	2/2 (100.00%)	3
Infections and infestations
Urinary tract infection † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Investigations
Blood bilirubin increased † 1	2/2 (100.00%)	3	1/1 (100.00%)	1	0/2 (0.00%)	0
Haptoglobin decreased † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Metabolism and nutrition disorders
Decreased appetite † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Back pain † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Flank pain † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Pain in extremity † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Nervous system disorders
Amnesia † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/2 (0.00%)	0
Dizziness † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/2 (0.00%)	0
Dysgeusia † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Headache † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/2 (0.00%)	0
Paraesthesia † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Dyspnoea † 2	1/2 (50.00%)	2	0/1 (0.00%)	0	1/2 (50.00%)	1
Skin and subcutaneous tissue disorders
Pruritus † 3	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
Skin hyperpigmentation † 2	0/2 (0.00%)	0	0/1 (0.00%)	0	1/2 (50.00%)	1
1 Term from vocabulary, MedDRA 22.1; 2 Term from vocabulary, MedDRA 23.0; 3 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

The study was terminated due to an unexpected toxicity finding.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Chief Medical Officer
• Organization: Eli Lilly and Company
• Phone: 800-545-5979
• EMail: ClinicalTrials.gov@lilly.com

• 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 Submitted: November 14, 2019
• First Posted: November 15, 2019
• Results First Submitted: October 27, 2021
• Results First Posted: November 24, 2021
• Last Update Posted: November 24, 2021