Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)

Sponsor

Eli Lilly and Company (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04956640

Collaborator

Loxo Oncology, Inc. (Industry), Merck Sharp & Dohme LLC (Industry)

360

Enrollment

Locations

Arms

27.4

Anticipated Duration (Months)

16.4

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find out whether the study drug, LY3537982, is safe and effective in cancer patients who have a specific genetic mutation (KRAS G12C). Patients must have already received or were not able to tolerate the standard of care. The study will last up to approximately 2 years.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung Colorectal Neoplams Endometrial Neoplasms Ovarian Neoplasms Pancreatic Neoplasms	Drug: LY3537982 Drug: Abemaciclib Drug: Erlotinib Drug: Pembrolizumab Drug: Temuterkib Drug: LY3295668 Drug: Cetuximab Drug: TNO155	Phase 1

Detailed Description

This is an open-label, multicenter Phase 1 study to evaluate safety, tolerability, and preliminary efficacy of oral LY3537982 in patients with KRAS G12C-mutant solid tumors.

This study will be conducted in 2 parts, Part 1a is a dose escalation and Part 1b is a dose expansion. Part 1a will establish a recommended Phase 2 dose. Part 1b will have multiple arms of either monotherapy or in combination with other drugs.

KRAS G12C mutations will be identified through standard of care testing.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

360 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1a/1b Study of LY3537982 in Patients With KRAS G12C-Mutant Advanced Solid Tumors

Actual Study Start Date :

Jul 19, 2021

Anticipated Primary Completion Date :

Nov 1, 2023

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY3537982 (Dose Escalation) LY3537982 administered orally.	Drug: LY3537982 Oral
Experimental: LY3537982 (Dose Expansion) LY3537982 administered orally either alone or with another investigational agent.	Drug: LY3537982 Oral Drug: Abemaciclib Oral Other Names: Verzenio LY2835219 Drug: Erlotinib Oral Other Names: Tarceva Drug: Pembrolizumab Intravenous Other Names: Keytruda Drug: Temuterkib Oral Other Names: LY3214996 Drug: LY3295668 Oral Drug: Cetuximab Intravenous Other Names: Erbitux Drug: TNO155 Oral

Arm

Intervention/Treatment

Experimental: LY3537982 (Dose Escalation)

LY3537982 administered orally.

Drug: LY3537982

Oral

Experimental: LY3537982 (Dose Expansion)

LY3537982 administered orally either alone or with another investigational agent.

Drug: LY3537982

Oral

Drug: Abemaciclib

Oral

Other Names:

Verzenio

LY2835219

Drug: Erlotinib

Oral

Other Names:

Tarceva

Drug: Pembrolizumab

Intravenous

Other Names:

Keytruda

Drug: Temuterkib

Oral

Other Names:

LY3214996

Drug: LY3295668

Oral

Drug: Cetuximab

Intravenous

Other Names:

Erbitux

Drug: TNO155

Oral

Outcome Measures

Primary Outcome Measures

Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy [Cycle 1 (21 Days)]
Measured by the number of patients with dose-limiting toxicities (DLTs)
Phase 1b: To assess the safety and tolerability of LY3537982 when administered alone or in combination with other investigational agents [Cycle 1 (21 Days)]
Measured by the number of patients with dose-limiting toxicities (DLTs)

Secondary Outcome Measures

To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR) [Estimated up to 2 years]
ORR
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Duration of Response (DOR) [Estimated up to 2 years]
DOR
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Best Overall Response (BOR) [Estimated up to 2 years]
BOR
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Time to response (TTR) [Estimated up to 2 years]
TTR
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Disease control rate (DCR) [Estimated up to 2 years]
DCR
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Progression-free survival (PFS) [Estimated up to 2 years]
PFS
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Overall survival (OS) [Estimated up to 2 years]
OS
To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC) [Predose estimated up to 2 years]
PK: AUC of LY3537982
To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax) [Predose estimated up to 2 years]
PK: Cmax of LY3537982

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
Patients must have disease with evidence of KRAS G12C mutation in tumor tissue or circulating tumor deoxyribonucleic acid (DNA).
Participants must have a histological or a cytologically proven diagnosis of locally advanced, unresectable, and/or metastatic cancer and meet cohort-specific criteria.
Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
Have adequate organ function.
Have discontinued all previous treatments for cancer with resolution of any significant ongoing adverse events (AEs).
Must be able to swallow capsule/tablet.
Agree and adhere to contraceptive use, if applicable.

Exclusion Criteria:

Disease suitable for local therapy administered with curative intent.
Have an active, ongoing, or untreated infection.
Have a serious pre-existing medical condition(s) that, in the judgment of the investigator, would preclude participation in this study.
Have a serious cardiac condition.
Have a second active primary malignancy or have been diagnosed and/or treated for an additional malignancy within 3 years prior to enrollment.
Have symptomatic central nervous system (CNS) malignancy or metastasis and/or carcinomatous meningitis. Patients with treated CNS metastases are eligible for this study if they are not currently receiving corticosteroids in excess of 10 milligrams (mg) per day prednisone/prednisolone (or equivalent) and their disease is asymptomatic and radiographically stable for at least 30 days.
Have received prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol.
For Cohorts B2, B3, and B5/C1, patients treated with drugs known to be strong inhibitors or inducers of cytochrome P450 (CYP)3A.
The following patients will be excluded from Cohort B4:
Experienced certain serious side effects with prior immunotherapy.
Have an active autoimmune disease that has required systemic anti-autoimmune treatment in the past 2 years.
Have received a live vaccine within 30 days prior to the first dose of study drug.
Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 180 days after the last dose of study medication.
Known allergic reaction against any of the components of the study treatments.
The following patients will be excluded from Cohorts B7 & C3:
Clinically significant cardiac disease or risk factors at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC Norris Cancer Hospital	Los Angeles	California	United States	90033
2	Chao Family Comprehensive Cancer Ctr.	Orange	California	United States	92868
3	Hoag Memorial Hospital Presbyterian	Tustin	California	United States	92782
4	Indiana Univ Melvin & Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
5	Community Health Network	Indianapolis	Indiana	United States	46250
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
8	NYU Langone Health- Long Island	Mineola	New York	United States	11501
9	NYU Langone Medical Center- Perlmutter Cancer Center (NYU Cancer Institute)	New York	New York	United States	10016
10	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
11	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
12	Vanderbilt Univeristy School of Medicine	Nashville	Tennessee	United States	37212-6303
13	South Texas Accelerated Research Therapeutics, LLC	San Antonio	Texas	United States	78229-3307
14	START Mountain Region	West Valley City	Utah	United States	84119
15	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
16	University of Wisconsin-Madison Hospital and Health Clinic	Madison	Wisconsin	United States	53792-4108
17	St Vincent's Hospital Sydney	Sydney	New South Wales	Australia	2010
18	Alberta Health Services Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
19	Aichi Cancer Center Hospital	Nagoya	Aichi	Japan	464-8681
20	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577
21	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
22	National Cancer Center	Goyang-si	Gyeonggi-do	Korea, Republic of	10408