Study Of LY3537982 In Cancer Patients With A Specific Genetic Mutation (KRAS G12C)

Study Overview

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

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, except for specific groups who have not had cancer treatment. The study will last up to approximately 4 years.

This is an open-label, multicenter Phase 1/2 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 4 parts: Phase 1a dose escalation, Phase 1b dose expansion, Phase 1b dose optimization, and Phase 2. KRAS G12C mutations will be identified through standard of care testing.

Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Endometrial Neoplasms
Ovarian Neoplasms
Pancreatic Neoplasms
Biliary Tract Neoplasms

DRUG: LY3537982
DRUG: Pembrolizumab
DRUG: Cetuximab
DRUG: Pemetrexed
DRUG: Cisplatin
DRUG: Carboplatin

LOXO-RAS-20001
2021-000595-12 (EUDRACT_NUMBER Identifier) (EUDRACT_NUMBER: )
J3M-OX-JZQA (OTHER Identifier) (OTHER: Eli Lilly and Company)
MK-3475-E27/KEYNOTE E27 (OTHER Identifier) (OTHER: Merck Sharp & Dohme LLC)
2022-502756-31-00 (CTIS Identifier) (CTIS: )

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2021-07-02	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-03-05
First Submitted that Met QC Criteria 2021-07-02	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-03-07
First Posted (ACTUAL) 2021-07-09	Results First Posted N/A	Last Verified 2025-03

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

Arms and Interventions

Participant Group/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: Pembrolizumab Intravenous DRUG: Cetuximab Intravenous DRUG: Pemetrexed Intravenous DRUG: Cisplatin Intravenous DRUG: Carboplatin Intravenous
EXPERIMENTAL: LY3537982 (Dose Optimization) LY3537982 administered orally either alone or with another investigational agent	DRUG: LY3537982 Oral DRUG: Pembrolizumab Intravenous DRUG: Cetuximab Intravenous

Participant Group/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: Pembrolizumab

Intravenous

DRUG: Cetuximab

Intravenous

DRUG: Pemetrexed

Intravenous

DRUG: Cisplatin

Intravenous

DRUG: Carboplatin

Intravenous

EXPERIMENTAL: LY3537982 (Dose Optimization)

LY3537982 administered orally either alone or with another investigational agent

DRUG: LY3537982

Oral

DRUG: Pembrolizumab

Intravenous

DRUG: Cetuximab

Intravenous

Primary Outcome Measures	Measure Description	Time Frame
Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy	Measured by the number of patients with dose-limiting toxicities (DLTs)	Cycle 1 (21 Days)
Phase 1b: To assess the safety and tolerability of LY3537982 when administered alone or in combination with other investigational agents	Measured by the number of patients with dose-limiting toxicities (DLTs)	Cycle 1 (21 Days)
Phase 1b: To determine the optimal dose of LY3537982 to be administered to treatment-naïve participants with advanced NSCLC in combination with pembrolizumab	Measured by TEAEs	Estimated up to 2 years
To determine the optimal dose of LY3537982 to be administered to participants who have received at least one prior oxaliplatin- or irinotecan-containing regimen for advanced or metastatic CRC in combination with cetuximab		Estimated up to 2 years
To assess the antitumor activity of LY3537982 monotherapy in participants with advanced pancreatic cancer with KRAS G12C mutation		Estimated up to 2 years

Secondary Outcome Measures	Measure Description	Time Frame
To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR)	ORR	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Duration of Response (DOR)	DOR	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Best Overall Response (BOR)	BOR	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Time to response (TTR)	TTR	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Disease control rate (DCR)	DCR	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Progression-free survival (PFS)	PFS	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Overall survival (OS)	OS	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Intracranial DOR based on modified RECIST v1.1 (Certain arms of the study only)	Intracranial DOR	Estimated up to 2 years
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Whole-body ORR based on RECIST v1.1 and modified RECIST v1.1 (Certain arms of the study only)	Whole-body ORR	Estimated up to 2 years
To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC)	PK: AUC of LY3537982	Predose estimated up to 2 years
To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax)	PK: Cmax of LY3537982	Predose estimated up to 2 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Phone Number: 13176154559

Email: clinical_inquiry_hub@lilly.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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), (except in certain scenarios).
Must be able to swallow capsule/tablet.
Agree and adhere to contraceptive use, if applicable.
For some parts of the study, (i.e., one of the two arms with LY3537982 in combination with pembrolizumab and the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy) histologically or cytologically confirmed Stage IIIB-IIIC or Stage IV NSCLC that is previously untreated in the advanced/metastatic setting and not suitable for curative intent radical surgery or radiation therapy. Previously untreated patients who received adjuvant and neoadjuvant therapy are eligible if the last dose of the systemic treatment was completed at least 6 months prior to enrollment. For untreated patients in the arm with LY3537982 in combination with pembrolizumab noted above, a single cycle of pembrolizumab may be initiated within 21 days prior to enrollment. For untreated patients in the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy, a single cycle of any or all of the drugs other than LY3537982 may be initiated within 21 days prior to enrollment. Start of study treatment may be delayed to allow sufficient time for recovery from treatment-related toxicity.
For one part of the study, participants must have received at least one prior oxaliplatin- or irinotecan-containing regimen for advanced or metastatic CRC.

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.
For some parts of the study only: have untreated active central nervous system (CNS) metastases and/or leptomeningeal disease. Patients with treated CNS metastases are eligible for this study if their disease is asymptomatic, radiographically stable for at least 30 days, and they do not require treatment with steroids in the two-week period prior to study treatment. Patients with active CNS metastases are eligible for one part of the study.
Have received prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol.
The following patients will be excluded from some parts of the study:

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 35 days after the last dose of study medication.
Known allergic reaction against any of the components of the study treatments.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Merck Sharp & Dohme LLC

Investigators

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

Publications

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