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

A Phase 1/2 Study of LY3537982 in Patients With KRAS G12C-Mutant Advanced Solid Tumors

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.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Pancreatic Neoplasms; Ovarian Neoplasms; Endometrial Neoplasms; Biliary Tract Neoplasms
• Intervention / Treatment: Drug: Carboplatin; Drug: Cisplatin; Drug: LY3537982; Drug: Pembrolizumab; Drug: Cetuximab; Drug: Pemetrexed

Detailed Description

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 3 parts: Phase 1a dose escalation, Phase 1b dose expansion and dose optimization, and Phase 2.

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

• Study Type: Interventional
• Enrollment (Estimated): 450
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Patient Advocacy; Phone Number: 855-569-6305; Email: clinicaltrials@loxooncology.com

Study Locations

• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Recruiting
      • Royal North Shore Hospital
      • Contact: Phone Number: 855-569-6305
    • Sydney, New South Wales, Australia, 2010
      • Recruiting
      • St Vincent's Hospital Sydney
      • Contact: Phone Number: 855-569-6305
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Recruiting
      • Cross Cancer Institute
      • Contact: Phone Number: 855-569-6305
• France
  • Villejuif Cedex, France, 94805
    • Recruiting
    • Gustave Roussy
    • Contact: Phone Number: 855-569-6305
  • Rhône-Alpes
    • Lyon, Rhône-Alpes, France, 69008
      • Recruiting
      • Centre Leon Berard
      • Contact: Phone Number: 855-569-6305
• Japan
  • Wakayama, Japan, 641-8510
    • Recruiting
    • Wakayama Medical University Hospital
    • Contact: Phone Number: 855-569-6305
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Recruiting
      • Aichi Cancer Center Hospital
      • Contact: Phone Number: 855-569-6305
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Recruiting
      • National Cancer Center Hospital East
      • Contact: Phone Number: 855-569-6305
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Recruiting
      • National Cancer Center Hospital
      • Contact: Phone Number: 855-569-6305
• Korea, Republic of
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of, 10408
      • Recruiting
      • National Cancer Center
      • Contact: Phone Number: 855-569-6305
    • Suwon-si, Gyeonggi-do, Korea, Republic of, 16247
      • Recruiting
      • The Catholic university of Korea, St. Vincent's Hospital
      • Contact: Phone Number: 855-569-6305
  • Jeonranamdo
    • Hwasun-gun, Jeonranamdo, Korea, Republic of, 58128
      • Recruiting
      • Chonnam National University Hwasun Hospital
      • Contact: Phone Number: 855-569-6305
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Recruiting
      • Asan Medical Center
      • Contact: Phone Number: 855-569-6305
    • Seoul, Korea, Korea, Republic of, 03080
      • Recruiting
      • Seoul National University Hospital
      • Contact: Phone Number: 855-569-6305
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC Norris Cancer Hospital
      • Contact: Phone Number: 855-569-6305
    • Orange, California, United States, 92868
      • Recruiting
      • Chao Family Comprehensive Cancer Ctr.
      • Contact: Phone Number: 855-569-6305
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale University School Of Medicine
      • Contact: Phone Number: 855-569-6305
  • Florida
    • Orlando, Florida, United States, 32803
      • Recruiting
      • AdventHealth Orlando
      • Contact: Phone Number: 855-569-6305
    • Sarasota, Florida, United States, 34236
      • Recruiting
      • Florida Cancer Specialists
      • Contact: Phone Number: 855-569-6305
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Recruiting
      • Community Health Network
      • Contact: Phone Number: 855-569-6305
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana Univ Melvin & Bren Simon Cancer Center
      • Contact: Phone Number: 855-569-6305
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Phone Number: 855-569-6305
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Recruiting
      • Dartmouth-Hitchcock Medical Center
      • Contact: Phone Number: 855-569-6305
  • New York
    • Mineola, New York, United States, 11501
      • Recruiting
      • NYU Langone Health- Long Island
      • Contact: Phone Number: 855-569-6305
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Recruiting
      • Novant Health Cancer Institute - Forsyth
      • Contact: Phone Number: 855-569-6305
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Recruiting
      • Fox Chase Cancer Center
      • Contact: Phone Number: 855-569-6305
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • UPMC Hillman Cancer Center
      • Contact: Phone Number: 855-569-6305
  • Tennessee
    • Nashville, Tennessee, United States, 37212-6303
      • Recruiting
      • Vanderbilt Univeristy School of Medicine
      • Contact: Phone Number: 855-569-6305
  • Texas
    • San Antonio, Texas, United States, 78229-3307
      • Recruiting
      • South Texas Accelerated Research Therapeutics (START)
      • Contact: Phone Number: 855-569-6305
  • Utah
    • West Valley City, Utah, United States, 84119
      • Recruiting
      • START Mountain Region
      • Contact: Phone Number: 855-569-6305
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists, PC
      • Contact: Phone Number: 855-569-6305
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-4108
      • Recruiting
      • University of Wisconsin-Madison Hospital and Health Clinic
      • Contact: Phone Number: 855-569-6305

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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), (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.

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 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. This only applies to some parts 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 180 days after the last dose of study medication.
• Known allergic reaction against any of the components of the study treatments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

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: Carboplatin; Intravenous; Drug: Cisplatin; Intravenous; Drug: LY3537982; Oral; Drug: Pembrolizumab; Intravenous; Other Names: Keytruda; Drug: Cetuximab; Intravenous; Other Names: Erbitux; Drug: Pemetrexed; Intravenous; Other Names: Alimta; LY231514

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Outcome Measure	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 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
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Intracranial ORR based on modified RECIST v1.1 (Certain arms of the study only)	Intracranial ORR	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

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Merck Sharp & Dohme LLC; Loxo Oncology, Inc.
• Investigators: Study Director: Melinda Willard, PhD, Loxo Oncology, Inc.

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2021
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: July 2, 2021
• First Submitted That Met QC Criteria: July 2, 2021
• First Posted (Actual): July 9, 2021

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Frontline; 1L; First Line
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Lung Diseases; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Neoplasms; Biliary Tract Diseases; Pancreatic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Ovarian Neoplasms; Endometrial Neoplasms; Pancreatic Neoplasms; Biliary Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Carboplatin; Pembrolizumab; Pemetrexed; Cetuximab
• Other Study ID Numbers: LOXO-RAS-20001; 2021-000595-12 (EudraCT Number); J3M-OX-JZQA (Other Identifier: Eli Lilly and Company); KEYNOTE E27 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No