A Study of the Pan-KRAS Inhibitor LY4066434 in Participants With KRAS Mutant Solid Tumors

A Phase 1a/1b Study of the Pan-KRAS Inhibitor LY4066434 in Participants With KRAS Mutant Solid Tumors

The main purpose of the study is to assess whether the study drug, LY4066434, is safe and tolerable when administered to participants with locally advanced or metastatic solid tumors with certain KRAS mutations. LY4066434 will be given alone or in combination with other treatments. The study will have 2 parts: monotherapy dose escalation and dose optimization. The study is expected to last up to approximately 5 years.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer; Advanced Solid Tumor; Metastatic Solid Tumor; Non-small Cell Lung Cancer; Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: Carboplatin; Drug: LY4066434.; Drug: Cetuximab; Drug: Nab paclitaxel; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Irinotecan; Drug: 5Fluorouracil; Drug: Cisplatin; Drug: Pemetrexed; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 750
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-luc
  • Brussels, Belgium, 1070
    • Universite Libre de Bruxelles (ULB) - Institut Jules Bordet
  • Ghent, Belgium, 9000
    • UZ Gent
• France
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Frankfurt, Germany, 60488
    • Krankenhaus Nordwest GmbH
  • Hamburg, Germany, 22763
    • Asklepios Kliniken Hamburg GmbH - Asklepios Klinik Altona
  • Heilbronn, Germany, 74078
    • SLK-Kliniken Heilbronn GmbH
  • Würzburg, Germany, 97080
    • Universitaetsklinikum Wuerzburg
• Italy
  • Verona, Italy, 37134
    • Centro Ricerche Cliniche di Verona s.r.l.
• Japan
  • Chiba, Japan, 277-8577
    • National Cancer Center Hospital East
  • Kyoto, Japan, 606-8507
    • Kyoto University Hospital
  • Shizuoka, Japan, 411-8777
    • Shizuoka Cancer Center
  • Tokyo, Japan, 104-0045
    • National Cancer Center Hospital
  • Tokyo, Japan, 135-8550
    • Cancer Institute Hospital of Jfcr
• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08908
    • Institut Català d'Oncologia - L'Hospitalet
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Malaga
• Taiwan
  • Hsinchu, Taiwan, 300195
    • National Taiwan University Hospital Hsin-Chu Branch
  • Taipei, Taiwan, 10016
    • National Taiwan University Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Santa Monica, California, United States, 90404
      • University of California, Los Angeles (UCLA)
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8028
      • Yale University School of Medicine - Yale Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center (UCMC)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University (IU)
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Grand Rapids, Michigan, United States, 49546
      • South Texas Accelerated Research Therapeutics (START) Midwest
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute/SCRI
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners
  • Texas
    • Dallas, Texas, United States, 75244
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Therapeutics (START)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute (SCI)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have evidence of KRAS G12C, G12D, G12V, G12A, G12S, or G13D mutation in tumor tissue or circulating tumor DNA
• Histological or cytologically proven diagnosis of a locally advanced, unresectable, and/or metastatic solid tumor cancer
• Have measurable disease per RECIST 1.1
• Have an ECOG performance status of ≤1
• Must not be pregnant and/or planning to breastfeed during the trial or within 180 days of the last dose of trial intervention
• Must be able to swallow tablets
• Participants with asymptomatic or treated CNS disease may be eligible

Exclusion Criteria:

• Have known active CNS metastases and/or carcinomatous meningitis
• Have any unresolved toxicities from prior therapy greater than NCI CTCAE Version 5.0 Grade 1 at the time of starting trial treatment, except for alopecia, hearing loss, peripheral neuropathy and ongoing endocrinopathies controlled on appropriate replacement therapy
• Have significant cardiovascular disease defined as unstable angina or acute coronary syndrome, history of myocardial infarction, known left ventricular ejection fraction or heart failure, uncontrolled or symptomatic arrhythmias.
• Have known active hepatitis B virus (HBV), hepatitis C virus (HCV) or untreated HIV infection
• Have other active malignancy unless in remission with life expectancy greater than 2 years.
• Have active uncontrolled systemic bacterial, viral, fungal, or parasitic infection
• Have history of non-infectious pneumonitis/interstitial lung disease that received steroids or has current clinically significant pneumonitis/interstitial lung disease

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: LY4066434 Monotherapy Dose Escalation; Escalating doses of LY4066434 administered orally.	Drug: LY4066434.; Administered orally.
Experimental: LY4066434 Dose Optimization; LY4066434 administered orally either alone or with another investigational agent.	Drug: Carboplatin; Administered intravenously.; Drug: LY4066434.; Administered orally.; Drug: Cetuximab; Administered intravenously.; Drug: Nab paclitaxel; Administered intravenously.; Drug: Gemcitabine; Administered intravenously.; Drug: Oxaliplatin; Administered intravenously.; Drug: Leucovorin; Administered intravenously.; Other Names: Folinic Acid; Drug: Irinotecan; Administered intravenously.; Drug: 5Fluorouracil; Administered intravenously.; Drug: Cisplatin; Administered intravenously.; Drug: Pemetrexed; Administered intravenously.; Drug: Pembrolizumab; Administered intravenously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Dose-limiting Toxicities (DLTs)		During the first cycle of LY4066434 treatment (up to 28 days)
Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration	A summary of TEAEs, SAEs and other non-serious adverse events (AEs), regardless of causality, will be reported in the Reported Adverse Events module.	Up to approximately 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR as assessed by investigator per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)	Up to approximately 5 years
Best Overall Response (BOR)	BOR as assessed by investigator per RECIST v1.1	Up to approximately 5 years
Duration of Response (DOR)	DOR as assessed by investigator per RECIST v1.1	Up to approximately 5 years
Disease Control Rate (DCR)	DCR as assessed by investigator per RECIST v1.1	Up to approximately 5 years
Time to Response (TTR)	TTR as assessed by investigator per RECIST v1.1	Up to approximately 5 years
Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY4066434 Alone	PK: Cmax of LY4066434	Predose through Day 168
Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of LY4066434 in Combination With Other Agents	PK: Cmax of LY4066434	Predose through Day 168
PK: Time to Maximum Concentration (Tmax) of LY4066434 Alone	PK: Tmax of LY4066434	Predose through Day 168
PK: Time to Maximum Concentration (Tmax) of LY4066434 in Combination With Other Agents	PK: Tmax of LY4066434	Predose through Day 168
PK: Area Under the Concentration Versus Time Curve (AUC) of LY4066434 Alone	PK: AUC of LY4066434	Predose through Day 168
PK: Area Under the Concentration Versus Time Curve (AUC) of LY4066434 in Combination With Other Agents	PK: AUC of LY4066434	Predose through Day 168

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

Helpful Links

• A Study of the Pan-KRAS Inhibitor LY4066434 in Participants With KRAS Mutant Solid Tumors

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2024
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: September 19, 2024
• First Submitted That Met QC Criteria: September 19, 2024
• First Posted (Actual): September 23, 2024

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; Rectal cancer; Ovarian cancer; Lung cancer; Targeted therapy; KRAS mutation; Cholangiocarcinoma; Esophageal cancer; KRAS; Pancreas cancer; Endometrial cancer; Colon cancer; KRASG12C; KRASG12D; KRASG12V; KRASG12S; KRASG12A; KRASG13D; LY4066434; KRAS-mutant tumor; PanKRAS; Pan KRAS
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Lung Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Neoplastic Processes; Esophageal Diseases; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Uterine Neoplasms; Pathological Conditions, Signs and Symptoms; Rectal Neoplasms; Lung Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Esophageal Neoplasms; Ovarian Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung; Cholangiocarcinoma; Endometrial Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Camptothecin; Alkaloids; Enzymes and Coenzymes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Health Care Economics and Organizations; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Platinum Compounds; Economics; Oxaliplatin; Irinotecan; Pemetrexed; Cetuximab; Gemcitabine; Fluorouracil; Carboplatin; Leucovorin; Cisplatin; pembrolizumab; Taxes
• Other Study ID Numbers: 27237; J5Q-OX-JRDA (Other Identifier: Eli Lilly and Company)

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