A study to characterise the safety, tolerability and efficacy of the pan-KRAS inhibitor LY4066434 in participants with KRAS mutant advanced solid tumors.

Phase 1

Recruiting

Conditions: KRAS mutant solid tumors.

Interventions: Drug: LY4066434.
Drug: Cetuximab
Drug: Nab paclitaxel
Drug: Gemcitabine
Drug: Oxaliplatin
Drug: Leucovorin
Drug: Irinotecan
Drug: 5Fluorouracil
Drug: Carboplatin
Drug: Cisplatin
Drug: Pemetrexed
Drug: Pembrolizumab

Registration Number: 2024-516733-12-00

Lead Sponsor: Eli Lilly & Co.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised, recruiting

Sex: All

Target Recruitment: 353

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, 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) and 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 & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
LY4066434 Dose Optimization	Nab paclitaxel	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Monotherapy Dose Escalation	LY4066434.	Escalating doses of LY4066434 administered orally.
LY4066434 Dose Optimization	LY4066434.	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Cetuximab	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Gemcitabine	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Oxaliplatin	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Leucovorin	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Irinotecan	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	5Fluorouracil	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Carboplatin	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Cisplatin	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Pemetrexed	LY4066434 administered orally either alone or with another investigational agent.
LY4066434 Dose Optimization	Pembrolizumab	LY4066434 administered orally either alone or with another investigational agent.

Primary Outcome Measures

Name	Time	Method
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	Up to approximately 5 years	A summary of TEAEs, SAEs and other non-serious adverse events (AEs), regardless of causality, will be reported in the Reported Adverse Events module.

Secondary Outcome Measures

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

Trial Locations

Locations (18): Cliniques Universitaires Saint-Luc
🇧🇪
Sint-Lambrechts-Woluwe, Belgium
Universitair Ziekenhuis Gent
🇧🇪
Gent, Belgium
Institut Jules Bordet
🇧🇪
Anderlecht, Belgium
Hospital Del Mar
🇪🇸
Barcelona, Spain
Hospital Universitario 12 De Octubre
🇪🇸
Madrid, Spain
Hospital Universitario Ramon Y Cajal
🇪🇸
Madrid, Spain
Hospital Universitari Vall D Hebron
🇪🇸
Barcelona, Spain
Hospital Universitario Regional De Malaga
🇪🇸
Malaga, Spain
Institut Catala D'oncologia
🇪🇸
L'hospitalet De Llobregat, Spain
Universitaetsklinikum Wuerzburg AöR
🇩🇪
Wuerzburg, Germany
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Cliniques Universitaires Saint-Luc
🇧🇪Sint-Lambrechts-Woluwe, Belgium
Rachel Galot
Site contact
003227641037
rachel.galot@saintluc.uclouvain.be