Recruiting
Phase 1

LOXO-435

Sponsor:

Eli Lilly and Company

Code:

NCT05614739

Conditions

Urinary Bladder Neoplasms

Neoplasm Metastasis

Ureteral Neoplasms

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Vepugratinib

Pembrolizumab

enfortumab vedotin

Trastuzumab Deruxtecan

Midazolam

Study Details

Brief summary:

The main purpose of this study is to learn more about the safety, side effects, and effectiveness of Vepugratinib by itself or when it is combined with other medicines that treat cancer. Vepugratinib may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Study participation could last up to approximately 6 years, depending on which part of the study you join.

Conditions

Urinary Bladder Neoplasms

Neoplasm Metastasis

Ureteral Neoplasms

Study ID

NCT05614739

Start date

Jan 12, 2023

Status verified date

Aug, 2026

Completion date

Jun, 2027

Anticipated

Primary completion date

Jun, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Cohort A1, C1, D1, and D2: Locally advanced or metastatic solid tumor malignancy with a qualifying FGFR3 alteration.
  • Cohort A2, B2, B5 and B7: Urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration.
  • Cohorts B1 and B4: Urothelial cancer that is locally advanced or metastatic and have received prior erdafitinib.
  • Cohort B6: Muscle Invasive Bladder Cancer with a qualifying FGFR3 alteration.
  • Cohort B7: Urothelial cancer that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration and expression of human epidermal growth factor receptor 2 (HER2).
  • Cohort B8: Low Grade Intermediate Risk Non-Muscle Invasive Bladder cancer and a qualifying FGFR3 genetic alteration.
  • Measurability of disease:

  • Cohort A1, D1, and D2: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1).
  • Cohorts A2, B1, B2, B4, B5, B7, and C1: Measurable disease required as defined by RECIST v1.1.
  • Cohort B8: Baseline disease which includes at least 1 lesion.
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of:

  • 0 or 1 for Cohorts A1, A2, B5, B6, B7, and B8.
  • Less than or equal to 2 for Cohorts B1, B2, B4, C1, DI and D2.
  • Cohort B6: Must be eligible for radical cystectomy plus pelvic lymph node dissection and agree to undergo curative intent standard radical cystectomy plus pelvic lymph node dissection.

Exclusion Criteria:

  • Participants with primary central nervous system (CNS) malignancy.
  • Untreated or uncontrolled CNS metastases.
  • Current evidence of corneal keratopathy or retinal disorder. Individuals with asymptomatic ophthalmic conditions may be eligible.
  • Any serious unresolved toxicities from prior therapy.
  • Significant cardiovascular disease.
  • Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF).
  • Active uncontrolled systemic infection or other clinically significant medical conditions.
  • Participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. Participants who have stopped breastfeeding may be enrolled.
  • Cohort D1 only:

  • Have had renal transplantation.
  • Have a known history of nephrotic syndrome.
  • Have uncontrolled fluid overload, including clinically significant ascites, pleural effusion, or peripheral edema.
  • Have uncontrolled hypertension.
  • Are on hemodialysis or similar.
  • Cohort D2 only:

  • Have a history of:
  • Ventricular tachycardia or ventricular fibrillation.
  • Hypertrophic obstructive cardiomyopathy unless managed concurrently with atrial fibrillation.
  • Wolff-Parkinson-White syndrome.
  • Second- or third-degree atrioventricular block unless a functioning pacemaker is in place.
  • Heart rate less than (<) 50 bpm.
  • Have any of these medical conditions:
  • Severe respiratory insufficiency.
  • Sleep apnea syndrome.
  • Myasthenia gravis.
  • Acute narrow-angle glaucoma.
  • Active liver disease or clinically significant hepatic impairment.
  • History of myopathy or rhabdomyolysis with any HMG-CoA reductase inhibitor.

Study Design

Enrollment

677 participants

Anticipated

Allocation

Non randomized

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Phase 1a: Cohort A1 Vepugratinib Monotherapy Dose Escalation

Vepugratinib administered orally

experimental: Phase 1a: Cohort A2 Vepugratinib Monotherapy Dose Optimization

Vepugratinib administered orally

experimental: Phase 1b: Cohort B1, B2, B4, C1, and D1 Vepugratinib Monotherapy Dose Expansion

Vepugratinib administered orally

experimental: Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin

Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV

experimental: Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin

Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV

experimental: Experimental: Phase 1b: Cohort B7 Vepugratinib Plus Trastuzumab Deruxtecan

Vepugratinib administered orally in combination with trastuzumab deruxtecan administered IV

experimental: Phase 1b: NMIBC Cohort B8 Vepugratinib Monotherapy Dose Expansion

Vepugratinib administered orally

experimental: Phase 1b: Cohort D2 (Drug to Drug Interaction)

Vepugratinib Plus Midazolam Plus Digoxin Plus Rosuvastatin (Lead-In Only) followed by Vepugratinib Monotherapy

Vepugratinib administered orally

Midazolam with digoxin with rosuvastatin administered orally once per cycle for 2 cycles.

Interventions

Vepugratinib

Oral

Pembrolizumab

IV

enfortumab vedotin

IV

Trastuzumab Deruxtecan

IV

Midazolam

Oral

Digoxin

Oral

Rosuvastatin

Oral

Primary outcome measure

  • Overall Response Rate (ORR) [ Time Frame: Up to Approximately 30 Months or 2.5 Years ]
  • Pharmacokinetics (PK) of Vepugratinib: Area Under the Concentration versus Time Curve (AUC) [ Time Frame: Up to 2 Months ]
  • PK of Midazolam, Rosuvastatin, and Digoxin Administered Alone and in the Presence of Vepugratinib: Area Under the Concentration versus Time Curve (AUC[0-inf]) [ Time Frame: Up to 2 Months ]
  • Complete Response Rate (CRR) in Participants with Low-Grade Intermediate-Risk Non-Muscle Invasive Bladder Cancer (LG IR NMIBC) [ Time Frame: Up to approximately 24 months or 5 years ]

Central Contacts and Locations

Central contacts

Trial questions or participation questions: 1-877-CTLILLY (1-877-285-4559) or

1-317-615-4559LillyTrials@Lilly.com

Physicians interested in becoming principal investigators please contact

clinical_inquiry_hub@lilly.com

Locations

University of Arizona - Cancer Center

Recruiting

Tucson, Arizona, United States, 85719

City of Hope

Recruiting

Duarte, California, United States, 91010

University of California, Los Angeles (UCLA) - Division of Hematology-Oncology

Recruiting

Los Angeles, California, United States, 90095

University of California - Irvine

Recruiting

Orange, California, United States, 92868

University of California (UC) Davis Comprehensive Cancer Center

Recruiting

Sacramento, California, United States, 95817

Stanford Medicine Cancer Center

Recruiting

Stanford, California, United States, 94305

Advent Health

Recruiting

Orlando, Florida, United States, 32804

Emory University Hospital

Recruiting

Atlanta, Georgia, United States, 30322

The University of Chicago Medical Center (UCMC)

Recruiting

Chicago, Illinois, United States, 60637

Indiana University (IU) Melvin and Bren Simon Cancer Center

Recruiting

Indianapolis, Indiana, United States, 46202

Mary Bird Perkins Cancer Center

Recruiting

Baton Rouge, Louisiana, United States, 70809

Ochsner Clinic Foundation

Recruiting

New Orleans, Louisiana, United States, 70121

Johns Hopkins Kimmel Cancer Center

Recruiting

Baltimore, Maryland, United States, 21231-2410

Massachusetts General Hospital

Recruiting

Boston, Massachusetts, United States, 02114

Barbara Ann Karmanos Cancer Institute

Recruiting

Detroit, Michigan, United States, 48201

Washington University in St. Louis

Recruiting

St Louis, Missouri, United States, 63108

New York University (NYU)

Recruiting

New York, New York, United States, 10016

Weill Cornell Medicine

Recruiting

New York, New York, United States, 10021

Icahn School of Medicine at Mount Sinai

Recruiting

New York, New York, United States, 10029

Columbia University

Recruiting

New York, New York, United States, 10032

David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center

Recruiting

New York, New York, United States, 10065

University of Rochester - Wilmot Cancer Institute

Recruiting

Rochester, New York, United States, 14642

Montefiore Medical Center

Recruiting

The Bronx, New York, United States, 10467

University of North Carolina (UNC) - Chapel Hill

Recruiting

Chapel Hill, North Carolina, United States, 27599

University of Cincinnati Medical Center (UCMC)

Recruiting

Cincinnati, Ohio, United States, 45267

The Ohio State University (OSU)

Recruiting

Columbus, Ohio, United States, 43210

University of Oklahoma - Health Sciences Center

Recruiting

Oklahoma City, Oklahoma, United States, 73104

Penn Medicine Lancaster General Hospital - Ann B. Barshinger Cancer Institute

Recruiting

Lancaster, Pennsylvania, United States, 17601

University of Pennsylvania

Recruiting

Philadelphia, Pennsylvania, United States, 19104

Thomas Jefferson University

Recruiting

Philadelphia, Pennsylvania, United States, 19107

Allegheny General Hospital

Recruiting

Pittsburgh, Pennsylvania, United States, 15212

University of Pittsburgh Medical Center

Recruiting

Pittsburgh, Pennsylvania, United States, 15213

Carolina Urologic Research Center

Recruiting

Myrtle Beach, South Carolina, United States, 29572

Sarah Cannon and HCA Research Institute

Recruiting

Nashville, Tennessee, United States, 37203

Tennessee Oncology

Recruiting

Nashville, Tennessee, United States, 37203

Vanderbilt University Medical Center

Recruiting

Nashville, Tennessee, United States, 37212

University of Texas Southwestern

Recruiting

Dallas, Texas, United States, 75244

Texas Oncology, P.A

Recruiting

Dallas, Texas, United States, 75251

MD Anderson Cancer Center

Recruiting

Houston, Texas, United States, 77030

University of Utah

Recruiting

Salt Lake City, Utah, United States, 84132

University of Vermont Medical Center

Recruiting

Burlington, Vermont, United States, 05401

Princess Margaret Hospital

Recruiting

Toronto, Canada, M5G 2M9

British Columbia Cancer Agency

Recruiting

Vancouver, Canada, V5Z 1J3

More Information

Sponsor

Eli Lilly and Company

Last update posted

Aug 20, 2026

Last verified

Aug, 2026

Keywords

  • Bladder Cancer
  • Bladder Urothelial Carcinoma
  • Urinary Bladder Cancer
  • Urinary Tract Cancer
  • Renal Pelvis Cancer
  • Ureter Cancer
  • Non-Muscle Invasive Bladder Cancer
  • Muscle Invasive Bladder Cancer

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by Eli Lilly and Company on 2026-08-20.