FORAGER-1: A Study of Vepugratinib (LY3866288; LOXO-435) in Participants With Cancer With a Change in a Gene Called FGFR3

NCT05614739 | Recruiting Phase 1 FDA Drug

• 4 other identifiers: 18594J4G-OX-JZVA2022-502755-59-00LOXO-FG3-22001
• Study Type: interventional
• Target: 677
• Locations: 14 countries
• Sites: 82

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

Neoplasm Metastasis; Ureteral Neoplasms; Urinary Bladder Neoplasms

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

Outcome Measures

Primary Outcomes (4)

• Overall Response Rate (ORR)

  Up to Approximately 30 Months or 2.5 Years

• Pharmacokinetics (PK) of Vepugratinib: Area Under the Concentration versus Time Curve (AUC)

  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])

  Up to 2 Months

• Complete Response Rate (CRR) in Participants with Low-Grade Intermediate-Risk Non-Muscle Invasive Bladder Cancer (LG IR NMIBC)

  Up to approximately 24 months or 5 years

Secondary Outcomes (3)

• Change from Baseline in Bladder-Related Symptoms, Measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) Subscale (BlCS)

  Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 (28 Day Cycles)

• Change from Baseline in Physical Function, Measured by FACT- Physical Well-Being Scale (PWB) Subscale

  Up to Approximately 30 Months or 2.5 Years

• Event-Free Survival (EFS) in Participants with Muscle Invasive Bladder Cancer (MIBC)

  Up to approximately 30 months or 2.5 years

Study Arms (8)

Phase 1a: Cohort A1 Vepugratinib Monotherapy Dose Escalation

EXPERIMENTAL

Vepugratinib administered orally

Drug: Vepugratinib

Phase 1a: Cohort A2 Vepugratinib Monotherapy Dose Optimization

EXPERIMENTAL

Vepugratinib administered orally

Drug: Vepugratinib

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

EXPERIMENTAL

Vepugratinib administered orally

Drug: Vepugratinib

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

EXPERIMENTAL

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

Drug: Vepugratinib; Drug: Pembrolizumab; Drug: enfortumab vedotin

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

EXPERIMENTAL

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

Drug: Vepugratinib; Drug: Pembrolizumab; Drug: enfortumab vedotin

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

EXPERIMENTAL

Vepugratinib administered orally in combination with trastuzumab deruxtecan administered IV

Drug: Vepugratinib; Drug: Trastuzumab Deruxtecan

Phase 1b: NMIBC Cohort B8 Vepugratinib Monotherapy Dose Expansion

EXPERIMENTAL

Vepugratinib administered orally

Drug: Vepugratinib

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

EXPERIMENTAL

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.

Drug: Vepugratinib; Drug: Midazolam; Drug: Digoxin; Drug: Rosuvastatin

Interventions

Pembrolizumab DRUG

IV

Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin; Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin

enfortumab vedotin DRUG

IV

Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin; Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin

Vepugratinib DRUG

Oral

Also known as: LY3866288, LOXO-435

Experimental: Phase 1b: Cohort B7 Vepugratinib Plus Trastuzumab Deruxtecan; Phase 1a: Cohort A1 Vepugratinib Monotherapy Dose Escalation; Phase 1a: Cohort A2 Vepugratinib Monotherapy Dose Optimization; Phase 1b: Cohort B1, B2, B4, C1, and D1 Vepugratinib Monotherapy Dose Expansion; Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin; Phase 1b: Cohort D2 (Drug to Drug Interaction); Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin; Phase 1b: NMIBC Cohort B8 Vepugratinib Monotherapy Dose Expansion

Trastuzumab Deruxtecan DRUG

IV

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

Midazolam DRUG

Oral

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

Digoxin DRUG

Oral

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

Rosuvastatin DRUG

Oral

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.

You may not qualify if:

• 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:

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (82)

University of Arizona - Cancer Center

Tucson, Arizona, 85719, United States

RECRUITING

City of Hope

Duarte, California, 91010, United States

RECRUITING

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

Los Angeles, California, 90095, United States

RECRUITING

University of California - Irvine

Orange, California, 92868, United States

RECRUITING

University of California (UC) Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

RECRUITING

Stanford Medicine Cancer Center

Stanford, California, 94305, United States

RECRUITING

Advent Health

Orlando, Florida, 32804, United States

RECRUITING

Emory University Hospital

Atlanta, Georgia, 30322, United States

RECRUITING

The University of Chicago Medical Center (UCMC)

Chicago, Illinois, 60637, United States

RECRUITING

Indiana University (IU) Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

RECRUITING

Mary Bird Perkins Cancer Center

Baton Rouge, Louisiana, 70809, United States

RECRUITING

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

RECRUITING

Johns Hopkins Kimmel Cancer Center

Baltimore, Maryland, 21231-2410, United States

RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

RECRUITING

Washington University in St. Louis

St Louis, Missouri, 63108, United States

RECRUITING

New York University (NYU)

New York, New York, 10016, United States

RECRUITING

Weill Cornell Medicine

New York, New York, 10021, United States

RECRUITING

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

RECRUITING

Columbia University

New York, New York, 10032, United States

RECRUITING

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

New York, New York, 10065, United States

RECRUITING

University of Rochester - Wilmot Cancer Institute

Rochester, New York, 14642, United States

RECRUITING

Montefiore Medical Center

The Bronx, New York, 10467, United States

RECRUITING

University of North Carolina (UNC) - Chapel Hill

Chapel Hill, North Carolina, 27599, United States

RECRUITING

University of Cincinnati Medical Center (UCMC)

Cincinnati, Ohio, 45267, United States

RECRUITING

The Ohio State University (OSU)

Columbus, Ohio, 43210, United States

RECRUITING

University of Oklahoma - Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

RECRUITING

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

Lancaster, Pennsylvania, 17601, United States

RECRUITING

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

RECRUITING

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

RECRUITING

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

RECRUITING

Carolina Urologic Research Center

Myrtle Beach, South Carolina, 29572, United States

RECRUITING

Sarah Cannon and HCA Research Institute

Nashville, Tennessee, 37203, United States

RECRUITING

Tennessee Oncology

Nashville, Tennessee, 37203, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

RECRUITING

University of Texas Southwestern

Dallas, Texas, 75244, United States

RECRUITING

Texas Oncology, P.A

Dallas, Texas, 75251, United States

RECRUITING

MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

University of Utah

Salt Lake City, Utah, 84132, United States

RECRUITING

University of Vermont Medical Center

Burlington, Vermont, 05401, United States

RECRUITING

St Vincent's Hospital

Darlinghurst, NSW 2010, Australia

RECRUITING

Calvary Mater Newcastle

Hunter Region, NSW, 2310, Australia

RECRUITING

GenesisCare North Shore

St Leonards, 2065, Australia

RECRUITING

Macquarie University

Sydney, 2109, Australia

RECRUITING

Princess Margaret Hospital

Toronto, M5G 2M9, Canada

RECRUITING

British Columbia Cancer Agency

Vancouver, V5Z 1J3, Canada

RECRUITING

Beijing Cancer hospital

Beijing, 100142, China

RECRUITING

Beijing Hospital

Beijing, 100730, China

RECRUITING

Sun Yat-Sen University- Cancer Center

Guangdong, 510060, China

RECRUITING

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

Hangzhou, 310002, China

RECRUITING

Renji Hospital, Shanghai Jiaotong University School of Medicine

Shanghai, 200000, China

RECRUITING

Tianjin Medical University Cancer Institute & Hospital

Tianjin, 300060, China

RECRUITING

The First Affiliated Hospital of Xi'an Jiaotong University

Xi'an, 710061, China

RECRUITING

Zhejiang Provincial People's Hospital

Zhejiang, 310003, China

RECRUITING

Institut Bergonie

Bordeaux, 33076, France

RECRUITING

Centre Leon Berard

Lyon, 69373, France

RECRUITING

Institut Gustave Roussy

Villejuif, 94805, France

RECRUITING

Klinikum der Technischen Universitaet Muenchen (TUM Klinikum)

München, 81675, Germany

RECRUITING

Universitaetsklinikum Tuebingen

Tübingen, 72016, Germany

RECRUITING

Rabin Medical Center, Beilinson Hospital

Petah Tikva, 49100, Israel

RECRUITING

Sheba Medical Center

Tel Litwinsky, 5265601, Israel

RECRUITING

IRCCS Ospedale San Raffaele

Milan, 20132, Italy

RECRUITING

UOC Fase I - Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuore

Roma, 00168, Italy

RECRUITING

National Cancer Center Hospital East

Chiba, 277-8577, Japan

RECRUITING

Aichi Cancer Center Hospital

Nagoya, 464-8681, Japan

RECRUITING

National Cancer Center Hospital

Tokyo, 104-0045, Japan

RECRUITING

Cancer Institute Hospital of JFCR

Tokyo, 135-8550, Japan

RECRUITING

Erasmus MC

GE Rotterdam, 3015, Netherlands

RECRUITING

Haukeland University Hospital

Bergen, 5021, Norway

RECRUITING

Oslo University Hospital

Oslo, 0450, Norway

RECRUITING

Seoul National University Hospital

Seoul, 03080, South Korea

RECRUITING

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

RECRUITING

Asan Medical Center

Seoul, 05505, South Korea

RECRUITING

Samsung Medical Center

Seoul, 06351, South Korea

RECRUITING

Institut Catala d'Oncologia - L'Hospitalet

Barcelona, 08908, Spain

RECRUITING

Fundacion MD Anderson International Espana

Madrid, 28033, Spain

RECRUITING

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

RECRUITING

South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC

Madrid, 28050, Spain

RECRUITING

Hospital Universitario Marques De Valdecilla

Santander, 39008, Spain

RECRUITING

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

RECRUITING

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, S10 2SB, United Kingdom

RECRUITING

Related Links

• A Study of LOXO-435 in Patients With Cancer With a Change in a Gene Called FGFR3

MeSH Terms

Conditions

Urinary Bladder Neoplasms; Neoplasm Metastasis; Ureteral Neoplasms; Urologic Neoplasms; Non-Muscle Invasive Bladder Neoplasms

Interventions

pembrolizumab; enfortumab vedotin; trastuzumab deruxtecan; Midazolam; Digoxin; Rosuvastatin Calcium

Condition Hierarchy (Ancestors)

Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ureteral Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates; Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• 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

  STUDY DIRECTOR

Central Study Contacts

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

CONTACT

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

Physicians interested in becoming principal investigators please contact

CONTACT

clinical_inquiry_hub@lilly.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2022
• First Posted: November 14, 2022
• Study Start: January 12, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: August 20, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

NO (2); DE (2); GB (2); FR (3); IT (2); IL (2); AU (4); JP (4); CN (8); CA (2); KR (4); US (41); NL (1); ES (5)