Trial: FORAGER-1: A Study of LOXO-435 (LY38662…

Trial Details

Sponsor: Eli Lilly and Company (industry)

Phase: 1

Start date: Jan. 12, 2023

Planned enrollment: 535

Trial ID: NCT05614739

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: LOXO-435 (LY3866288, LOX-24350)

Overview

LOXO-435 (LY3866288; preclinical code LOX-24350) is an oral, highly isoform‑selective FGFR3 inhibitor in early clinical development for cancers harboring FGFR3 alterations, most prominently metastatic urothelial carcinoma (mUC). Initial phase 1 (FORAGER‑1; NCT05614739) readouts presented in February 2025 showed encouraging antitumor activity with a favorable tolerability profile relative to pan‑FGFR inhibitors. The study remains recruiting as of July 2025, with estimated primary completion in 2027. (ascopubs.org, ichgcp.net, cdek.pharmacy.purdue.edu)

Mechanism of action

Target: selective inhibition of FGFR3, designed to spare FGFR1/2/4 and thereby reduce off‑target toxicities such as FGFR1‑mediated hyperphosphatemia. LOXO‑435 is also designed to retain potency against FGFR3 “gatekeeper” resistance mutations (for example V555M) and is active against FGFR3 fusions (e.g., FGFR3‑TACC3) and oncogenic point mutations (e.g., S249C). Preclinical work with the closely linked compound LOX‑24350 demonstrated >50‑fold selectivity for FGFR3 over FGFR1 and tumor regressions in FGFR3‑driven models, supporting the isoform‑selective strategy. (aacrjournals.org)

Efficacy

Phase 1 FORAGER‑1 (dose‑escalation/optimization; cutoff August–September 2024; results presented February 2025):

Metastatic urothelial carcinoma with activating FGFR3 alterations, dosed ≥200 mg twice daily:
Objective response rate (ORR): 42% (14/33; 10 confirmed at data cutoff, 4 pending confirmation). Responses occurred across FGFR3 mutations (Y373C, S249C, R248C, S371C) and FGFR3‑TACC3 fusions. Most partial responses (14/16; 88%) were ongoing at the time of reporting. (ascopubs.org)
Prior FGFR inhibitor–treated mUC subgroup: ORR 45% (5/11). (ascopubs.org)
Signals beyond mUC: single partial responses reported in NSCLC (FGFR3 S249C) and biliary tract cancer (FGFR3‑TACC3). (ascopubs.org)
An independent meeting report summarizing the same dataset noted a confirmed ORR of 41% (16/39) and 90% disease control in evaluable mUC patients at ≥200 mg BID, including 50% confirmed ORR after prior FGFR inhibitor. (urotoday.com)

Exploratory biomarkers: - Decreases in FGFR3 circulating tumor DNA variant allele fraction were seen in 92% (12/13) of evaluable patients by cycle 2/3; 8 achieved ctDNA clearance (5 with PR; 3 with SD). (ascopubs.org)

Study design/status: - Ongoing phase 1a/1b dose‑escalation and expansion (monotherapy; combinations with pembrolizumab ± enfortumab vedotin); estimated enrollment ~535; non‑randomized, open‑label. (ichgcp.net, cdek.pharmacy.purdue.edu)

Safety

Across 101 treated patients (6 mg QD–400 mg BID), no dose‑limiting toxicities were observed in dose escalation. At doses ≥200 mg BID, the most common treatment‑emergent adverse events were diarrhea (67%), hyperphosphatemia (28%), fatigue (23%), and transaminase increases (ALT 22%, AST 22%); most events were grade 1–2. Treatment‑related AEs led to dose reductions in 5% and no discontinuations. Toxicities typically associated with pan‑FGFR inhibitors (e.g., retinopathy, onycholysis, hand‑foot syndrome) were ≤5% and low grade. (ascopubs.org)
A meeting report similarly highlighted a favorable safety profile with very rare high‑grade FGFR1/2/4‑mediated adverse events. (urotoday.com)

HealthScout AI Analysis

Goal: Evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of the selective FGFR3 inhibitor LOXO-435 as monotherapy and in combination with pembrolizumab with or without enfortumab vedotin in advanced solid tumors harboring FGFR3 alterations, with a focus on metastatic urothelial cancer, and determine a recommended dose for expansion.

Patients: Adults with locally advanced or metastatic solid tumors with actionable FGFR3 pathway alterations; expansion cohorts predominantly enroll urothelial carcinoma. ECOG 0–1 for early cohorts and some expansions, up to 2 for other expansion cohorts. Prior therapy requirements vary by cohort: dose-escalation/optimization cohorts require standard options exhausted or inappropriate; expansion cohorts include both post–FGFR inhibitor mUC, FGFR inhibitor–naïve mUC, treatment-naïve mUC, and non-urothelial solid tumors with FGFR3 alterations. Key exclusions include primary CNS malignancy, untreated/uncontrolled CNS metastases, significant ocular, cardiovascular, or infectious comorbidities, and prolonged QTcF.

Design: Phase 1, open-label, multicenter, non-randomized study with Phase 1a dose escalation and dose optimization to define the recommended dose, followed by Phase 1b dose-expansion cohorts evaluating monotherapy and combinations. Planned enrollment approximately 535 participants.

Treatments: LOXO-435 given orally as monotherapy in dose escalation, optimization, and several expansion cohorts; LOXO-435 combined with pembrolizumab IV in one expansion cohort; and with pembrolizumab plus enfortumab vedotin IV in a first-line expansion cohort. LOXO-435 (LY3866288) is a highly isoform-selective FGFR3 inhibitor designed to spare FGFR1/2/4 to reduce off-target toxicities such as FGFR1-mediated hyperphosphatemia and to retain potency against FGFR3 resistance mutations and fusions. Early Phase 1 readouts have shown encouraging activity in metastatic urothelial cancer with FGFR3 alterations, including responses after prior FGFR inhibitor exposure, and a favorable tolerability profile with mostly low-grade adverse events compared with pan-FGFR inhibitors. Pembrolizumab is a PD-1 inhibitor used as standard immunotherapy in urothelial cancer; enfortumab vedotin is an antibody–drug conjugate targeting Nectin-4 used in advanced urothelial cancer.

Outcomes: Primary endpoints include dose-limiting toxicities in Phase 1a, overall response rate by RECIST v1.1 in Phase 1b, and the incidence of treatment-emergent and serious adverse events related to study drugs. Secondary endpoints include pharmacokinetics of LOXO-435 (AUC and Cmin), overall survival, objective response rate, duration of response, time to response, progression-free survival, disease control rate, and patient-reported outcomes including bladder-related symptoms (FACT-Bl subscale) and physical well-being (FACT-PWB).

Burden on patient: High. As a Phase 1 trial with dose escalation/optimization and combination cohorts, participants should expect frequent on-site visits, intensive safety monitoring, serial pharmacokinetic blood draws in early cycles, and protocol-mandated ophthalmologic and cardiac assessments due to class effects and QTc risk. Imaging for response per RECIST will be performed regularly. Tumor tissue is required with potential for repeat biopsies if feasible. Combination cohorts add IV infusions for pembrolizumab (every 3–6 weeks) and enfortumab vedotin (days 1 and 8 of 21- or 28-day cycles depending on regimen), increasing visit frequency and infusion-related monitoring. Total participation may extend up to 30 months, requiring ongoing travel and adherence to visit schedules.

Eligibility

Show Criteria

Inclusion Criteria:

* Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable

* Cohort A1: Presence of an alteration in FGFR3 or its ligands

* Cohort A2, B2, B3, and B5: Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration

* Cohorts B1 and B4: Histological diagnosis of urothelial cancer that is locally advanced or metastatic

* Cohort C1: Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration

* Measurability of disease:

* Cohort A1 and B3: 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, and C1: Measurable disease required as defined by RECIST v1.1

* Have adequate tumor tissue sample available. Participants with inadequate tissue sample availability may still be considered for enrollment upon review

* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 for Cohorts A1, A2, B3, and B5

* Less than or equal to 2 for Cohorts B1, B2, B4, and C1

* Prior Systemic Therapy Criteria:

* Cohort A1/C1: Participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating Investigator; OR the participant is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.

* Cohort A2, B2, B3 participants must have received at least one prior regimen, and cohorts B1 and B4 participants at least 2 prior regimens, in the locally advanced or metastatic setting

* There is no restriction on number of prior therapies

* Cohort B5: Participants have not received prior systemic therapy for locally advanced or metastatic UC

* FGFR inhibitor specific requirements:

* Cohort A1/A2/B3: Prior FGFR inhibitor treatment is permitted but not required

* Cohort B1/B4: Participants must have been previously treated with erdafitinib

* Cohort B2, B5, and C1: Participants must be FGFR inhibitor naïve

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

Sites (84)

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GenesisCare North Shore

St Leonards, 2065, Australia

No email / No phone

Status: Recruiting

Calvary Mater Newcastle

Hunter Region, NSW, 2310, Australia

No email / No phone

Status: Recruiting

St Vincent's Hospital

Darlinghurst, NSW 2010, Australia

No email / No phone

Status: Recruiting

Macquarie University

Sydney, 2109, Australia

No email / No phone

Status: Not yet recruiting

British Columbia Cancer Agency

Vancouver, V5Z 1J3, Canada

No email / No phone

Status: Recruiting

Princess Margaret Hospital

Toronto, M5G 2M9, Canada

No email / No phone

Status: Recruiting

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

Hangzhou, 310002, China

No email / No phone

Status: Recruiting

Zhejiang Provincial People's Hospital

Zhejiang, 310003, China

No email / No phone

Status: Recruiting

First Affiliated Hospital of Medical College of Xian jiaotong University

Xi'an, 710061, China

No email / No phone

Status: Recruiting

Renji Hospital, Shanghai Jiaotong University School of Medicine

Shanghai, 200000, China

No email / No phone

Status: Recruiting

Sun Yat-Sen University- Cancer Center

Guangdong, 510060, China

No email / No phone

Status: Recruiting

Beijing Hospital

Beijing, 100730, China

No email / No phone

Status: Recruiting

Beijing Cancer hospital

Beijing, 100142, China

No email / No phone

Status: Recruiting

Tianjin Medical University Cancer Institute & Hospital

Tianjin, 300060, China

No email / No phone

Status: Recruiting

Centre Leon Berard

Lyon, 69008, France

No email / No phone

Status: Recruiting

Institut Bergonie

Bordeaux, 33076, France

No email / No phone

Status: Recruiting

Institut Gustave Roussy

Villejuif, 94805, France

No email / No phone

Status: Recruiting

Klinikum der Technischen Universitaet Muenchen (TUM Klinikum)

München, 81675, Germany

No email / No phone

Status: Recruiting

Universitaetsklinikum Schleswig-Holstein - Campus Luebeck

Lübeck, 23538, Germany

No email / No phone

Status: Not yet recruiting

Universitaetsklinikum Tuebingen

Tübingen, 72016, Germany

No email / No phone

Status: Recruiting

Rabin Medical Center, Beilinson Hospital

Petah Tikva, 49100, Israel

No email / No phone

Status: Recruiting

Sheba Medical Center

Tel Litwinsky, 5265601, Israel

No email / No phone

Status: Recruiting

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

Roma, 00168, Italy

No email / No phone

Status: Recruiting

IRCCS Ospedale San Raffaele

Milan, 20132, Italy

No email / No phone

Status: Recruiting

National Cancer Center Hospital East

Chiba, 277-8577, Japan

No email / No phone

Status: Recruiting

Cancer Institute Hospital of JFCR

Tokyo, 135-8550, Japan

No email / No phone

Status: Recruiting

National Cancer Center Hospital

Tokyo, 104-0045, Japan

No email / No phone

Status: Recruiting

Aichi Cancer Center Hospital

Nagoya, 464-8681, Japan

No email / No phone

Status: Recruiting

Erasmus MC

GE Rotterdam, 3015, Netherlands

No email / No phone

Status: Recruiting

Haukeland University Hospital

Bergen, 5021, Norway

No email / No phone

Status: Recruiting

Oslo University Hospital

Oslo, 0450, Norway

No email / No phone

Status: Recruiting

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

No email / No phone

Status: Recruiting

Seoul National University Hospital

Seoul, 03080, South Korea

No email / No phone

Status: Recruiting

Samsung Medical Center

Seoul, 06351, South Korea

No email / No phone

Status: Recruiting

Asan Medical Center

Seoul, 05505, South Korea

No email / No phone

Status: Recruiting

Institut Catala d'Oncologia - L'Hospitalet

Barcelona, 08908, Spain

No email / No phone

Status: Recruiting

Fundacion MD Anderson International Espana

Madrid, 28033, Spain

No email / No phone

Status: Recruiting

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

No email / No phone

Status: Recruiting

South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC

Madrid, 28050, Spain

No email / No phone

Status: Recruiting

Hospital Universitario Marques De Valdecilla

Santander, 39008, Spain

No email / No phone

Status: Recruiting

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

No email / No phone

Status: Recruiting

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, S10 2SB, United Kingdom

No email / No phone

Status: Recruiting

University of Arizona - Cancer Center

Tucson, Arizona, 85719, United States

No email / No phone

Status: Not yet recruiting

City of Hope

Duarte, California, 91010, United States

No email / No phone

Status: Recruiting

Stanford Cancer Center

Stanford, California, 94305, United States

No email / No phone

Status: Not yet recruiting

University of California (UC) Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

No email / No phone

Status: Not yet recruiting

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

Los Angeles, California, 90095, United States

No email / No phone

Status: Recruiting

University of California - Irvine

Orange, California, 92868, United States

No email / No phone

Status: Not yet recruiting

Advent Health

Orlando, Florida, 32804, United States

No email / No phone

Status: Recruiting

Emory University Hospital

Atlanta, Georgia, 30322, United States

No email / No phone

Status: Recruiting

The University of Chicago Medical Center (UCMC)

Chicago, Illinois, 60637, United States

No email / No phone

Status: Recruiting

Indiana University (IU) Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

No email / No phone

Status: Recruiting

Mary Bird Perkins Cancer Center

Baton Rouge, Louisiana, 70809, United States

No email / No phone

Status: Not yet recruiting

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

No email / No phone

Status: Not yet recruiting

Johns Hopkins Kimmel Cancer Center

Baltimore, Maryland, 21231-2410, United States

No email / No phone

Status: Recruiting

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

No email / No phone

Status: Recruiting

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

No email / No phone

Status: Recruiting

Washington University in St. Louis

St Louis, Missouri, 63108, United States

No email / No phone

Status: Recruiting

Columbia University

New York, New York, 10032, United States

No email / No phone

Status: Not yet recruiting

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

New York, New York, 10065, United States

No email / No phone

Status: Recruiting

University of Rochester - Wilmot Cancer Institute

Rochester, New York, 14642, United States

No email / No phone

Status: Recruiting

Montefiore Medical Center

The Bronx, New York, 10467, United States

No email / No phone

Status: Not yet recruiting

New York University (NYU)

New York, New York, 10016, United States

No email / No phone

Status: Recruiting

Weill Cornell Medicine

New York, New York, 10021, United States

No email / No phone

Status: Not yet recruiting

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

No email / No phone

Status: Recruiting

University of North Carolina (UNC) - Chapel Hill

Chapel Hill, North Carolina, 27599, United States

No email / No phone

Status: Recruiting

University of Cincinnati Medical Center (UCMC)

Cincinnati, Ohio, 45267, United States

No email / No phone

Status: Not yet recruiting

The Ohio State University (OSU)

Columbus, Ohio, 43210, United States

No email / No phone

Status: Not yet recruiting

University of Oklahoma - Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

No email / No phone

Status: Recruiting

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

Lancaster, Pennsylvania, 17601, United States

No email / No phone

Status: Recruiting

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

No email / No phone

Status: Recruiting

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

No email / No phone

Status: Not yet recruiting

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, United States

No email / No phone

Status: Not yet recruiting

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

No email / No phone

Status: Recruiting

Carolina Urologic Research Center

Myrtle Beach, South Carolina, 29572, United States

No email / No phone

Status: Recruiting

Tennessee Oncology

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Not yet recruiting

Sarah Cannon and HCA Research Institute

Nashville, Tennessee, 37203, United States

No email / No phone

Status: Recruiting

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

No email / No phone

Status: Not yet recruiting

MD Anderson Cancer Center

Houston, Texas, 77030, United States

No email / No phone

Status: Recruiting

University of Texas Southwestern

Dallas, Texas, 75244, United States

No email / No phone

Status: Recruiting

Texas Oncology, P.A

Dallas, Texas, 75251, United States

No email / No phone

Status: Recruiting

University of Utah

Salt Lake City, Utah, 84132, United States

No email / No phone

Status: Recruiting

University of Vermont Medical Center

Burlington, Vermont, 05401, United States

No email / No phone

Status: Not yet recruiting

Inova Schar Cancer Institute

Falls Church, Virginia, 22042, United States

No email / No phone

Status: Not yet recruiting

FORAGER-1: A Phase 1, Open-Label, Multicenter Study of LOXO-435 (LY3866288) in Locally Advanced or Metastatic Solid Tumors Including Urothelial Cancer With FGFR3 Alterations

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: LOXO-435 (LY3866288, LOX-24350)

Overview

Mechanism of action

Efficacy

Safety

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (84)

GenesisCare North Shore

Calvary Mater Newcastle

St Vincent's Hospital

Macquarie University

British Columbia Cancer Agency

Princess Margaret Hospital

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

Zhejiang Provincial People's Hospital

First Affiliated Hospital of Medical College of Xian jiaotong University

Renji Hospital, Shanghai Jiaotong University School of Medicine

Sun Yat-Sen University- Cancer Center

Beijing Hospital

Beijing Cancer hospital

Tianjin Medical University Cancer Institute & Hospital

Centre Leon Berard

Institut Bergonie

Institut Gustave Roussy

Klinikum der Technischen Universitaet Muenchen (TUM Klinikum)

Universitaetsklinikum Schleswig-Holstein - Campus Luebeck

Universitaetsklinikum Tuebingen

Rabin Medical Center, Beilinson Hospital

Sheba Medical Center

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

IRCCS Ospedale San Raffaele

National Cancer Center Hospital East

Cancer Institute Hospital of JFCR

National Cancer Center Hospital

Aichi Cancer Center Hospital

Erasmus MC

Haukeland University Hospital

Oslo University Hospital

Severance Hospital, Yonsei University Health System

Seoul National University Hospital

Samsung Medical Center

Asan Medical Center

Institut Catala d'Oncologia - L'Hospitalet

Fundacion MD Anderson International Espana

Hospital Universitario 12 de Octubre

South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC

Hospital Universitario Marques De Valdecilla

The Christie NHS Foundation Trust

Sheffield Teaching Hospitals NHS Foundation Trust

University of Arizona - Cancer Center

City of Hope

Stanford Cancer Center

University of California (UC) Davis Comprehensive Cancer Center

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

University of California - Irvine

Advent Health

Emory University Hospital

The University of Chicago Medical Center (UCMC)

Indiana University (IU) Melvin and Bren Simon Cancer Center

Mary Bird Perkins Cancer Center

Ochsner Clinic Foundation

Johns Hopkins Kimmel Cancer Center

Massachusetts General Hospital

Barbara Ann Karmanos Cancer Institute

Washington University in St. Louis

Columbia University

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

University of Rochester - Wilmot Cancer Institute

Montefiore Medical Center

New York University (NYU)

Weill Cornell Medicine

Icahn School of Medicine at Mount Sinai