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

Official title

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

Overview

The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435 by itself or when it is combined with other standard medicines that treat cancer. LOXO-435 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). Participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.

Detailed description

This is an open-label, multi-center, phase 1 study in participants with FGFR3-altered advanced solid tumor malignancy including metastatic urothelial cancer (UC). The study will be conducted in 2 phases: Phase 1a dose escalation (Cohort A1) and dose optimization (Cohort A2) and Phase 1b dose expansion. Phase 1a will assess safety, tolerability, and pharmacokinetics of LOXO-435 to determine the optimal dose for further expansion.

Phase 1b will include 6 dose expansion cohorts to evaluate the efficacy and safety of LOXO-435 as monotherapy or in combinations with pembrolizumab with or without enfortumab vedotin.

Interventions

• Drug LOXO-435
  Oral
• Drug Pembrolizumab
  IV
• Drug enfortumab vedotin
  IV

Primary outcome measures

• Phase 1a: To determine the recommended dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs) [Time frame: Minimum of the first 21-day cycle of LOXO-435 treatment]
• Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR) [Time frame: Up to approximately 30 months or 2.5 years]
• 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 [Time frame: Up to approximately 30 months or 2.5 years]

Secondary outcome measures (10)

• To assess the pharmacokinetics (PK) of LOXO-435: Area under the concentration versus time curve (AUC) [Time frame: Up to 2 months]
• To assess the PK of LOXO-435: Minimum plasma concentration (Cmin) [Time frame: Up to 2 months]
• To evaluate the preliminary antitumor activity of LOXO-435: Objective response rate (ORR) [Time frame: Up to approximately 30 months or 2.5 years]]
• To evaluate the preliminary antitumor activity of LOXO-435: Duration of response (DoR) [Time frame: Up to approximately 30 months or 2.5 years]
• To evaluate the preliminary antitumor activity of LOXO-435: Time to response (TTR) [Time frame: Up to approximately 30 months or 2.5 years]
• To evaluate the preliminary antitumor activity of LOXO-435: Progression-free survival (PFS) [Time frame: Up to approximately 30 months or 2.5 years]
• To evaluate the preliminary antitumor activity of LOXO-435: Disease control rate (DCR) [Time frame: Up to approximately 30 months or 2.5 years]
• To evaluate the preliminary antitumor activity of LOXO-435: Overall survival (OS) [Time frame: Up to approximately 30 months or 2.5 years]
• Change from baseline in bladder-related symptoms, measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) subscale (BlCS) [Time frame: 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 [Time frame: Up to approximately 30 months or 2.5 years]

Eligibility 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 41 centers

• University of Arizona - Cancer Center — Tucson
• City of Hope — Duarte
• University of California, Los Angeles (UCLA) - Division of Hematology-Oncology — Los Angeles
• University of California - Irvine — Orange
• University of California (UC) Davis Comprehensive Cancer Center — Sacramento
• Stanford Medicine Cancer Center — Stanford
• Advent Health — Orlando
• Emory University Hospital — Atlanta
• … and 33 more centers

China · 8 centers

• Beijing Cancer hospital — Beijing
• Beijing Hospital — Beijing
• Sun Yat-Sen University- Cancer Center — Guangdong
• Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University — Hangzhou
• Renji Hospital, Shanghai Jiaotong University School of Medicine — Shanghai
• Tianjin Medical University Cancer Institute & Hospital — Tianjin
• The First Affiliated Hospital of Xi'an Jiaotong University — Xi'an
• Zhejiang Provincial People's Hospital — Zhejiang

Spain · 5 centers

• Institut Catala d'Oncologia - L'Hospitalet — Barcelona
• Fundacion MD Anderson International Espana — Madrid
• Hospital Universitario 12 de Octubre — Madrid
• South Texas Accelerated Research Therapeutics (START) Madrid - CIOCC — Madrid
• Hospital Universitario Marques De Valdecilla — Santander

Australia · 4 centers

• St Vincent's Hospital — Darlinghurst
• Calvary Mater Newcastle — Hunter Region, NSW
• GenesisCare North Shore — St Leonards
• Macquarie University — Sydney

Japan · 4 centers

• National Cancer Center Hospital East — Chiba
• Aichi Cancer Center Hospital — Nagoya
• National Cancer Center Hospital — Tokyo
• Cancer Institute Hospital of JFCR — Tokyo

South Korea · 4 centers

• Seoul National University Hospital — Seoul
• Severance Hospital, Yonsei University Health System — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul

France · 3 centers

• Institut Bergonie — Bordeaux
• Centre Leon Berard — Lyon
• Institut Gustave Roussy — Villejuif

Canada · 2 centers

• Princess Margaret Hospital — Toronto
• British Columbia Cancer Agency — Vancouver

Germany · 2 centers

• Klinikum der Technischen Universitaet Muenchen (TUM Klinikum) — München
• Universitaetsklinikum Tuebingen — Tübingen

Israel · 2 centers

• Rabin Medical Center, Beilinson Hospital — Petah Tikva
• Sheba Medical Center — Tel Litwinsky

Italy · 2 centers

• IRCCS Ospedale San Raffaele — Milan
• UOC Fase I - Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica — Roma

Norway · 2 centers

• Haukeland University Hospital — Bergen
• Oslo University Hospital — Oslo

United Kingdom · 2 centers

Center list to be confirmed — check the primary protocol.

Netherlands · 1 center

• Erasmus MC — GE Rotterdam

Identifiers

NCT: NCT05614739 · 18594 · J4G-OX-JZVA · 2022-502755-59-00 · LOXO-FG3-22001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗