Clinical trial NCT05614739: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Urinary Bladder Neoplasms
Neoplasm Metastasis
Ureteral Neoplasms
Keywords: Bladder Cancer
Bladder Urothelial Carcinoma
Urinary Bladder Cancer
Urinary Tract Cancer
Renal Pelvis Cancer
Ureter Cancer
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2022-11-14
Enrollment: 535
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Phase 1a: To determine the recommended dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs)
timeFrame: Minimum of the first 21-day cycle of LOXO-435 treatment
measure: Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR)
timeFrame: Up to approximately 30 months or 2.5 years
measure: 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
timeFrame: Up to approximately 30 months or 2.5 years
Secondary outcomes:
measure: To assess the pharmacokinetics (PK) of LOXO-435: Area under the concentration versus time curve (AUC)
timeFrame: Up to 2 months
measure: To assess the PK of LOXO-435: Minimum plasma concentration (Cmin)
timeFrame: Up to 2 months
measure: To evaluate the preliminary antitumor activity of LOXO-435: Objective response rate (ORR)
timeFrame: Up to approximately 30 months or 2.5 years]
measure: To evaluate the preliminary antitumor activity of LOXO-435: Duration of response (DoR)
timeFrame: Up to approximately 30 months or 2.5 years
measure: To evaluate the preliminary antitumor activity of LOXO-435: Time to response (TTR)
timeFrame: Up to approximately 30 months or 2.5 years
measure: To evaluate the preliminary antitumor activity of LOXO-435: Progression-free survival (PFS)
timeFrame: Up to approximately 30 months or 2.5 years
measure: To evaluate the preliminary antitumor activity of LOXO-435: Disease control rate (DCR)
timeFrame: Up to approximately 30 months or 2.5 years
measure: To evaluate the preliminary antitumor activity of LOXO-435: Overall survival (OS)
timeFrame: Up to approximately 30 months or 2.5 years
measure: Change from baseline in bladder-related symptoms, measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) subscale (BlCS)
timeFrame: Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 (28 day cycles)
measure: Change from baseline in physical function, measured by FACT- Physical Well-being Scale (PWB) subscale
timeFrame: Up to approximately 30 months or 2.5 years
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center - North Campus
state: Arizona
city: Duarte
country: United States
facility: City Of Hope National Medical Center
state: California
city: Irvine
country: United States
facility: University of California - Irvine Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Medicine-Hematology/Oncology
state: California
city: Sacramento
country: United States
facility: University of California, Davis - Health Systems
state: California
city: Stanford
country: United States
facility: Stanford University Clinic
state: California
city: Orlando
country: United States
facility: AdventHealth Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center
state: Louisiana
city: Baltimore
country: United States
facility: SKCCC at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester - Wilmot Cancer Institute
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: The University of Oklahoma Health Sciences Center
state: Oklahoma
city: Lancaster
country: United States
facility: Penn Medicine Lancaster General Hospital - Ann B. Barshinger Cancer Institute
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: AHN Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology P.A.
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Murray
country: United States
facility: University of Utah
state: Utah
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Falls Church
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital
city: Vancouver
country: Canada
facility: BC Cancer Vancouver
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital (Ontario)
state: Ontario
city: Beijing
country: China
facility: Beijing Cancer hospital
state: Beijing
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
state: Shaanxi
city: Shanghai
country: China
facility: Renji Hospital Affliated to Shanghai Jiaotong University
state: Shanghai
city: Hangzhou
country: China
facility: Zhejiang Provincial People's Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang University
state: Zhejiang
city: Beijing
country: China
facility: Beijing Cancer hospital
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
city: Lyon
country: France
facility: Centre Leon Berard
state: Rhône-Alpes
city: Bordeaux
country: France
facility: Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest
city: Villejuif Cedex
country: France
facility: Gustave Roussy
city: Tübingen
country: Germany
facility: Universitaetsklinikum Tuebingen
state: Württemberg
city: München
country: Germany
facility: Klinikum Rechts Der Isar Der Technischen Universität München
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center
state: Ramat Gan
city: Petah Tiqva
country: Israel
facility: Beilinson Hospital
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
state: Milan
city: Roma
country: Italy
facility: UOC Fase I - Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuore
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
state: Zuid-Holland
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital Ullevaal
city: L'Hospitalet de Llobregat
country: Spain
facility: Institut Catala d'Oncologia L'Hospitalet
state: Barcelona
city: Madrid
country: Spain
facility: Centro Oncológico MD Anderson
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Santander
country: Spain
facility: Hospital Universitario Marques De Valdecilla
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References: