FORAGER-1: A Study of LOXO-435 (LY3866288) in Participants With Cancer With a Change in a Gene Called FGFR3
- Conditions
- Neoplasm MetastasisUrinary Bladder NeoplasmsUreteral Neoplasms
- Interventions
- Registration Number
- NCT05614739
- Lead Sponsor
- Eli Lilly and Company
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 535
-
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1a: Cohort A1 LOXO-435 Monotherapy Dose Escalation LOXO-435 LOXO-435 administered orally Phase 1a: Cohort A2 LOXO-435 Monotherapy Dose Optimization LOXO-435 LOXO-435 administered orally Phase 1b: Cohort B3 LOXO-435 Plus Pembrolizumab Pembrolizumab LOXO-435 administered orally in combination with pembrolizumab administered intravenously (IV) Phase 1b: Cohort B5 LOXO-435 Plus Pembrolizumab Plus Enfortumab Vedotin Pembrolizumab LOXO-435 administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV Phase 1b: Cohort B1, B2, B4, and C1 LOXO-435 Monotherapy Dose Expansion LOXO-435 LOXO-435 administered orally Phase 1b: Cohort B3 LOXO-435 Plus Pembrolizumab LOXO-435 LOXO-435 administered orally in combination with pembrolizumab administered intravenously (IV) Phase 1b: Cohort B5 LOXO-435 Plus Pembrolizumab Plus Enfortumab Vedotin LOXO-435 LOXO-435 administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV Phase 1b: Cohort B5 LOXO-435 Plus Pembrolizumab Plus Enfortumab Vedotin enfortumab vedotin LOXO-435 administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
- Primary Outcome Measures
Name Time Method 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 Up to approximately 30 months or 2.5 years A summary of TEAEs and SAEs regardless of causality, will be reported in the Reported Adverse Events module
Phase 1a: To determine the recommended dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs) Minimum of the first 21-day cycle of LOXO-435 treatment Number of participants with DLTs
Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR) Up to approximately 30 months or 2.5 years ORR per investigator assessed RECIST v1.1
- Secondary Outcome Measures
Name Time Method To assess the pharmacokinetics (PK) of LOXO-435: Area under the concentration versus time curve (AUC) Up to 2 months PK of LOXO-435: AUC
To assess the PK of LOXO-435: Minimum plasma concentration (Cmin) Up to 2 months PK of LOXO-435: Cmin
To evaluate the preliminary antitumor activity of LOXO-435: Objective response rate (ORR) Up to approximately 30 months or 2.5 years] ORR per investigator assessed RECIST 1.1
To evaluate the preliminary antitumor activity of LOXO-435: Duration of response (DoR) Up to approximately 30 months or 2.5 years DOR per investigator assessed RECIST 1.1
To evaluate the preliminary antitumor activity of LOXO-435: Time to response (TTR) Up to approximately 30 months or 2.5 years TTR
To evaluate the preliminary antitumor activity of LOXO-435: Progression-free survival (PFS) Up to approximately 30 months or 2.5 years PFS per investigator assessed RECIST 1.1
To evaluate the preliminary antitumor activity of LOXO-435: Disease control rate (DCR) Up to approximately 30 months or 2.5 years DCR per investigator assessed RECIST 1.1
To evaluate the preliminary antitumor activity of LOXO-435: Overall survival (OS) Up to approximately 30 months or 2.5 years OS
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) The BlCS has 12 items with a total score range of 0 to 48, with higher scores representing better bladder-related symptoms. A ≥ 4-point score change from baseline will be considered as clinically meaningful improvement in bladder-related symptoms
Change from baseline in physical function, measured by FACT- Physical Well-being Scale (PWB) subscale Up to approximately 30 months or 2.5 years The PWB subscale has 7 items with a total score range of 0-28, with higher scores representing better physical function. A ≥ 3-point score change from baseline for a participant will be considered as clinically meaningful improvement in physical function.
Trial Locations
- Locations (83)
University of Arizona - Cancer Center
🇺🇸Tucson, Arizona, United States
City of Hope
🇺🇸Duarte, California, United States
University of California, Los Angeles (UCLA) - Division of Hematology-Oncology
🇺🇸Los Angeles, California, United States
University of California - Irvine
🇺🇸Orange, California, United States
University of California (UC) Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
Stanford Cancer Center
🇺🇸Stanford, California, United States
Advent Health
🇺🇸Orlando, Florida, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
The University of Chicago Medical Center (UCMC)
🇺🇸Chicago, Illinois, United States
Indiana University (IU) Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Scroll for more (73 remaining)University of Arizona - Cancer Center🇺🇸Tucson, Arizona, United States