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

Lilly

Status and phase: Enrolling; Phase 1

Conditions: Urinary Bladder Neoplasms; Neoplasm Metastasis; Ureteral Neoplasms

Treatments: Drug: enfortumab vedotin; Drug: LOXO-435; Drug: Pembrolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT05614739

2022-502755-59-00 (Other Identifier)

J4G-OX-JZVA (Other Identifier)

LOXO-FG3-22001

18594

Details and patient eligibility

About

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.

Full 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.

Enrollment: 535 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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535 participants in 5 patient groups

Phase 1a: Cohort A1 LOXO-435 Monotherapy Dose Escalation

Experimental group

Description:

LOXO-435 administered orally

Treatment:

Drug: LOXO-435

Phase 1a: Cohort A2 LOXO-435 Monotherapy Dose Optimization

Experimental group

Description:

LOXO-435 administered orally

Treatment:

Drug: LOXO-435

Phase 1b: Cohort B1, B2, B4, and C1 LOXO-435 Monotherapy Dose Expansion

Experimental group

Description:

LOXO-435 administered orally

Treatment:

Drug: LOXO-435

Phase 1b: Cohort B3 LOXO-435 Plus Pembrolizumab

Experimental group

Description:

LOXO-435 administered orally in combination with pembrolizumab administered intravenously (IV)

Treatment:

Drug: Pembrolizumab

Drug: LOXO-435

Phase 1b: Cohort B5 LOXO-435 Plus Pembrolizumab Plus Enfortumab Vedotin

Experimental group

Description:

LOXO-435 administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV

Treatment:

Drug: Pembrolizumab

Drug: LOXO-435

Drug: enfortumab vedotin