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.

Age: 18 Years and older

Gender: All

Start Date: 01/12/2023

Primary Completion Date (Estimated): 06/01/2027

Study Completion Date (Estimated): 06/01/2027

Accepts Healthy Volunteers: No

Trial Purpose and 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

Age: 18 Years and older

Gender: All

Accepts Healthy Volunteers: No

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