A Study of LOXO-435 in Participants With Cancer With a Change in a Gene Called FGFR3

Open to people ages 18 years and up

• Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable.
  • Cohort A1 (Dose Escalation): Presence of an alteration in FGFR3 or its ligands.
  • Cohort A2 (Dose Optimization): Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 alteration.
  • Cohorts B1, B2 and B3 (Dose Expansion): Histological diagnosis of urothelial cancer that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
  • Cohort C (Dose Expansion): Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
• Measurability of disease:
  • Cohort A1: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1)
  • Cohorts A2, B1, B2, B3, and C1: Measurable disease required as defined by RECIST v1.1
• Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country-specific regulations.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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/B1/B2/B3: Participants must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
• FGFR inhibitor specific requirements:
  • Cohort A1/A2: Prior FGFR inhibitor treatment is permitted, but not required.
  • Cohort B1: Participants must have been previously treated with a FGFR inhibitor.
  • Cohort B2, B3, C1: Participants must be FGFR inhibitor naïve.

• Participants with primary central nervous system (CNS) malignancy.
• Known or suspected history of uncontrolled CNS metastases.
• Current evidence of corneal keratopathy or retinal disorder.
• Have a history and/or current evidence of extensive tissue calcification.
• 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.