Brief Title: LOXO-435 in Patients With Cancer With a Change in a Gene Called FGFR3

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Phase 1a: To determine the recommended dose of LOXO-435: Safety

Primary Outcome 1 - Timeframe: Minimum of the first 21-day cycle of LOXO-435 treatment

Primary Outcome 2 - Measure: number of participants with dose-limiting toxicities (DLTs)

Primary Outcome 2 - Timeframe: Up to approximately 30 months or 2.5 years

Primary Outcome 3 - Measure: Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR)

Primary Outcome 3 - Timeframe: Up to approximately 30 months or 2.5 years

Primary Outcome 4 - 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

Primary Outcome 4 - Timeframe: N/A

CONDITION

• Urinary Bladder Neoplasms
• Neoplasm Metastasis
• Ureteral Neoplasms

ELIGIBILITY

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST)

Role: Study Director

Affiliation: Eli Lilly and Company

Overall Contact

Name: Trial questions or participation questions: 1-877-CTLILLY (1-877-285-4559) or, Physicians interested in becoming principal investigators please contact

Phone: 1-317-615-4559

Email: [email protected], [email protected]

LOCATION