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

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Overall Response Rate (ORR)

Primary Outcome 1 - Timeframe: Up to Approximately 30 Months or 2.5 Years

Primary Outcome 2 - Measure: Pharmacokinetics (PK) of Vepugratinib: Area Under the Concentration versus Time Curve (AUC)

Primary Outcome 2 - Timeframe: Up to 2 Months

Primary Outcome 3 - Measure: PK of Midazolam

Primary Outcome 3 - Timeframe: Up to 2 Months

Primary Outcome 4 - Measure: Rosuvastatin

Primary Outcome 4 - Timeframe: Up to approximately 24 months or 5 years

Primary Outcome 5 - Measure: and Digoxin Administered Alone and in the Presence of Vepugratinib: Area Under the Concentration versus Time Curve (AUC[0-inf])

Primary Outcome 5 - Timeframe: N/A

Primary Outcome 6 - Measure: Complete Response Rate (CRR) in Participants with Low-Grade Intermediate-Risk Non-Muscle Invasive Bladder Cancer (LG IR NMIBC)

Primary Outcome 6 - Timeframe: N/A

CONDITION

• Urinary Bladder Neoplasms
• Neoplasm Metastasis
• Ureteral Neoplasms

ELIGIBILITY

Inclusion Criteria:
* Cohort A1, C1, D1, and D2: Locally advanced or metastatic solid tumor malignancy with a qualifying FGFR3 alteration.

- * Cohort A2, B2, B5 and B7: Urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration.

- * Cohorts B1 and B4: Urothelial cancer that is locally advanced or metastatic and have received prior erdafitinib.

- * Cohort B6: Muscle Invasive Bladder Cancer with a qualifying FGFR3 alteration.

- * Cohort B7: Urothelial cancer that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration and expression of human epidermal growth factor receptor 2 (HER2).

- * Cohort B8: Low Grade Intermediate Risk Non-Muscle Invasive Bladder cancer and a qualifying FGFR3 genetic alteration.

- * Measurability of disease:
* Cohort A1, D1, and D2: 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, B7, and C1: Measurable disease required as defined by RECIST v1.1.

- * Cohort B8: Baseline disease which includes at least 1 lesion.

- * Have an Eastern Cooperative Oncology Group (ECOG) performance status of:
* 0 or 1 for Cohorts A1, A2, B5, B6, B7, and B8.

- * Less than or equal to 2 for Cohorts B1, B2, B4, C1, DI and D2.

- * Cohort B6: Must be eligible for radical cystectomy plus pelvic lymph node dissection and agree to undergo curative intent standard radical cystectomy plus pelvic lymph node dissection.
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.

- * Cohort D1 only:
* Have had renal transplantation.

- * Have a known history of nephrotic syndrome.

- * Have uncontrolled fluid overload, including clinically significant ascites, pleural effusion, or peripheral edema.

- * Have uncontrolled hypertension.

- * Are on hemodialysis or similar.

- * Cohort D2 only:
* Have a history of:

- * Ventricular tachycardia or ventricular fibrillation.

- * Hypertrophic obstructive cardiomyopathy unless managed concurrently with atrial fibrillation.

- * Wolff-Parkinson-White syndrome.

- * Second- or third-degree atrioventricular block unless a functioning pacemaker is in place.

- * Heart rate less than (<) 50 bpm. - * Have any of these medical conditions: - * Severe respiratory insufficiency. - * Sleep apnea syndrome. - * Myasthenia gravis. - * Acute narrow-angle glaucoma. - * Active liver disease or clinically significant hepatic impairment. - * History of myopathy or rhabdomyolysis with any HMG-CoA reductase inhibitor.

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