Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2 overexpressed/amplified (HER2+) metastatic breast cancer, is being developed as a novel therapy for patients (pts) with metastatic CRC, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and trastuzumab (Tras) showed superior activity to either agent alone. Despite the development of several new therapies for metastatic urothelial cancer, response durations generally remain short and the great majority of pts succumb to the disease, highlighting the need for therapeutic approaches. Given that 20-30% of urothelial cancers have molecular alterations of the ErbB family, TUC in combination with Tras warrants further evaluation in this population. The SGNTUC-019 basket study is evaluating TUC in combination with Tras in pts with HER2+ or HER2-mut solid tumors, including a cohort of pts with locally advanced or metastatic (LAUM) urothelial cancer. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase II study evaluating pts with previously treated solid tumors displaying HER2 overexpression/amplification or activating mutations. Eligible pts must have HER2+ or HER2-mut LAUM solid tumors, with progression on or after the last systemic therapy for advanced disease. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulatory, and cardiac function, and no prior exposure to HER2-directed therapy. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification urothelial cancer cohort will enroll 12 RECIST 1.1 response-evaluable pts. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Pts with HER2-mut urothelial cancer will be enrolled in a cohort of 30 pts for all solid tumor types except breast cancer and non-squamous NSCLC. If justified, a separate cohort for HER2-mut urothelial cancer may be opened. The primary objective is antitumor activity in each cohort, with confirmed ORR as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of TUC will be evaluated in all pts in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites will open in the US, EU, and Asia; enrollment is anticipated to begin in Dec 2020. Clinical trial information: NCT04579380