Background: Castrate resistant prostate cancer (CRPC) is an immunologically cold tumor, with a 5% response rate reported to the PD-L1 inhibitor pembrolizumab. VEGF secreted by tumors may play a key role in hindering the anti-tumor immune response, leading to the development of an abnormal vasculature that may limit immune surveillance. VEGF also inhibits dendritic cell differentiation, limiting the presentation of tumor antigens. The inhibition of VEGF may therefore potentiate the effect of PD-1/L1 directed therapy by enabling immune surveillance and antigen presentation. VEGF-TKI and checkpoint inhibitor combinations are currently approved in the treatment of advanced kidney, cervical, and endometrial cancers. This signal-seeking study aims to determine whether the combination of the VEGF-TKI tivozanib and the PD-L1 inhibitor atezolizumab may be effective in CRPC and certain other immunologically cold tumors. Methods: The trial is a single center phase Ib/II basket study in multiple immunologically cold tumors. Co-primary endpoints are safety and the overall response rate as measured via RECIST v1.1. The phase Ib 3+3 dose de-escalation portion of the study has been completed. The study is designed to test for a 25%+ response rate as compared to a null hypothesis of <7% (one-sided alpha = 0.05; 80% power). A Simon’s two-stage design will be utilized and if ≥2 responses among the first 16 evaluable patients, a further 10 evaluable patients will be accrued for a total of 26. Up to 33 subjects will be enrolled to account for a 20% dropout rate. The null hypothesis will be rejected if at least 5 responses are observed. The University of Florida's Data Integrity and Safety Committee will review significant adverse events. Atezolizumab is given at a dose of 1,680 mg every 28 days. A subsequent protocol amendment decreased the starting dose of tivozanib from 1.34 mg/day for 21 days of each 28-day cycle to 0.89 mg/day for 21 days of each 28-day cycle. Treatment is until disease progression or intolerance. Key inclusion criteria include a diagnosis of certain advanced and unresectable or metastatic immunologically cold tumors (CRPC previously treated with an androgen inhibitor or cytotoxic chemotherapy in the advanced or metastatic setting, bile duct or gallbladder cancer, certain HR-negative HER2-positive breast cancers, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, or vulvar cancer), at least one prior systemic therapy in this setting, ECOG 0-1 (phase Ib) or ECOG 0-2 (phase II), age ≥ 18, adequate hematologic and end-organ function, life expectancy of at least 12 weeks, and measurable disease by RECIST v1.1. Key exclusion criteria include known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. Active enrollment continues. Clinical trial information: NCT05000294.