Background: Immune checkpoint inhibitor (ICI) therapy represents a significant advance in cancer care however it is not an effective intervention in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and bile duct malignancies where ICIs have produced objective response rates of 0-6%. VEGF is thought to play a key role in modulating the anti-tumor immune response as it is secreted by tumors and leads to endothelial cell proliferation, vascular permeability, and vasodilation. This in turn leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of ICIs. Combined use of a VEGF receptor tyrosine kinase inhibitor (TKI) and ICI is already approved for advanced kidney and endometrial cancer. Methods: This is a single institution, single arm, open-label phase Ib/II study with the co-primary endpoints of safety and efficacy of the combination of the VEGFR-TKI tivozanib and the ICI atezolizumab. Eligible patients are those with metastatic cancer progressing on at least one line of therapy of the following organs: pancreatic, gallbladder, bile duct, well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian, vulvar, soft tissue sarcoma, castrate resistant prostate, and HER2 positive hormone receptor negative breast. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Three patients will be treated with tivozanib 1.34 mg per day (dose level 0) for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. If one dose limiting toxicity (DLT) is found then 3 more patients will be enrolled at dose level 0. If >1 DLT occurs in the first 3 patients or >1 DLT in the first 6, another 3+3 study will begin at dose level -1 (0.89 mg of tivozanib). If 1 DLT occurs in these 3 patients at dose level -1 then another 3 will be enrolled at this dose. The study will be stopped for toxicity if there is >1 DLT in the first 3 patients at dose level -1 or if there are >1 DLT in the 6 patients at dose level -1. A subsequent protocol amendment was made to reduce tivozanib dose level 0 to 0.89 mg per day and dose level -1 to 0.89 mg every other day. The phase II portion will enroll up to 26 patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessment every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. Enrollment is ongoing. Clinical trial information: NCT05000294.