Background: Non-clear cell RCC (nccRCC) accounts for 25% of RCC cases and encompasses a heterogeneous group of tumors with poor prognosis. Most RCC trials have enrolled clear cell RCC (ccRCC) and excluded nccRCC. Due to the rarity of nccRCC and limited prospective data, there is a need to develop effective therapies for nccRCC. Tivozanib is a selective VEGFR1-3 tyrosine kinase inhibitor (TKI) approved for patients (pts) with metastatic ccRCC who have had at least 2 prior lines of therapy, one of which included a VEGFR TKI. In nccRCC, tivozanib had an unconfirmed objective response rate (ORR) of 32% and disease control rate of 74% in a subgroup analysis of a phase 2 study. The combination of tivozanib and nivolumab has been evaluated in a phase 1b/2 study which showed an ORR of 56% in metastatic ccRCC, and results from the subsequent phase 3 trial are awaited. However, this combination has not been studied in nccRCC. Based on the potential activity of tivozanib in nccRCC and promising results of the combination with nivolumab, we hypothesize that tivozanib and nivolumab may be efficacious in advanced nccRCC. Methods: FORTUNE is a multi-center, single arm, phase 2 trial assessing the efficacy of tivozanib and nivolumab in pts with advanced nccRCC. Pts with histologically-confirmed metastatic nccRCC of any nccRCC histology (except medullary and collecting duct tumors) who are either treatment-naïve or have received up to 1 line of systemic therapy (including prior immunotherapy) with measurable disease per RECIST 1.1 will be eligible. Enrolled pts will receive oral tivozanib 0.89 mg daily on days 1-21 of 28-day cycles in combination with nivolumab 480 mg on day 1 every 28-day cycles. Treatment will continue until disease progression, death, intolerable toxicity, or consent withdrawal. The primary endpoint is ORR by RECIST 1.1. Key secondary endpoints include progression-free survival, overall survival, duration of therapy, and adverse events (AEs). The trial will utilize a Bayesian optimal phase 2 (BOP2) design with a planned accrual of 48 total pts in 12-patient cohorts with interval safety and toxicity analyses. After the first 12-patient cohort is enrolled, the study will stop if only 1 pt has a response or if >5 pts develop a treatment-limiting AE. Otherwise, the study will continue enrolling pts in 12-patient cohorts for a total of 48 pts with additional interval stopping boundaries for efficacy and safety. This trial will test the joint null hypothesis that the true ORR rate is 15% (vs 30%) and a null hypothesis that the treatment-limiting AE rate is 40% (vs 20%) against their one-sided alternative at a 0.025 type I error. Exploratory analyses with circulating tumor DNA (pre-treatment, cycle 2, and end of treatment), archival tissue, and on-treatment biopsy (cycle 4) are planned to examine the biologic correlates associated with therapy response. Enrollment began in January 2024. Clinical trial information: NCT06053658.