Background: The potent tumor suppressor SMARCB1 (also known as INI-1, hSNF5, or BAF47) is inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as most malignant rhabdoid tumors (MRT) of the kidney. Although rare, these kidney malignancies are highly lethal and often occur in young patients. The role of immune checkpoint inhibitor therapy remains to be prospectively defined in tumors harboring SMARCB1 defects. Although a case report noted efficacy of single-agent Nivo in a patient with RMC (Beckermann et al J Immunother Cancer, 2017), there were no durable responses in subsequent cases (Sodji et al. J Immunother Cancer, 2017). We hypothesize that the combination of anti-PD1 (Nivo) with anti-CTLA4 (Ipi) immune checkpoint inhibitor therapy will lead to more potent antitumor responses compared to those reported with single-agent Nivo. Methods: This single-arm phase II trial will test the efficacy of Nivo + Ipi in up to 30 patients with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs. Any number of prior therapies is allowed. Patients will be treated with Ipi 1 mg/kg + Nivo 3 mg/kg every 3 weeks x4 doses followed by maintenance Nivo 480 mg every 4 weeks for up to 2 years. Ongoing monitoring for safety and futility will be implemented per the method of Thall et al. (Stat Med, 1995; 14:357-79) using cohorts of 10 patients each. The primary endpoint is objective response rate (ORR) and the trial objective is to achieve a similar or greater ORR compared with the historical ORR of 29% achieved in our institution using conventional cytotoxic chemotherapies. Secondary endpoints include progression-free survival, overall survival, and disease control rate. To evaluate potential biomarkers for treatment response, correlative analyses will be performed in tumor tissue and peripheral blood samples obtained i) pre- treatment (baseline) up to 6 weeks (42 days) prior to initiation of treatment on Day 1, ii) after completion of the combination therapy (Nivo + Ipi) phase, and iii) upon disease progression. At the time of the abstract submission, 2 patients have been enrolled on this study. Clinical trial information: NCT03274258