Background: SMARCB1 (also known as INI-1, hSNF5, or BAF47) is a potent tumor suppressor inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as the majority of malignant rhabdoid tumors (MRT). These highly aggressive malignancies often occur in young patients (pts) and are associated with poor prognosis. There are currently no approved therapies targeting SMARCB1 defects. We previously showed that SMARCB1 loss induces a synthetically lethal vulnerability to perturbations of the cellular proteostasis machinery by proteasome inhibitors (Genovese et al. Nature, 542:362-366, 2017). The present study was designed to determine whether the addition of the second-generation proteasome inhibitor ixazomib to cytotoxic chemotherapy with gemcitabine and doxorubicin (IGD regimen) can improve outcomes of pts with aggressive SMARCB1-deficient kidney malignancies. Methods: This single-arm trial uses the Bayesian optimal phase II (BOP2) design (Heng et al. Stat Med 2017) to determine if the IGD regimen will improve the two co-primary endpoints of objective response rate (ORR) to 50% and 28-week disease control rate (DCR) to 30% compared with the historical ORR and 28-week DCR of 29% and 14%, respectively, achieved using gemcitabine plus doxorubicin alone as first-line or salvage therapy in pts with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs treated at our institution. Up to 30 pts aged ≥ 12 years old will be enrolled and any number of prior therapies is allowed. Ongoing monitoring for safety and futility will be implemented in 10-patient cohorts. If both the ORR and DCR improve to 50% and 30%, respectively, then there is only a 3.5% chance of stopping early and a 93.1% chance of claiming that IGD is efficacious. Secondary endpoints include progression-free survival, and overall survival. Tissue correlative analyses will be performed to determine whether tumors from pts responding to IGD have increased levels of endoplasmic reticulum stress markers involved in protein turnover. At the time of the abstract submission, 5 pts have been enrolled on this study. Clinical trial information: NCT03587662