Background: RRx-001 is a small molecule anticancer agent that preclinically protects non-malignant tissues, but not tumors, against the cytotoxicities of chemotherapy and radiation. In a completed, multicenter Phase 2 trial, QUADRUPLE THREAT, patients with previously platinum-treated extrapulmonary small cell cancer (SCC), high-grade neuroendocrine carcinoma (HGNEC), non-small cell lung cancer (NSCLC), and genitourinary cancer (GUC) received 4 mg IV RRx-001 followed by etoposide plus cisplatin or carboplatin (EP). In addition to overall survival (OS), and progression-free survival (PFS), this study also evaluated the possible prevention of nephrotoxicity by RRx-001. Methods: 90 patients with SCC, HGNEC, NSCLC, and GUC that previously received ≥2 lines of therapy including a platinum doublet were treated with 4 mg RRx-001 IV once per week. At progression, RRx-001 was discontinued and 40 patients were re-challenged with IV etoposide 80-100 mg/m² (Days 1, 2, and 3) and cisplatin 60-80 mg/m² on Day 1 for 4-6 cycles. The co-primary endpoints were PFS and OS. For all patients, serum creatinine (Cr), blood urea nitrogen (BUN), and electrolytes were determined prior to, during and after each treatment cycle. Results: After 2 cycles of chemotherapy, no patients experienced BUN elevations above 20 mg/dL and creatinine beyond 1.5 mg/dL. After four cycles of chemotherapy, 36/40 (90%) patients experienced no elevations of BUN above 20 mg/dL and creatinine above 1.5 mg/dL and none of the patients experienced > Grade 2 elevations of creatinine. 1/40 (2.5%) patients experienced Grade 3 hypomagnesemia (0 Grade 4). 3/40 (7.5%) patients were dose reduced or withdrawn from the trial due to platinum-related adverse events. No patients experienced renal-related serious adverse events (SAEs). One patient experienced a renal failure SAE, which was not drug related. The cumulative OS and PFS median of all the tumor types were 8.6 and 6.4 months, respectively. Conclusions: 20%-35% of patients develop acute kidney injury after cisplatin administration. Based on published clinical literature, approximately 33% of patients experience kidney injury just days following initial treatment (p = 0.0034, two-sided chi-square test comparing our study nephrotoxicity of 10% (4/40) in the first four cycles against 33% historical rate), and 20% of patients taking high-dose cisplatin experience severe renal dysfunction. The nephrotoxic effect of cisplatin is cumulative. In this heavily platinum-treated population, none of the patients were ineligible to receive cisplatin as scheduled because their serum creatinine levels had failed to return to < or = 1.5 mg/dL. RRx-001 pretreatment did not affect the antitumor effects of EP as assessed by PFS and OS. This dose of RRx-001 warrants further evaluation as a nephroprotectant that reduces the cumulative renotoxic effects of cisplatin but not its antitumor efficacy. Clinical trial information: NCT02489903.