Background: Cisplatin based chemotherapy is a standard of care therapy for urothelial bladder cancer for palliative first line treatment of advanced/metastatic disease or radical neoadjuvant treatment of localized muscle invasive disease. However, cisplatin resistance, associated with disease progression or relapse, is common and remains a critical barrier to therapeutic advance. Pre-clinical data suggest cisplatin resistance in bladder cancer, and other cancers, might be avoided by co-administration of a DNA hypomethylating agent. Methods: SPIRE is a phase Ib/IIa trial evaluating whether the DNA methyltransferase inhibitor SGI-110 (guadecitabine), in combination with gemcitabine and cisplatin chemotherapy (GC), is safe and biologically effective. It incorporates a dose escalation phase in advanced/metastatic solid tumors, including bladder cancer, followed by a randomized dose expansion phase as neoadjuvant treatment prior to cystectomy for bladder cancer (T2-4a N0 M0). The primary objective is to determine a recommended phase II dose (RP2D) of SGI-110 in combination with GC, using pre-defined dose limiting toxicity criteria assessed by CTCAE v4.03, and a biologically effective dose based on serum DNA LINE-1 methylation and hemoglobin F re-expression status. Dose Escalation Phase: Treatment comprises GC (G 1000 mg/m², IVI, days 8 and 15; C 70 mg/m², IVI, day 8), and SGI-110 (SC, days 1-5), for up to 6 cycles of 21 days. Up to 6 patients are enrolled in each of up to 4 SGI-110 dose level cohorts utilizing a ‘rolling 6’ design. Dose Expansion Phase: 20 patients will be randomized 1:1 to GC, or GC + SGI-110 at the established RP2D, to expand safety and pharmacodynamic endpoint data. SPIRE is coordinated by the CRUK Southampton Clinical Trials Unit and is currently recruiting to a 3rd dose escalation cohort through the UK Experimental Cancer Medicine Centre (ECMC) network. It was developed through the CRUK Combinations Alliance. Funding: Cancer Research UK (C9317/A19903) and Astex Pharmaceuticals. Sponsor: University Hospital Southampton NHS Foundation Trust. Clinical trial information: ISRCTN16332228.