ASCO 2018: SPIRE: A Phase 1b/Randomized 2a Open Label Clinical Trial Combining Guadecitabine (SGI-110) with Cisplatin and Gemcitabine Chemotherapy for Solid Malignancies Including Bladder Cancer

Chicago, IL ( In an effort to address cisplatin resistance in the setting of urothelial carcinoma (either in the palliative/primary treatment setting for advanced/metastatic UC or as neoadjuvant therapy for MIBC), there has been increasing interest in the co-administration of a DNA hypomethylating agent SGI-110, which has been demonstrated in pre-clinical studies to help overcome platinum-resistance and increase efficacy. Yet, little is known about its efficacy in the clinical setting or how it should be administered.

Hence, the SPIRE group out of the UK is running this phase 1b and randomized IIa trial to assess safety, dosing and biologic efficacy. They are co-administering a DNA methyltransferase inhibitor SGI-110 (guadecitabine) with standard gemcitabine and cisplatin chemotherapy (GC).

Study structure: (see pictures below)
- Dose escalation phase (initial)
- Followed by a randomized dose expansion phase

image 13   image 13b

Target population:
- Patients with advanced/metastatic solid tumors, including bladder cancer
- GC as neoadjuvant treatment prior to cystectomy for bladder cancer (T2-4a N0 M0)

Primary objectives:
- 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
- To determine a biologically effective dose based on serum DNA LINE-1 methylation and hemoglobin F re-expression status.

Dose Escalation Phase: Treatment comprises GC (Gemcitabine 1000 mg/m2, IVI, days 8 and 15; Cisplatin 70 mg/m2, IVI, day 8), and SGI-110 (subcutaneous, 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.

image 13c

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.

Presented by: Simon J. Crabb, MD

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA