Title

A phase Ib/randomised IIa open label clinical trial combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer.

Description

SGI-110 is a DNA methyltransferase inhibitor developed for optimised delivery of the active metabolite decitabine. Pre-clinical data support that cisplatin resistance in bladder and other cancers is derived, at least in part, through promotor methylation of silenced genes relevant to a cisplatin resistance phenotype. Experimentally this is reversible through co-administration of DNA hypomethylating agents. The central hypothesis to be tested in this clinical trial is that SGI-110 can be safely combined with GC in bladder cancer at doses able to induce demethylation of genes associated with cisplatin resistance.

Objectives

PrimaryObjective:

• To establish a safe and biologically effective dose and schedule for SGI-110 in combination with GC chemotherapy for future phase II/III investigation as a neoadjuvant therapy in bladder cancer.

Secondary Objectives:

• To evaluate the safety and toxicity profile of SGI-110 when combined with GC.
• To provide evidence of the pharmacodynamic effect of SGI-110 in combination with GC in blood and bladder cancer tissue.
• To provide pharmacokinetic data for SGI-110 exposure.
• To evaluate the safety and deliverability of SGI-110 when combined with GC as a neoadjuvant treatment for muscle invasive bladder cancer prior to radical local therapy.

Trial Design

SPIRE is for a phase Ib/IIa clinical trial to develop a combination of SGI-110 with GC. It incorporates an initial Dose Escalation Phase in advanced solid tumours (including advanced/metastatic bladder cancer). This will be followed by a randomised Dose Expansion Phase in bladder cancer patients receiving neoadjuvant chemotherapy.

Trial Status

Closed

Population

Patients with Bladder cancer with a pure or a predominant component of transitional cell carcinoma, planned to commence Gemcitabine/Cisplatin for 3 or 4 cycles with neoadjuvant (i.e. curative) intent prior to a planned radical cystectomy.

Publications

Phase I trial of DNA methyltransferase inhibitor guadecitabine combined with cisplatin and gemcitabine for solid malignancies including urothelial carcinoma (SPIRE) .?S.J. Crabb et al. Clinical Cancer Research, Jan 2021.

SPIRE: combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for phase Ib/randomised phase IIa open label clinical trial. Simon Crabb et al. Trials, 2018.

Contact Details

All trial enquiries should be sent to ctu@soton.ac.uk

Funder

This trial was funded by Cancer Research UK (award reference no. CRUKD/16/004) and Astex Pharmaceuticals Incorporated.