Cisplatin resistance derives, in part, via tumour suppressor gene promotor methylation. In Vitro this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a DNA methyltransferase inhibitor developed for optimised delivery of the active metabolite decitabine. SPIRE is an ECMC Combinations Alliance phase Ib/IIa clinical trial to establish a safe dose and schedule to combine guadecitabine with cisplatin/gemcitabine chemotherapy (GC). We report the phase Ib component.
Patients (pts) with incurable metastatic solid cancer, received GC (G: 1000 mg/m2, IV, day (D) 8 + 15; C: 70 mg/m2, IV, D8), and guadecitabine (SC, D1-5) for up to 6 x 21D cycles. Maximum tolerated dose (MTD) was determined with pre-defined criteria for dose limiting toxicity (DLT; CTCAE v4.03) in cohorts of 3-6 (rolling 6 design). The recommended phase II dose/schedule (RP2D) was expanded to include 6 bladder cancer pts. Subsequent cohorts incorporated GCSF (filgrastim, 300 μg SC, D15-21) if DLTs occurred due to neutropenia. Primary endpoint: guadecitabine MTD. Secondary endpoints: pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Coordination: CRUK Southampton Clinical Trials Unit. Sponsor: University Hospital Southampton NHS Foundation Trust. Funding: Cancer Research UK (C9317/A19903) and Astex Pharmaceuticals.
DLT occurred in 3 of 4 pts (thromboembolism; G4 neutropenia ≥7 days; febrile neutropenia) in cohort 1 (guadecitabine 20 mg/m2 D1-5), in 1 of 8 pts (febrile neutropenia) in cohort 2 (guadecitabine 20 mg/m2 D1-5 + GCSF) and 3 of 5 pts (febrile neutropenia; G3 diarrhoea + hypokalaemia; G4 neutropenia/thrombocytopenia ≥7 days + G3 tooth infection) in cohort 3 (guadecitabine 30 mg/m2 D1-5 + GCSF). PD endpoints of mean plasma LINE-1 methylation depletion and haemoglobin F re-expression were consistent with guadecitabine target effect and PK parameters consistent with guadecitabine single agent data.
Guadecitabine 20 mg/m2, day 1-5, with GCSF prophylaxis, is the RP2D in combination with GC. A randomised dose expansion is proceeding as neoadjuvant treatment for bladder cancer.
Clinical trial identification
Legal entity responsible for the study
University Hospital Southampton NHS Foundation Trust.
Cancer Research UK, Astex Pharmaceuticals.
S.J. Crabb: Consulting/advisory: Roche, Clovis Oncology, Merck; Research support: Clovis Oncology. J.W. Catto: Advisory boards: AstraZeneca; Speaker fees: Nucleix, Roche. R. Huddart: CoI BMS, MSD, Roche, Janssen (ad boards, meeting sponsorship, involvement in trials/trial funding); Elekta- consortium member. All other authors have declared no conflicts of interest.