Abstract 2120
Background
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.
Methods
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.
Results
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.
Conclusions
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
EudraCT: 2015-004062-29.
Legal entity responsible for the study
University Hospital Southampton NHS Foundation Trust.
Funding
Cancer Research UK, Astex Pharmaceuticals.
Editorial Acknowledgement
Disclosure
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.