NUC-1031 (Acelarin) is a first-in-class nucleotide analogue that overcomes key cancer cell resistance mechanisms to generate high intracellular levels of dFdCTP. In the PRO-001 study, single agent NUC-1031 achieved impressive clinical activity across multiple solid tumors. In this PRO-002 study, NUC-1031 was combined with carboplatin in 25 pts with recurrent ovarian cancer (OC).
NUC-1031 was administered in a dose-escalation schedule as a 30-min infusion on days 1 & 8 with carboplatin on day 1, every 3 weeks for ≤6 cycles. Four dose cohorts of NUC-1031 (500, 625 and 750 mg/m2) with carboplatin (AUC4 or 5) were studied. The primary endpoint was to determine RP2D. Secondary endpoints included safety, RECIST response, PFS and PK/PD.
25 pts (median age 64 yrs) participated, having received a median of 3 (range 2-6) prior lines of therapy. All had received prior platinum regimens (10 had prior carboplatin + gemcitabine). 23 pts were response-evaluable, of whom 7 were platinum refractory, 10 were platinum resistant, 4 were partially platinum sensitive and 2 were platinum sensitive. Strong efficacy signals were achieved with 1 unconfirmed CR at the end of treatment (4%), 8 PRs (35%, 4 confirmed), 12 SDs (52%, 10 confirmed) and 2 PD (9%). Median PFS was 7.4 months (range 1.2-11.2). The combination regimen was well tolerated. 5 DLTs occurred in 4 pts: 2 Grade (G) 4 thrombocytopenia; 2 G3 fatigue and 1 G4 neutropenia. No DLTs occurred in the NUC-1031 500 mg/m2 + carboplatin AUC5 group. 7 pts reported treatment-related SAEs. The most common SAE was thrombocytopenia, reported in 3 pts. NUC-1031 was stable in plasma (apparent t1/2=3.8 h). Combination with carboplatin rapidly generated very high intracellular dFdCTP levels (Cmax=12.1 μM/mg, TP/500 mg/m2 and Tmax=30 min) that were maintained for 24 h.
NUC-1031 combined with carboplatin is well tolerated and effective in recurrent platinum resistant and sensitive OC. dFdCTP levels were increased 25% by the addition of carboplatin. The RP2D was 500 mg/m2 NUC-1031 on days 1 & 8 with AUC5 carboplatin day 1, q21d. The efficacy and synergy of this schedule and the ability to deliver carboplatin at AUC5 makes this an attractive therapeutic combination.
Clinical trial identification
Legal entity responsible for the study
S.P. Blagden: Acted on advisory boards for Novartis and Clovis Oncology and has directorship of RNA Guardian Ltd. S. Nicum: Consultant/Advisory Boards: Roche, AstraZeneca, Abbvie, Tesaro, Clovis Speaker: AstraZeneca, Roche Clinical Trials Sponsored: AstraZeneca. D.J. Harrison: DJH has a research consultancy and research sponsored by Nucana Biomed. Family member has stock options with Nucana Biomed. All other authors have declared no conflicts of interest.