PRO-002, a phase Ib dose-escalation study of NUC-1031 with carboplatin for recurrent ovarian cancer

Abstract

Background: 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). Methods: 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. Results: 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. Conclusions: 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.