A phase Ib study of NUC1031 and carboplatin for patients with recurrent ovarian cancer.

Authors:
Publisher website
Google Scholar
Abstract
5565 Background: Acelarin is a first-in-class nucleotide analogue utilising phosphoramidate chemistry to overcome the key gemcitabine resistance mechanisms and generate high intracellular levels of the active cytotoxic dFdCTP. In a Phase I, single agent, dose escalation study, Acelarin was well tolerated with impressive clinical activity. In a subset of 13 patients (pts) with ovarian cancer, Acelarin achieved a durable disease control rate, DCR intention-to-treat (ITT) 69%; on-treatment analyses (OTA) 90% and median PFS 8.3 months in evaluable pts. Therefore, we undertook a Phase Ib dose escalation study combining Acelarin with carboplatin in women with advanced ovarian cancer. Methods: Acelarin was administered as an injection on days 1 & 8 with carboplatin at AUC 4 or 5 on day 1, every 3 weeks for ≤ 6 cycles. Primary endpoint was RP2D; secondary endpoints included safety, ORR, PFS and PK/PD. Results: To date, 15 pts (mean age 65 yrs) with metastatic ovarian cancer, a median platinum free interval of 4 months and an average of 2.9 prior lines of chemotherapy, have been enrolled. Four dose cohorts of Acelarin (500; 625 and 750 mg/m2) with carboplatin (AUC4 or 5) have been studied. Nine pts completed 6 cycles of treatment and 3 pts remain on study. Strong early efficacy signals were achieved: 1 RECIST Complete Response (7%); 2 Partial Responses (13%) and 11 Stable Diseases (73%) resulting in a DCR ITT 93%; OTA 100%. Median PFS was 6.0 months (range 1.2 - 11.5) and 7 pts have ongoing disease control. PK showed that Acelarin was stable in the plasma (t1/2 = 3.8 hrs). The combination regimen rapidly generated very high intracellular dFdCTP levels (Cmax = 12.1 µM/mgTP/500mg/m2 and Tmax = 30 min) and significant levels were maintained for 24 hrs. The combination regimen was well tolerated. SAEs were reported in 4 pts: febrile neutropaenia (2); thrombocytopaenia (2); dyspnoea (1) and dizziness (1). Two DLTs were observed: grade 4 thrombocytopaenia at Acelarin 625mg/m2 and 750mg/m2 plus carboplatin AUC4. Conclusions: The combination of Acelarin with carboplatin was well tolerated and demonstrated remarkable clinical activity with durable disease control rate (ITT 93%; OTA 100%). Phase II studies in ovarian cancer are being planned. Clinical trial information: NCT02303912.