PRO-105, a phase II open-label study of NUC-1031 in patients with platinum-resistant ovarian cancer.

Abstract

Background: Patients with platinum-resistant ovarian cancer, following ≥3 lines of chemotherapy have limited treatment options. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome the three key resistance mechanisms associated with gemcitabine: transport, activation and breakdown. By overcoming these resistance mechanisms, NUC-1031 achieves ≥ 200-times higher intracellular concentrations of the active anticancer metabolite, dFdCTP, compared to gemcitabine. NUC-1031 was well tolerated and demonstrated anti-tumor activity in ovarian cancer patients (Blagden et al, ASCO 2015; Blagden et al, ESMO 2017). Based on these data, a Phase II dose-confirming study was initiated to investigate NUC-1031 in patients with platinumresistant ovarian cancer. Methods: PRO-105 is a randomized openlabel, two-part clinical study designed to determine the optimal dose of NUC-1031 in patients with platinum-resistant ovarian cancer who have received ≥3 lines of chemotherapy. The primary endpoint is Objective Response Rate at the selected dose level (500 mg/m or 750 mg/m ), assessed by a blinded independent central reviewer. Secondary endpoints include duration of response, progression-free survival, overall survival, PK/PD and patientreported outcomes. In Part I, up to 40 patients will be randomized to NUC-1031 at 500 mg/m or 750 mg/m on days 1, 8 and 15 of a 28-day cycle. Randomization is stratified for BRCA 1/2 mutation status and number of prior chemotherapy lines. One dose level will be selected for further evaluation in Part II based on safety, PK, dosing intensity and clinical activity. Enrollment will continue in Part II until 44 response evaluable patients are recruited at the selected dose. To date, 22 patients with platinum-resistant ovarian cancer have been randomized into Part I of the study, which is currently recruiting across 15 US and 8 UK sites.