Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study. Issue 7 (2nd October 2018)

• Record Type: Journal Article
• Authors: Blagden, Sarah; Rizzuto, Ivana; Suppiah, Puvan; O'Shea, Daniel; Patel, Markand; Spiers, Laura; Sukumaran, Ajithkumar; Bharwani, Nishat; Rockall, Andrea; Gabra, Hani; El-Bahrawy, Mona; Wasan, Harpreet; Leonard, Robert; Habib, Nagy; Ghazaly, Essam
• Is Part Of: British journal of cancer. Volume 119:Issue 7(2018)
• Page Start: 815
• Page End: 822
• Publication Date: 2018-10-02
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; Tumors -- Periodicals; 616.994
• DOI: 10.1038/s41416-018-0244-1
• Languages: English
• ISSNs: 0007-0920

Abstract

Abstract Background Gemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. Methods Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. Results Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate.C max levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Conclusions NUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.