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Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study

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Title: Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study
Authors: Blagden, SP
Rizzuto, I
Suppiah, P
O'Shea, D
Patel, M
Spiers, L
Sukumaran, A
Bharwani, N
Rockall, A
Gabra, H
El-Bahrawy, M
Wasan, H
Leonard, R
Habib, N
Ghazaly, E
Item Type: Journal Article
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. Cmax 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.
Issue Date: 2-Oct-2018
Date of Acceptance: 2-Aug-2018
URI: http://hdl.handle.net/10044/1/63925
DOI: https://dx.doi.org/10.1038/s41416-018-0244-1
ISSN: 0007-0920
Publisher: Cancer Research UK
Start Page: 815
End Page: 822
Journal / Book Title: British Journal of Cancer
Volume: 119
Issue: 7
Copyright Statement: © 2018 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
ADVANCED SOLID TUMORS
PANCREATIC-CANCER
PHARMACOKINETIC EVALUATION
GEMCITABINE TRIPHOSPHATE
CELLULAR PHARMACOLOGY
MOLECULAR-MECHANISMS
DOSE-INTENSITY
BREAST-CANCER
RESISTANCE
ADENOCARCINOMA
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2018-09-12
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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