385P - Interim pharmacokinetic (PK) and pharmacodynamic (PD) data from the first-in-human study of NUC-3373, a pyrimidine nucleotide analogue, in patients...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Drug Development
Pharmacology
Presenter Essam Ghazaly
Citation Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367
Authors E. Ghazaly1, V.K. Woodcock2, P. Spilipoulou3, L. Spiers2, J. Moschandreas4, L. Griffiths2, C. Gnanaranjan1, D.J. Harrison5, T.R..J. Evans3, S.P. Blagden2
  • 1Centre For Haemato-oncology, Barts Cancer Institute, EC1M 6BQ - London/GB
  • 2Early Phase Clinical Trials Unit, Churchill Hospital University of Oxford NHS Trust, OX3 7LE - Oxford/GB
  • 3University Of Glasgow, Beatson Institute for Cancer Research, G61 1BD - Glasgow/GB
  • 4Nuffield Department Of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford, Oxford/GB
  • 5School Of Medicine, University of St Andrews, KY169TF - Fife/GB

Abstract

Background

NUC-3373, a phosphoramidate transformation of FUDR, is designed to bypass 5-FU and capecitabine resistance. Intracellular levels of the active 5-FU metabolite FUDR-MP in vitro were 363x higher than with 5-FU. Here, we report the interim PK and PD data from the ongoing first-in-human dose-escalation study of NUC-3373 in patients (pts) with advanced solid tumors (NuTide:301).

Methods

NUC-3373 was administered as 30- min IV infusion on days 1, 8, 15 and 22 of a 28-day cycle. The first 3 pt cohorts received NUC-3373 at 125mg/m2, 250mg/m2 and 500mg/m2. The primary objective was to determine RP2D. Secondary objectives included safety, PK and PD profiles, and anti-tumour activity. Blood samples were collected pre-dose and at 11 time-points up to 48h post-dose during cycle 1. Plasma and intracellular metabolites were measured by UPLC-MS/MS; western blotting of extracted PBMCs measured thymidylate synthase (TS) within ternary complexes (TS-T).

Results

PK/PD analyses were conducted on 16 of the 17 pts recruited to the first 3 dosing cohorts pts (94%), median age 59 yrs (range 24-71), with 7 cancer types, the majority (76%) being colorectal cancer. Mean plasma Cmax and AUC of NUC-3373 were dose proportional. Linear PK was confirmed across the studied dose range with clearance of 3.4 ± 0.6 L/hr and plasma t1/2 of 9.4h ±0.98h. Intracellular FUDR-MP was detectable at 5 minutes post-infusion with t1/2 of 14.3h ±1.7h and was still present at 48h. In the 500mg/m2 cohort the mean intracellular Cmax and AUC0-24 of FUDR-MP were 4.2pmol/106 cells and 16.5pmol/106 cells/hr. Within 1 hour of infusion, FUDR-MP was present within TS-T leading to depletion of the intracellular dTMP pool after 2-4h. Toxic metabolites FBAL and FUTP were undetectable intracellularly or in plasma. Dose escalation continues.

Conclusions

PK/PD data demonstrate NUC-3373 generates high intracellular concentrations of the active cytotoxic metabolite FUDR-MP, which efficiently sequester TS into TS-T inhibiting its activity. This and lack of toxic metabolite accumulation indicate NUC-3373 has a favorable PK profile compared to the established fluoropyrimidines.

Clinical trial identification

ClinicalTrials.gov NCT02723240 EudraCT Number: 2015-002250-13 Release date: December 8, 2015

Legal entity responsible for the study

University of Oxford

Funding

Nucana BioMed Ltd

Disclosure

D.J. Harrison: Advisory in Cytosystems, Nucana and Ryboquin. Leadership role in Ryboquin The Institute received research funding from Nucana Ltd and Ryboquin Ltd. T.R.J. Evans: Advisory role in Bristol-Myers Squibb, Vertex, GSK, Baxter and Celgene. The institute received research funding from several Pharmaceutical companies. S.P. Blagden: Advisory role in Celgene and Novartis. Holder of an IP in RNA Guardian. Travel grant from Nucana. All other authors have declared no conflicts of interest.