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).
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).
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.
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
Nucana BioMed Ltd
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.