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

Br J Cancer. 2018 Oct;119(7):815-822. doi: 10.1038/s41416-018-0244-1. Epub 2018 Sep 12.


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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Cytidine Monophosphate / administration & dosage
  • Cytidine Monophosphate / adverse effects
  • Cytidine Monophosphate / analogs & derivatives*
  • Cytidine Monophosphate / pharmacokinetics
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms / drug therapy*
  • Neoplasms / pathology*
  • Recurrence
  • Survival Analysis
  • Treatment Outcome
  • Young Adult


  • Antineoplastic Agents
  • NUC-1031
  • Cytidine Monophosphate