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NUC-1031, use of ProTide technology to circumvent gemcitabine resistance: current status in clinical trials

Zainul Abedin Kapacee1, Jennifer J Knox2, Daniel Palmer3

  • 1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.

Medical Oncology (Northwood, London, England)
|June 13, 2020
PubMed
Abstract

Insights

NUC-1031, a novel gemcitabine compound, shows promise in treating biliary tract and ovarian cancers, with ongoing trials to determine its impact on pancreatic cancer survival.

Area of Science:

  • Oncology
  • Cancer Therapeutics
  • Drug Development

Background:

  • Gemcitabine resistance is a significant challenge in pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), and ovarian cancers (OC).
  • NUC-1031, a novel ProTide derivative of gemcitabine, is designed for improved cellular uptake and activation, bypassing common resistance mechanisms.
  • NUC-1031 exhibits enhanced stability against enzymatic degradation, potentially leading to better therapeutic outcomes.

Purpose of the Study:

  • To evaluate the safety and efficacy of NUC-1031 in patients with advanced solid tumors.
  • To assess the potential of NUC-1031 as a treatment for gemcitabine-resistant cancers, including PDAC, BTC, and OC.
  • To compare NUC-1031-based regimens with standard chemotherapy in ongoing clinical trials.

Main Methods:

  • Phase I (PRO-001) trial assessed safety and preliminary efficacy of NUC-1031 in advanced solid tumors.
  • Phase II (PRO-002) trial evaluated NUC-1031 combined with carboplatin in ovarian cancer.
  • Phase II (ABC-08) trial investigated NUC-1031 with cisplatin in advanced BTC.
  • Phase III (ACELARATE) trial compared NUC-1031 to gemcitabine in PDAC (paused for futility analysis).

Main Results:

  • Phase I trial: 10% partial response (PR) and 67% stable disease (SD) in response-evaluable patients.
  • Phase II OC trial (preliminary): 4% unconfirmed complete response (CR), 35% PR, and 57% SD.
  • Phase II BTC trial (interim): 50% objective response rate in the intention-to-treat population.
  • Phase III PDAC trial paused for futility analysis.

Conclusions:

  • NUC-1031 demonstrates a favorable safety and pharmacokinetic profile in early studies.
  • Encouraging disease control in BTC and OC supports further development of NUC-1031.
  • Ongoing Phase III trials (e.g., NuTide 121) will clarify the role of NUC-1031 in improving patient survival compared to gemcitabine.
Keywords:
AcelarinBiliary tract cancerGemcitabine resistanceNUC-1031Ovarian cancerPancreatic ductal adenocarcinomaPhase I trial

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