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

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    Authors
    Kapacee, Zainul Abedin
    Knox, JJ
    Palmer, D
    Blagden, SP
    Lamarca, Angela
    Valle, Juan W
    McNamara, Mairead G
    Affiliation
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
    Issue Date
    2020
    
    Metadata
    Show full item record
    Abstract
    Background: Resistance to gemcitabine chemotherapy is common in patients with pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC) and ovarian cancers (OC), conferring poor survival. Use of ProTide technology led to the development of a 'partially-activated' monophosphorylated gemcitabine compound, termed NUC-1031. NUC-1031 enters cancer cells independent of the human equilibrative nucleoside transporter, does not require deoxycytidine kinase-mediated activation and resists cytidine deaminase-mediated breakdown into toxic by-products. Current findings: The phase I PRO-001 trial recruited 68 patients with advanced solid tumours; of the 49 patients that had response-evaluable disease, 5 (10%) had a partial response (PR) and 33 (67%) had stable disease (SD). Subsequently, the PRO-002 study assessed the safety and efficacy of NUC-1031 combined with carboplatin for patients with OC (n = 25); preliminary data from this study reported one (4%) unconfirmed complete response (CR), 8 (35%) PRs and 13 (57%) patients with SD, the final outcome data are awaited. The ABC-08 trial for advanced BTC assessed safety and efficacy of NUC-1031 combined with cisplatin; 14 patients were recruited with a 50% objective response rate in the intention to treat population at interim analysis. ACELARATE, the phase III trial in first-line advanced PDAC comparing NUC-1031 to gemcitabine monotherapy, recruited 200 patients but has been paused for futility analysis. Conclusion: Early studies demonstrate NUC-1031 is well tolerated with favourable pharmacokinetic profiles. NUC-1031 use in PDAC remains unclear, but encouraging results of disease control in BTC and OC has prompted phase II and III trial development. NuTide 121, is a phase III trial comparing cisplatin-NUC 1031 combination to the standard of care cisplatin-gemcitabine and recruitment is ongoing. Recruiting trials and mature data from existing studies will help inform on the impact of NUC-1031 on patient survival over standard gemcitabine. Keywords: Acelarin; Biliary tract cancer; Gemcitabine resistance; NUC-1031; Ovarian cancer; Pancreatic ductal adenocarcinoma; Phase I trial. Background: Resistance to gemcitabine chemotherapy is common in patients with pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC) and ovarian cancers (OC), conferring poor survival. Use of ProTide technology led to the development of a 'partially-activated' monophosphorylated gemcitabine compound, termed NUC-1031. NUC-1031 enters cancer cells independent of the human equilibrative nucleoside transporter, does not require deoxycytidine kinase-mediated activation and resists cytidine deaminase-mediated breakdown into toxic by-products. Current findings: The phase I PRO-001 trial recruited 68 patients with advanced solid tumours; of the 49 patients that had response-evaluable disease, 5 (10%) had a partial response (PR) and 33 (67%) had stable disease (SD). Subsequently, the PRO-002 study assessed the safety and efficacy of NUC-1031 combined with carboplatin for patients with OC (n = 25); preliminary data from this study reported one (4%) unconfirmed complete response (CR), 8 (35%) PRs and 13 (57%) patients with SD, the final outcome data are awaited. The ABC-08 trial for advanced BTC assessed safety and efficacy of NUC-1031 combined with cisplatin; 14 patients were recruited with a 50% objective response rate in the intention to treat population at interim analysis. ACELARATE, the phase III trial in first-line advanced PDAC comparing NUC-1031 to gemcitabine monotherapy, recruited 200 patients but has been paused for futility analysis. Conclusion: Early studies demonstrate NUC-1031 is well tolerated with favourable pharmacokinetic profiles. NUC-1031 use in PDAC remains unclear, but encouraging results of disease control in BTC and OC has prompted phase II and III trial development. NuTide 121, is a phase III trial comparing cisplatin-NUC 1031 combination to the standard of care cisplatin-gemcitabine and recruitment is ongoing. Recruiting trials and mature data from existing studies will help inform on the impact of NUC-1031 on patient survival over standard gemcitabine. Keywords: Acelarin; Biliary tract cancer; Gemcitabine resistance; NUC-1031; Ovarian cancer; Pancreatic ductal adenocarcinoma; Phase I trial.
    Citation
    Kapacee ZA, Knox JJ, Palmer D, Blagden SP, Lamarca A, Valle JW, et al. NUC-1031, use of ProTide technology to circumvent gemcitabine resistance: current status in clinical trials. Medical oncology. 2020;37(7):61.
    Journal
    Medical Oncology
    URI
    http://hdl.handle.net/10541/623074
    DOI
    10.1007/s12032-020-01386-6
    PubMed ID
    32529264
    Additional Links
    https://dx.doi.org/10.1007/s12032-020-01386-6
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1007/s12032-020-01386-6
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