A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08)

Oncologist. 2021 Apr;26(4):e669-e678. doi: 10.1002/onco.13598. Epub 2020 Dec 3.

Abstract

Background: Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites.

Methods: Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0-1 received NUC-1031 (625 or 725 mg/m2 ) and cisplatin (25 mg/m2 ) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS).

Results: Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3-4 adverse events occurring in more than one patient with 625 mg/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2 , increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3-10.1), and median OS was 9.6 months (95% CI, 6.7-13.1). The median estimates of area under the plasma concentration-time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218-324 μg•h/mL and 309-889 μg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47-1.56 μg•h/mL and 0.284-0.522 μg/mL, respectively).

Conclusion: This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26).

Implications for practice: The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.

Keywords: Advanced disease; Biliary tract cancer; Cisplatin; NUC-1031; Phase Ib.

Publication types

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

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Bile Duct Neoplasms* / drug therapy
  • Bile Ducts, Intrahepatic
  • Biliary Tract Neoplasms* / drug therapy
  • Cisplatin / therapeutic use
  • Cytidine Monophosphate / analogs & derivatives
  • Disease-Free Survival
  • Humans
  • Male
  • Middle Aged
  • Treatment Outcome

Substances

  • NUC-1031
  • Cytidine Monophosphate
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT02351765