Clinical Trial: ABC-08: Phase Ib Trial of Acelarin in Combination With Cisplatin in Locally Advanced/ Metastatic Biliary Tract Cancers

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase Ib, Multi-centre, Open-label Study of a First-in-class Nucleotide Analogue Acelarin (NUC-1031) in Combination With Cisplatin in Patients With Locally Advanced/Metastatic Biliary Tract Cancers

Brief Summary: The purpose of this study is to determine the recommended phase II dose, and to assess the safety of acelarin in combination with cisplatin in patients with locally advanced/ metastatic biliary tract cancers.

Detailed Summary:

Active chemotherapy drugs for the treatment of advanced biliary tract cancers (ABC) include gemcitabine, fluoropyrimidines and platinum agents. The United Kingdom (UK) National Cancer Research Network (NCRN) ABC-02 study established cisplatin and gemcitabine as the standard of care for the first-line treatment of patients with ABC and this regimen has been widely adopted in the UK and internationally. However, inherent and acquired tumour resistance limits the efficacy of gemcitabine and it is necessary to explore alternative treatments.

The study will explore the combination of acelarin, a drug designed to specifically overcome the key cancer resistance mechanisms associated with gemcitabine, with cisplatin. As this is the first time the combination of acelarin and cisplatin will be given to patients the aim of the study is to investigate the safety of the combination and to establish the recommended phase II dose of acelarin.

This is a phase Ib, single-arm, multi-centre, open-label trial. The trial design is a classic 3+3 design where patients are recruited into cohorts of 3 to 6 patients at different dose levels until the dose level for phase II is determined. Patients in each cohort will be monitored closely for safety and drug toxicity.

Secondary trial objectives will involve assessing the activity of acelarin in combination with cisplatin in terms of; progression-free survival, overall survival and response rate, as well as exploring the pharmacokinetic profile of the combination.

Current Primary Outcome:

• Safety profile of Acelarin in combination with Cisplatin, assessed by total incidence and rate of grade 3 and 4 adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) [ Time Frame: Adverse events recorded from initiation of therapy until 30 day post-treatment ]
  Safety will be assessed by comparing the total incidence and rate of grade 3 and 4 adverse events that occur after initiation of therapy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
• Maximum Tolerated Dose (MTD) of Aclerain in combination with Cisplatin [ Time Frame: After 13 months of first patient included ]
  The MTD will be defined as the maximum dose level at which 0/3 patients or 1/6 patients experience dose-limiting toxicity (DLT). At any dose level, DLT in 1/3 patients will lead to expansion to 6 patients. If 2/6 patients experience DLT the preceding dose level will be declared the MTD. At the MTD up to 6 additional patients may be enrolled. If this level is well tolerated, it will be declared the recommended phase II dose (RP2D).

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Progression-free survival [ Time Frame: Evaluated by 6 weekly follow-up until 12 months after the last patient included ]
  Clinical progression assessed every six weeks, radiological progression assessed to Response Evaluation Criteria in Solid Tumors (RECIST) criteria every 12 weeks.
• Overall survival [ Time Frame: Evaluated by 6 weekly follow-up until 12 months after the last patient included ]
• Response rate [ Time Frame: After 12 weeks of treatment ]
  Response will be calculated as a composite of objective response rate (ORR) by RECIST 1.1 (summation of patients with a complete or partial response [any time]).
• Exploration of the pharmacokinetic profile for the combination of Acelarin with Cisplatin [ Time Frame: At baseline (prior to chemotherapy administration), 30, 60 and 240 minutes following line flush at the end of acelarin administration. Cycle 1 day 1 only ]
  Plasma and intracellular levels of acelarin, cisplatin, gemcitibine (2', 2'-difluoro 2'-deoxycytidine) (dFdC), gemcitabine monophosphate (dFdCMP), gemcitabine diphosphate (dFdCDP), gemcitabine triphosphate (dFdCTP) and difluorodeoxyuridine (dFdU) will be measured and correlated with clinical activity and safety profile.

Original Secondary Outcome: Same as current

Information By: The Christie NHS Foundation Trust

Dates:
Date Received: January 27, 2015
Date Started: January 2016
Date Completion: September 2018
Last Updated: December 30, 2016
Last Verified: December 2016