McNamara, MG; Bridgewater, J; Palmer, DH; Faluyi, O; Wasan, H; Patel, A; Ryder, WD; ... Valle, JW; + view all McNamara, MG; Bridgewater, J; Palmer, DH; Faluyi, O; Wasan, H; Patel, A; Ryder, WD; Barber, S; Gnanaranjan, C; Ghazaly, E; Evans, TRJ; Valle, JW; - view fewer (2021) 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). The Oncologist , 26 (4) e669-e678. 10.1002/onco.13598.

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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/m^{2}) 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/m^{2} (n = 8 and expansion n = 7; median six cycles) or 725 mg/m^{2} (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/m^{2} 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/m^{2}, increased GGT, 67%, and fatigue, 33%. NUC‐1031 725 mg/m^{2} 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.

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