Dataset Information

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.

ABSTRACT: BACKGROUND:3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma. METHODS:Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 every 28 days) 1 h after completing a 4-h infusion of 3-AP given at a dose of 105 mg/m(2) in patients with normal liver function (stratum A) or 80 mg/m(2) if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B. RESULTS:Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3-4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24 h after 3-AP therapy showed increased R2 mRNA expression by in situ RT-PCR, suggesting RR inhibition. CONCLUSIONS:Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.

SUBMITTER: Ocean AJ

PROVIDER: S-EPMC3446256 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.

Ocean Allyson J AJ Christos Paul P Sparano Joseph A JA Matulich Dan D Kaubish Andreas A Siegel Abby A Sung Max M Ward Maureen M MM Hamel Nancy N Espinoza-Delgado Igor I Yen Yun Y Lane Maureen E ME

Cancer chemotherapy and pharmacology 20101028 2

<h4>Background</h4>3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma.<h4>Methods</h4>Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tr ...[more]

PMID: 20981545

Similar Datasets

Project description:BackgroundImmune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.MethodsIn this single-arm, open-label, phase II study, we enrolled stage IV BTC patients. Participants received camrelizumab (3 mg/kg) plus gemcitabine (800 mg/m2) and oxaliplatin (85 mg/m2). Primary endpoints were 6-month progression-free survival (PFS) rate and safety. Secondary endpoints were objective response rate (ORR), PFS and overall survival (OS). Exploratory endpoints included association between response and tumor mutational burden (TMB), blood TMB, dynamic change of ctDNA and immune microenvironment.Results54 patients with advanced BTC were screened, of whom 38 eligible patients were enrolled. One patient withdrew informed consent before first dose treatment. Median follow-up was 11.8 months. The 6-month PFS rate was 50% (95% CI 33 to 65). Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and median OS was 11.8 months. The most common treatment-related adverse events (TRAEs) were fatigue (27 (73%)) and fever (27 (73%)). The most frequent grade 3 or worse TRAEs were hypokalemia (7 (19%)) and fatigue (6 (16%)). The ORR was 80% in patients with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥1% versus 53.8% in PD-L1 TPS <1%. There was no association between response and TMB, blood TMB, immune proportion score or immune cells (p>0.05), except that PFS was associated with blood TMB. Patients with positive post-treatment ctDNA had shorter PFS (p=0.007; HR, 2.83; 95% CI 1.27 to 6.28).ConclusionCamrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line treatment in advanced BTC patients. Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration numberNCT03486678.

Project description:Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC.Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed.Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1?±?9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7?±?9.2%. No statistically significant differences in survival were seen between the two treatment cohorts.Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients.The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

Project description:BackgroundPatients with advanced biliary tract cancer who progress on first-line therapy have limited treatment options. The TreeTopp study assessed varlitinib, a reversible small molecule pan-human epidermal growth factor receptor inhibitor, plus capecitabine in previously treated advanced biliary tract cancer.Patients and methodsThis global, double-blind, randomized, placebo-controlled phase II study enrolled patients with confirmed unresectable or metastatic biliary tract cancer and disease progression after one prior line of gemcitabine-containing chemotherapy. Patients received oral varlitinib 300 mg or placebo twice daily (b.i.d.) for 21 days, plus oral capecitabine 1000 mg/m2 b.i.d. on days 1-14, in 21-day treatment cycles. Co-primary endpoints were objective response rate and progression-free survival (PFS) according to RECIST v1.1 by Independent Central Review.ResultsIn total, 127 patients received varlitinib plus capecitabine (n = 64) or placebo plus capecitabine (n = 63). The objective response rate was 9.4% with varlitinib plus capecitabine versus 4.8% with capecitabine alone (odds ratio 2.28; P = 0.42). Median PFS was 2.83 versus 2.79 months [hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.60-1.37; P = 0.63] and overall survival was 7.8 versus 7.5 months (HR, 1.11; 95% CI, 0.69-1.79; P = 0.66), respectively. In a subgroup analysis, the addition of varlitinib appeared to provide a PFS benefit in female patients (median, 4.1 versus 2.8 months; HR, 0.59; 95% CI, 0.28-1.23) and those with gallbladder cancer (median, 2.9 versus 1.6 months; HR, 0.55; 95% CI, 0.26-1.19). Grade ≥3 treatment-emergent adverse events were reported in 65.6% of patients receiving varlitinib plus capecitabine versus 58.7% of those receiving capecitabine alone.ConclusionsIn patients with advanced biliary tract cancer, second-line treatment with varlitinib plus capecitabine was well tolerated but did not improve efficacy versus capecitabine alone. A PFS benefit was suggested in female patients and those with gallbladder cancer.

Dataset Information

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.

Publications

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure