Final results of a prematurely discontinued Phase 1/2 study of eniluracil with escalating doses of 5-fluorouracil administered orally in patients with advanced hepatocellular carcinoma

Cancer Chemotherapy and Pharmacology

Volumn 68, Issue 4, 2011, Pages 1067-1073

  De Lima Lopes Jr , Gilberto ^a,b   Dicksey, Jennifer S ^c   Peters, William P ^c   Palalay, Melvin ^d   Chang, Alex Y ^a,b  

^a Johns Hopkins Singapore   (Singapore)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Adherex Inc   (United States)

^d UNIVERSITY OF HAWAII   (United States)

Author keywords

Chemotherapy; Eniluracil; Fluoropyrimidine; Fluorouracil; Hepatocellular carcinoma

Indexed keywords

5 ETHYNYLURACIL; DIHYDROPYRIMIDINE DEHYDROGENASE; DOXORUBICIN; FLUOROURACIL; THALIDOMIDE;

ADULT; ADVANCED CANCER; ANOREXIA; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; ASIAN; CANCER PATIENT; CHEMOEMBOLIZATION; CHEMOTHERAPY INDUCED EMESIS; CLINICAL ARTICLE; COHORT ANALYSIS; CONTROLLED STUDY; COUGHING; DIARRHEA; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG FATALITY; DRUG FEVER; DRUG HALF LIFE; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EVENING DOSAGE; FATIGUE; FEMALE; HUMAN; HYPOKALEMIA; LIVER CELL CARCINOMA; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MORNING DOSAGE; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; NAUSEA AND VOMITING; NEUROTOXICITY; PAIN; PANCYTOPENIA; PERIPHERAL BLOOD MONONUCLEAR CELL; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; SEIZURE; SINGAPORE; SINGLE DRUG DOSE; THROMBOCYTOPENIA; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT OUTCOME; UNITED STATES;

ADMINISTRATION, ORAL; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; ASIAN CONTINENTAL ANCESTRY GROUP; CARCINOMA, HEPATOCELLULAR; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG RESISTANCE, NEOPLASM; FEMALE; FLUOROURACIL; HUMANS; LIVER NEOPLASMS; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; TREATMENT OUTCOME; URACIL;

EID: 80054750761     PISSN: 03445704     EISSN: 14320843     Source Type: Journal    
DOI: 10.1007/s00280-011-1588-x     Document Type: Article

References (17)

1. MJ Heslin J Yan H Weiss L Shao J Owens VS Lucas, et al. 2003 Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by EU (GW776C85) in primary and metastatic colorectal cancer Cancer Chemother Pharmacol 52 399 404 12904894 10.1007/s00280-003-0681-1 1:CAS:528: DC%2BD3sXotFWmtLc%3D (Pubitemid 37363613)
2. XD Guo N Harold MW Saif B Schuler E Szabo JM Hamilton, et al. 2003 Pharmacokinetic and pharmacodynamic effects of oral EU, fluorouracil and leucovorin given on a weekly schedule Cancer Chemother Pharmacol 52 79 85 12707718 10.1007/s00280-003-0613-0 1:CAS:528:DC%2BD3sXltVWgtr0%3D (Pubitemid 36920632)
3. W Jiang Z Lu Y He R Diasio 1997 Dihydropyrimidine dehydrogenase activity in hepatocellular carcinoma: implication in 5-fluorouracil based chemotherapy Clin Cancer Res 3 395 399 9815697 1:CAS:528:DyaK2sXitVKms7g%3D (Pubitemid 27158063)
4. AB Benson III E Mitchell N Abramson B Klencke P Ritch JP Burnham, et al. 2002 Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma Ann Oncol 13 576 581 12056708 10.1093/annonc/mdf079 (Pubitemid 34461141)
5. JM Llovet P Ruff N Tassopoulos L Castells J Bruix I El-Hariry, et al. 2001 A phase II trial of oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma Eur J Cancer 37 1352 1358 11435064 10.1016/S0959-8049(01)00100-9 1:CAS:528:DC%2BD3MXkvVeisb0%3D (Pubitemid 32588745)
6. R Schilsky J Levin W West A Wong B Colwell M Thirlwell, et al. 2002 Randomized, open-label, phase III study of a 28-day oral regimen of EU plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer J Clin Oncol 20 1519 1526 11896100 10.1200/JCO.20.6.1519 1:CAS:528:DC%2BD38XivFeitr8%3D (Pubitemid 34260531)
7. B Keith XD Guo S Zentko N Harold B Schuler M Quinn 2002 Impact of two weekly schedules of oral EU given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition Clin Cancer Research 8 1045 1050 1:CAS:528:DC%2BD38XksVSqurk%3D (Pubitemid 34517638)
8. National Cancer Institute, Common Toxicity Criteria for Adverse Events, version 3.0. Available at: http://ctep.cancer.gov/forms/CTCAE-Index.pdf. Accessed on 10 December 2009
9. P Therasse SG Arbuck EA Eisenhauer, et al. 2000 New Guidelines to Evaluate the Response to Treatment in Solid Tumors J Natl Cancer Inst 92 205 216 10655437 10.1093/jnci/92.3.205 1:STN:280:DC%2BD3c7it1Gitg%3D%3D (Pubitemid 30099779)
10. Murphy PB, Raefsky E, Burris HA, Infante JR, Jones SF, Spigel DR, Dickson N, Lawton M, Dicksey JS, Peters WP (2008) A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5-FU). J Clin Oncol (Meeting Abstracts) 26:13519
11. RB Diasio BE Harris 1989 Clinical pharmacology of 5-fluoruracil Clin Pharmacokinet 16 4 215 237 2656050 10.2165/00003088-198916040-00002 1:CAS:528:DyaL1MXkslSisr4%3D
12. Xiong HQ, Abbruzzese JL (2004) Therapeutic principles of gastrointestinal neoplasia: chemotherapy. In: Abbruzzese JL, Evans DB, Willett CG, Fenoglio-Preiser C (eds) Gastrointestinal Oncology. Oxford University Press, New York, NY
13. R Okeda M Shibutani T Matsuo, et al. 1990 Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine Acta Neuropathol 81 1 66 73 2128162 10.1007/BF00662639 1:CAS:528:DyaK3MXhvF2itb4%3D (Pubitemid 20377478)
14. J Yen-Revollo R Goldberg HL McLeod 2008 Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines? Clin Cancer Res 114 8 13 10.1158/1078-0432.CCR-07-1225 (Pubitemid 351377972)
15. T Spector S Cao 2010 A possible cause and remedy for the clinical failure of 5-fluoruracil plus eniluracil Clin Colorectal Cancer 9 1 52 54 20100689 10.3816/CCC.2010.n.007 1:CAS:528:DC%2BC3cXisVehsLY%3D
16. XD Guo N Harold M Wasif Saif, et al. 2003 Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule Cancer Chem Pharm 52 1 79 85 10.1007/s00280-003-0613-0 1:CAS:528:DC%2BD3sXltVWgtr0%3D (Pubitemid 36920632)
17. T Spector JA Harrington DJ Porter 1993 5-Ethynyluracil (776C85): inactivation of dihydropyrimidine dehydrogenase in vivo Biochem Pharmacol 46 2243 2248 8274158 10.1016/0006-2952(93)90615-4 1:CAS:528:DyaK2cXpsV2qsA%3D%3D (Pubitemid 24012317)