A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors
| Autor: | PA Palmer, S. G. Eckhardt, Cindy L. O'Bryant, A. S. Pierson, Roger B. Cohen, Lia Gore, C Mikule, Steven Zhang, Scott N. Holden, Mark Morrow, M Persky, Daniel L. Gustafson |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Antimetabolites Antineoplastic Drug-Related Side Effects and Adverse Reactions Protein Prenylation Quinolones Pharmacology Neutropenia Deoxycytidine Capecitabine Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols Humans Medicine Aged Neoplasm Staging Farnesyl-diphosphate farnesyltransferase Alkyl and Aryl Transferases business.industry Farnesyltransferase inhibitor Hematology HSP40 Heat-Shock Proteins Middle Aged medicine.disease Oncology Fluorouracil Toxicity Female Tipifarnib business medicine.drug |
| Zdroj: | Annals of Oncology. 17:1709-1717 |
| ISSN: | 0923-7534 |
| DOI: | 10.1093/annonc/mdl282 |
| Popis: | BACKGROUND To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks. |
| Databáze: | OpenAIRE |
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