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Titolo:
Chronic oral administration of CI-994: A phase 1 study
Autore:
Prakash, S; Foster, BJ; Meyer, M; Wozniak, A; Heilbrun, LK; Flaherty, L; Zalupski, M; Radulovic, L; Valdivieso, M; LoRusso, PM;
Indirizzi:
Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Internal Med,Div Hematol & Oncol, Detroit, MI 48202 USA Wayne State Univ Detroit MI USA 48202 atol & Oncol, Detroit, MI 48202 USA Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, Ann Arbor, MI 48105 USA Warner Lambert Parke Davis Ann Arbor MI USA 48105 Ann Arbor, MI 48105 USA
Titolo Testata:
INVESTIGATIONAL NEW DRUGS
fascicolo: 1, volume: 19, anno: 2001,
pagine: 1 - 11
SICI:
0167-6997(200102)19:1<1:COAOCA>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
N-ACETYLDINALINE; TOXICITY; RAT; ANTITUMOR; MECHANISM; GOE-1734; DRUG;
Keywords:
dose limiting toxicity; maximum tolerated dose; pharmacokinetics of CI-994;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
17
Recensione:
Indirizzi per estratti:
Indirizzo: LoRusso, PM Wayne State Univ, Harper Hosp, Dept Hematol & Oncol, 5 Hudson,3990 John R,Detroit, MI 48201 USA Wayne State Univ 5 Hudson,3990 John R Detroit MI USA 48201 USA
Citazione:
S. Prakash et al., "Chronic oral administration of CI-994: A phase 1 study", INV NEW DR, 19(1), 2001, pp. 1-11

Abstract

Objectives: CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent active in a broad variety of murine and human tumor xenografts. While cytotoxic in the Brown Norway (BN) rat leukemia model, growth inhibition in other murine and human tumor xenografts is predominantly cytostatic. Its specificmechanism of action remains unknown. Following CI-994 administration, inhibition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in patients with solid tumors was carried out to determine a maximum tolerateddaily oral dose (MTD) for CI-994 administered on a chronic basis. Methods:Fifty-three patients received CI-994 daily for treatment durations rangingfrom 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosing Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort of patients (n = 13) received CI-994 at the recommended Phase 2 dose and schedule with 2 additional single doses of drug administered separated by a 1-week washout to assess the effect of food on CI-994 pharmacokinetics. Results: Thrombocytopenia was dose limiting at the MTD of 8 mg/m(2)/day for 8 weeks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic studies revealed that peak plasma levels and AUC's generally increased with dose and that food intake did not affect the rate or extent of drug absorption. One patient with heavily pre-treated adenocarcinoma of the lung achieved a Partial Response (PR) lasting over 2 years and 3 additional patients achieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, and renal cancer. Conclusions: The recommended Phase 2 starting dose is 8 mg/m(2)/day for 8 weeks repeated after a 2-week drug-free interval.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 10:45:09