A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors

Thierry Delaunoit, Patrick A. Burch, Joel M. Reid, John K. Camoriano, Tomowo Kobayash, Theodore A. Braich, Judith S. Kaur, Joseph Rubin, Charles Erlichman

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

CS-682 (1-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)-N 4-palmitoylcytosine) is a novel orally administered 2′-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m2/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3-4) were seen more frequently with 10 patients experiencing grade 3-4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m2/day. The maximum tolerated dose was determined to be 160 mg/m2/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 ± 0.9 h after drug administration and the terminal elimination half-life was 1.7 ± 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 ± 0.31 h, peak plasma concentrations were achieved 3.1 ± 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 ± 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m 2/day for 4 weeks repeated after a 2-week rest period.

Original languageEnglish (US)
Pages (from-to)327-333
Number of pages7
JournalInvestigational New Drugs
Volume24
Issue number4
DOIs
StatePublished - Jul 1 2006

Keywords

  • CS-682
  • Pharmacokinetics
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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