TY - JOUR
T1 - A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors
AU - Delaunoit, Thierry
AU - Burch, Patrick A.
AU - Reid, Joel M.
AU - Camoriano, John K.
AU - Kobayash, Tomowo
AU - Braich, Theodore A.
AU - Kaur, Judith S.
AU - Rubin, Joseph
AU - Erlichman, Charles
N1 - Funding Information:
1Supported in part by: Les Amis de l’Institut Bordet, grant Yvonne and Thomas Rucquois; 2Department of Oncology, Mayo Clinic, 200 First street sw Rochester, MN 55905, USA; 3Department of Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA; 4Sankyo Co., Ltd., Tokyo, Japan
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
KW - CS-682
KW - Pharmacokinetics
KW - Phase I
UR - http://www.scopus.com/inward/record.url?scp=33646508837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646508837&partnerID=8YFLogxK
U2 - 10.1007/s10637-006-5392-0
DO - 10.1007/s10637-006-5392-0
M3 - Article
C2 - 16502355
AN - SCOPUS:33646508837
SN - 0167-6997
VL - 24
SP - 327
EP - 333
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 4
ER -