Phase I and pharmacokinetic trial of the proapoptotic sulindac analog CP-461 in patients with advanced cancer.
CP-461 is a member of a class of novel proapoptotic drugs that specifically inhibit cyclic GMP phosphodiesterases but not cyclooxygenase-1 or -2. CP-461 inhibits the growth of a broad range of human tumor cell lines in vitro at micromolar concentrations and selectively induces apoptosis in cancer cell lines but not normal cells. Preclinical studies revealed good oral bioavailability and no toxicity in dogs and rats at single doses up to 500 mg/kg. In a Phase I trial, 21 patients with a range of solid tumors and good performance status received CP-461 p.o. twice daily for 28 consecutive days. Cycles were repeated without a treatment-free interval. CP-461 doses ranged from 100 to 800 mg/day. Therapy was well tolerated overall, and a maximum tolerated dose was not reached. Grade 3 asymptomatic aspartate aminotransferase/alanine aminotransferase elevation in 1 patient treated at 800 mg/day was the only dose-limiting toxicity. No hematologic toxicity was noted. Peak plasma concentrations occurred between 1 and 2 h after dosing, and doses above 200 mg/day exceeded the known in vitro EC(50) (1-2 micro M) for apoptosis in cancer cells. No drug was detectable after 24 h of administration, and the terminal half-life was 6.7 h. The area under the plasma concentration-time curve was dose-proportional from 200 to 800 mg/day. Four patients exhibited disease stability after two cycles of treatment. CP-461 is minimally toxic at doses up to 800 mg/day when administered p.o. on a twice-daily schedule.
Sun
Weijing
W
University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA.
Stevenson
James P
JP
Gallo
James M
JM
Redlinger
Maryann
M
Haller
Daniel
D
Algazy
Kenneth
K
Giantonio
Bruce
B
Alila
Hector
H
O'Dwyer
Peter J
PJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D051263:D-Alanine Transaminase; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013467:Sulindac / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution
C439285:(5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride; D010726:Phosphodiesterase Inhibitors; D013467:Sulindac; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D051263:D-Alanine Transaminase