Phase I evaluation and clinical pharmacology of tricyclic nucleoside 5'-phosphate using a weekly intravenous regimen.
Tricyclic nucleoside phosphate (TCN-P) was selected for clinical trials because of its unusual chemical structure and activity against L1210 murine leukemia and MX-1 mammary xenograft. Inhibiting DNA synthesis, TCN-P was more toxic during S-phase of cell cycle. A phase I study was conducted in 24 patients with advanced solid cancers. The drug was given as a slow i.v. injection over 5 min on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 12 to 96 mg/m2 were studied with 3 to 12 patients treated at each level; a total of 106 doses was administered. The major hematological toxicity was thrombocytopenia, with a median nadir occurring at Day 34 of the cycle and first appearing at doses greater than 24 mg/m2. Anemia was seen at each dose level occurring between Days 8 and 34. Non-myelosuppressive toxic effects included stomatitis, anorexia, transient fever, nausea and vomiting, and dose-limiting hyperglycemia and diarrhea. The highest tolerated dose was 48 mg/m2. Plasma, pleural fluid, urine, and tissue samples were analyzed for TCN-P and tricyclic nucleoside (TCN) in selected patients by high-performance liquid chromatography. Plasma decay curves revealed extended retention of both TCN and TCN-P. Autopsy specimens obtained 61 days after therapy showed the highest residues of TCN-P in liver metastases and of TCN in gall bladder, bile, and pancreas. No drug was detected in urine samples of two patients. Prolonged retention and erratic plasma levels of the drug are probably due to extensive enterohepatic circulation, as well as repeated interconversion between TCN-P and TCN within cells. This weekly schedule produced unexpected clinical toxicity and should not be pursued.
R B
RB
Schilcher
C D
CD
Haas
M K
MK
Samson
J D
JD
Young
L H
LH
Baker
D000073:Acenaphthenes; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D012265:Ribonucleotides / Q000009:adverse effects* / Q000378:metabolism; D013921:Thrombocytopenia / Q000139:chemically induced
D000073:Acenaphthenes; D000970:Antineoplastic Agents; D012265:Ribonucleotides; C014205:triciribine phosphate