Phase I study of TCNU, a novel nitrosourea.
TCNU is a chloroethyl nitrosourea based on the endogenous amino acid taurine. This paper reports its first evaluation in man. Eighty-four patients with refractory cancer received 12 dose escalations from 10-150 mg/m2 TCNU administered orally every 6 weeks. Clinical side-effects were predominantly gastro-intestinal but dose-limiting toxicity was thrombocytopenia. Pharmacokinetic monitoring with an HPLC assay sensitive to the nanogram range demonstrated unchanged TCNU in plasma for up to 8 h following administration. The mean half-life was 60 min. Clinical responses were seen in melanoma (four patients), lung cancer (two squamous, one small cell) and one patient each with renal and stomach cancer. These responses, together with the unusual pharmacokinetic profile of TCNU, warrant exploration in disease-orientated phase II studies at a recommended dose of 130 mg/m2 p.o. q 5 weeks.
Smyth
J F
JF
University Department of Clinical Oncology, Western General Hospital, Edinburgh, U.K.
Macpherson
J S
JS
Warrington
P S
PS
Kerr
M E
ME
Whelan
J M
JM
Cornbleet
M A
MA
Leonard
R C
RC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013654:Taurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D013654:Taurine; C052991:1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea