Phase I clinical and pharmacokinetic study of LY 195448.
LY 195448 is a phenethanolamine that has shown anti-tumour activity in a range of murine tumour models, although its mechanism of action is unknown. Pre-clinical studies have indicated the absence of "standard" side effects such as myelosuppression and gastrointestinal toxicity. The present phase I trial was carried out in nine patients at doses ranging up to 133 mg/m2. The major toxicities up to that dose were mild, reversible hypotension, tachycardia and tremor. No haematological or biochemical toxicity was observed. Murine pharmacokinetics were assessed at a dose level that was effective in experimental tumours and compared with human pharmacokinetic parameters derived from this study. The results indicated the clinical possibility of reaching peak drug levels associated with experimental activity. However, no responses were seen at the doses used. This study was terminated prior to its completion due to an unexplained loss of activity against murine tumours since September 1987. No significant loss of the in vitro anti-mitotic activity originally reported by Boder et al. [3] was observed. Possible reasons for the apparent loss of in vivo activity have been intensively investigated, but no cause has been determined. Therefore, clinical trials with LY 195448 have been discontinued.
Cassidy
J
J
CRC Department of Medical Oncology, University of Glasgow, U.K.
Lewis
C
C
Adams
L
L
Setanoians
A
A
Bayssas
M
M
Boder
G G
GG
Rankin
E M
EM
Kaye
S B
SB
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy; D004341:Drug Evaluation; D004983:Ethanolamines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D012004:Rectal Neoplasms / Q000188:drug therapy; D013610:Tachycardia / Q000139:chemically induced; D014202:Tremor / Q000139:chemically induced
D000970:Antineoplastic Agents; D001549:Benzamides; D004983:Ethanolamines; C060459:4-(3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl)benzamide