Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors.
OBJECTIVE
To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks.


METHODS
Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m(2)) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells.


RESULTS
Toxicity was acceptable at doses up to 28 mg/m(2). The cohort was expanded to three patients at 40 mg/m(2) because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m(2) had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m(2); none had dose-limiting toxicity. The maximum plasma concentrations (C(max)) of 17-AAG at 40 and 56 mg/m(2) were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours.ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with >/= 14 mg/m(2) and decreased protein content of either Lck or Raf1 with >/= 28 mg/m(2) of 17-AAG.


CONCLUSIONS
17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.
Grem
Jean L
JL
Nebraska Medical Center, Omaha, NE 68198-7680, USA. jgrem@unmc.edu
Morrison
Geraldine
G
Guo
Xiao-Du
XD
Agnew
Elizabeth
E
Takimoto
Chris H
CH
Thomas
Rebecca
R
Szabo
Eva
E
Grochow
Louise
L
Grollman
Frank
F
Hamilton
J Michael
JM
Neckers
Len
L
Wilson
Richard H
RH
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016227:Benzoquinones; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017828:Rifabutin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin