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Clin Cancer Res. 2005 May 1;11(9):3385-91.
Phase I pharmacokinetic pharmacodynamic study of 17AAG, a novel
inhibitor of heat shock protein 90, in patients with refractory advanced
cancers.
Ramanathan RK, Trump DL, Eiseman JL, Belani CP, Agarwala SS, Zuhowski EG, Lan
J, Potter DM, Ivy SP, Ramalingam S, Brufsky AM, Wong MK, Tutchko S, Egorin MJ.
PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone
antibiotic, down-regulates oncoproteins by binding specifically to heat shock
protein 90 (HSP90). We did a phase I study of 17AAG to establish the
dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG
pharmacokinetics and pharmacodynamics. EXPERIMENTAL DESIGN: Escalating doses of
17AAG were given i.v. over 1 or 2 hours on a weekly x 3 schedule every 4 weeks
to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and
17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance
liquid chromatography. Expression of HSP70 and HSP90 in peripheral
blood mononuclear cells was measured by Western blot. RESULTS: Forty-five
patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum
tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients
(grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common
drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea,
nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5%
of patients. Hematologic toxicity was minimal. No objective responses were
observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area
under the curve of 17AG, the active major metabolite of 17AAG, increased with
17AAG dose, but the relationships were more variable than with 17AAG.
17AAG and 17AG in plasma were >90% protein bound. There were no consistent
changes in peripheral blood mononuclear cell HSP90 or HSP70 content.
CONCLUSIONS: 17AAG doses between 10 and 295 mg/m2 are well tolerated.
17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and
HSP70 are uninformative pharmacodynamic markers. The dose recommended for future
studies is 295 mg/m2 weekly x 3, repeated every 4 weeks.
PMID: 15867239
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