A B S T R A C T PurposeTo define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG). Methods17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in preand post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n ϭ 7). ResultsFifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m 2 and 25 mg/m 2 , respectively. Grade 3/4 toxicities included liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) and thrombocytopenia (4%). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 Ϯ 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL ϫ h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5% (n ϭ 14), 124% (n ϭ 20), and 99.5% (n ϭ 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy. ConclusionThe recommended phase II doses of 17DMAG (16 mg/m 2 ϫ 5 days or 25 mg/m 2 ϫ 3 days, every 3 weeks) are well tolerated and suitable for further evaluation. Oncol 28:1520Oncol 28: -1526 J Clin

Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase IIdose of17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week. Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly  3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 Heat shock protein (HSP) 90 constitutes 1% to 2% of all cytosolic proteins, and its primary function is to chaperone multiple client proteins involved in cell signaling, proliferation, and survival (1, 2). HSP90 plays an important role in mediating conformational folding and activation of oncoproteins, such as mutant p53, HER-2/neu, Raf-1, and Bcr-Abl (1 -4). Geldanamycin and its analogues bind to HSP90 and prevent its chaperone function (5). The first geldamycin analogue to enter clinical trials is 17-(allylamino)-17-demethoxygeldanamycin (17AAG; refs. 6 -10). Previous phase I studies of 17AAG in adults have evaluated weekly, daily Â3 schedule, or daily Â5 schedule (Table 1; refs. 6 -10).The recommended phase 2 dose of 17AAG is 295 to 308 mg/m 2 when administered weekly Â3, every 4 weeks (7,8), and 450 mg/m 2 when administered weekly on a continuous schedule (6). In contrast, administration of 17AAG daily Â5 or daily Â3 is associated with doselimiting toxicity (DLT) at substantially lower doses, and the DLT, which was primarily reversible hepatitis (9, 10), reflected preclinical animal toxicology studies (11).17AAG is metabolized primarily by CYP3A, with the major metabolite, 17-(amino)-17-demethoxygeldanamycin, being equipotent to 17AAG in its ability to affect . The pharmacokinetics of 17AAG in humans is now well characterized. 17AAG and 17-(amino)-17-demethoxygeldanamycin are excreted primary through the liver and biliary system, and urinary excretion accounts for <10% of a dose. (6 -10, 15, 16).Biomarkers that may be affected by 17AAG therapy have been evaluated in clinical trials (6 -10). HSP90 has not shown a consistent increase or decrease in response to 17AAG therapy. However, several animal and human studies have shown HSP70 increases resulting from 17AAG-HSP90 interaction. (6 -13).

Dual EGFR inhibition with cetuximab and gefitinib is feasible; the combination can be safely administered and may have modest activity in advanced/metastatic NSCLC. Cetuximab 250 mg/m(2) weekly IV and gefitinib 250 mg/d PO is the recommended phase II dose, although the potential for late-onset hypomagnesemia warrants close monitoring of patients receiving this combined dosage.