PURPOSE: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(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 x 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m(2) and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m(2). Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins. RESULTS: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m(2), DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m(2) developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2. CONCLUSIONS: The recommended phase II doses of 17AAG are 175 to 200 mg/m(2) when given twice a week and consistently cause elevations in PBMC HSP70.
PURPOSE: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(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 x 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m(2) and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m(2). Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins. RESULTS: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m(2), DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m(2) developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2. CONCLUSIONS: The recommended phase II doses of 17AAG are 175 to 200 mg/m(2) when given twice a week and consistently cause elevations in PBMC HSP70.
Authors: Mark P S Dunphy; Christina Pressl; Nagavarakishore Pillarsetty; Milan Grkovski; Shanu Modi; Komal Jhaveri; Larry Norton; Bradley J Beattie; Pat B Zanzonico; Danuta Zatorska; Tony Taldone; Stefan O Ochiana; Mohammad M Uddin; Eva M Burnazi; Serge K Lyashchenko; Clifford A Hudis; Jacqueline Bromberg; Heiko M Schöder; Josef J Fox; Hanwen Zhang; Gabriela Chiosis; Jason S Lewis; Steven M Larson Journal: Clin Cancer Res Date: 2020-05-04 Impact factor: 12.531
Authors: Joleen Hubbard; Charles Erlichman; David O Toft; Rui Qin; Bridget A Stensgard; Sara Felten; Cynthia Ten Eyck; Gretchen Batzel; S Percy Ivy; Paul Haluska Journal: Invest New Drugs Date: 2010-01-15 Impact factor: 3.850