title: A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors.
abstract: OBJECTIVE
  To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.
  
  
  METHODS
  Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m(2). 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m(2) in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.
  
  
  RESULTS
  Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m(2)-17-AAG 650 mg/m(2) due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.
  
  
  CONCLUSIONS
  The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m(2) and 17-AAG 500 mg/m(2).
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors: Gopa
authors: G
authors: Iyer
authors: Michael J
authors: MJ
authors: Morris
authors: Dana
authors: D
authors: Rathkopf
authors: Susan F
authors: SF
authors: Slovin
authors: Macaulay
authors: M
authors: Steers
authors: Steven M
authors: SM
authors: Larson
authors: Lawrence H
authors: LH
authors: Schwartz
authors: Tracy
authors: T
authors: Curley
authors: Anthony
authors: A
authors: DeLaCruz
authors: Qing
authors: Q
authors: Ye
authors: Glenn
authors: G
authors: Heller
authors: Merrill J
authors: MJ
authors: Egorin
authors: S Percy
authors: SP
authors: Ivy
authors: Neal
authors: N
authors: Rosen
authors: Howard I
authors: HI
authors: Scher
authors: David B
authors: DB
authors: Solit
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D043823:Taxoids; D000077143:Docetaxel; C112765:tanespimycin