title: Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. ramanathanrk@upmc.edu
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: David
authors.initials: D
authors.lastname: Friedland
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Potter
authors.forename: Gurkamal
authors.initials: G
authors.lastname: Chatta
authors.forename: Eleanor G
authors.initials: EG
authors.lastname: Zuhowski
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Stoller
authors.forename: Cynthia
authors.initials: C
authors.lastname: Naret
authors.forename: Jianxia
authors.initials: J
authors.lastname: Guo
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001773:Blood Cells / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000097:blood / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin