title: Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors.
abstract: OBJECTIVE
  Heat shot protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell-cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity.
  
  
  METHODS
  Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3+3 design). Response was evaluated after two cycles.
  
  
  RESULTS
  Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n=1) and fatigue (n=1). Common toxicities at least possibly related to drug were grades 1 to 2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%), and abnormal dreams (17%). The concentration-time curves for day 1 and day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses showed significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human EGF receptor-2 extracellular domain in all patients who received BIIB028 at dose levels of 48 mg/m2 or more. Stable disease for at least eight cycles (24 weeks) was achieved in 5 (12%) patients (for durations of 6, 6, 8, 12.5, and 19 months).
  
  
  CONCLUSIONS
  BIIB028 is a well-tolerated molecule that showed target impact and was associated with prolonged stable disease in two patients.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. dshong@mdanderson.org
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Rabih
authors.initials: R
authors.lastname: Said
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder
authors.forename: Apostolia-Maria
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Gerald
authors.initials: G
authors.lastname: Galluppi
authors.forename: Naveen
authors.initials: N
authors.lastname: Dakappagari
authors.forename: Chris
authors.initials: C
authors.lastname: Storgard
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010755:Organophosphates / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D010755:Organophosphates; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human