title: A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers.
abstract: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer.
  
  
  
  Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated.
  
  
  
  Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response.
  
  
  
  Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway.
  
  
  
  NCT00487786.
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, Vancouver; Department of Urologic Sciences, Vancouver Prostate Center, University of British Columbia, Vancouver, Canada. Electronic address: kchi@bccancer.bc.ca.
authors.forename: K N
authors.initials: KN
authors.lastname: Chi
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle.
authors.forename: E Y
authors.initials: EY
authors.lastname: Yu
authors.affiliation: Clinical Development, OncoGenex Pharmaceuticals, Inc., Bothell, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jacobs
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Center, University of British Columbia, Vancouver, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Bazov
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, Vancouver.
authors.forename: C
authors.initials: C
authors.lastname: Kollmannsberger
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle.
authors.forename: C S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Department of Medical Oncology, Juravinski Cancer Centre, Hamilton, Canada.
authors.forename: S D
authors.initials: SD
authors.lastname: Mukherjee
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Center, University of British Columbia, Vancouver, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Clinical Development, OncoGenex Pharmaceuticals, Inc., Bothell, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Stewart
authors.affiliation: Department of Medical Oncology, Juravinski Cancer Centre, Hamilton, Canada.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hotte
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003975:Diazepam / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D003975:Diazepam
keywords: OGX-427; antisense oligonucleotide; apatorsen; heat shock protein 27; phase I clinical trial; solid tumors