Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors

M. A. Dickson, S. H. Okuno, M. L. Keohan, R. G. Maki, D. R. D'Adamo, T. J. Akhurst, C. R. Antonescu, G. K. Schwartz

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62 Scopus citations

Abstract

Background: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. Patients and methods: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021. Results: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response durationwas 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 μmol and the mean AUC was 2.9 μmol h.Cmax >1.5 μmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. Conclusions: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.

Original languageEnglish (US)
Article numbermds275
Pages (from-to)252-257
Number of pages6
JournalAnnals of Oncology
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Gastro-intestinal stromal tumors
  • HSP90 inhibitors
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase II trials
  • Sarcoma/soft-tissue malignancies

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Dickson, M. A., Okuno, S. H., Keohan, M. L., Maki, R. G., D'Adamo, D. R., Akhurst, T. J., Antonescu, C. R., & Schwartz, G. K. (2013). Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Annals of Oncology, 24(1), 252-257. [mds275]. https://doi.org/10.1093/annonc/mds275