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

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. (January 2013) Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Ann Oncol, 24 (1). pp. 252-7. ISSN 1569-8041 (Electronic)0923-7534 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/22898035
DOI: 10.1093/annonc/mds275

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 duration was 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 micromol and the mean AUC was 2.9 micromol h. Cmax>1.5 micromol 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.

Item Type: Paper
Uncontrolled Keywords: Adenine/adverse effects/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use Adult Aged Aged, 80 and over Female Fluorodeoxyglucose F18 Gastrointestinal Stromal Tumors/*drug therapy/radionuclide imaging HSP90 Heat-Shock Proteins/*antagonists & inhibitors Humans Male Middle Aged Positron-Emission Tomography Pyridines/adverse effects/pharmacokinetics/pharmacology/*therapeutic use Treatment Outcome
Subjects: diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: January 2013
Date Deposited: 20 Oct 2016 16:35
Last Modified: 20 Oct 2016 16:35
PMCID: PMC4023320
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33749

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