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)
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: | https://repository.cshl.edu/id/eprint/33749 |
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