Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors
2012; Elsevier BV; Volume: 24; Issue: 1 Linguagem: Inglês
10.1093/annonc/mds275
ISSN1569-8041
AutoresMark A. Dickson, Scott H. Okuno, Mary Louise Keohan, Robert G. Maki, David R. D’Adamo, Timothy Akhurst, Cristina R. Antonescu, Gary K. Schwartz,
Tópico(s)Colorectal Cancer Treatments and Studies
ResumoBackgroundHSP90 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 methodsThe 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: 12pts received 600mg twice a week (BIW) and 11 patients received 400mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021.ResultsThe 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 600mg 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 1.5µmol and the mean AUC was 2.9µmolh. Cmax >1.5µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment.ConclusionsThis 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.
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