Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors Journal Article
| Authors: | 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. |
| Article Title: | Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors |
| 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. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. |
| Keywords: | adult; clinical article; treatment response; aged; unclassified drug; constipation; fatigue; neutropenia; sorafenib; sunitinib; area under the curve; diarrhea; drug dose comparison; drug safety; drug withdrawal; hypertension; side effect; treatment duration; positron emission tomography; protein analysis; gastrointestinal stromal tumor; imatinib; enzyme inhibition; multiple cycle treatment; pharmacodynamics; phase 2 clinical trial; anemia; image analysis; leukopenia; nausea; antineoplastic activity; abdominal pain; dizziness; loading drug dose; chemotherapy induced emesis; heat shock protein 90 inhibitor; heat shock protein 90; open study; maximum plasma concentration; time to maximum plasma concentration; heat shock protein 70; drug absorption; drug blood level; retinol deficiency; nilotinib; drug substitution; fluorodeoxyglucose; pharmacokinetics; abdominal distension; abdominal disease; tumor necrosis; hsp90 inhibitors; biib 021; night blindness; phase ii trials; faintness; gastro-intestinal stromal tumors; sarcoma/soft-tissue malignancies; enzyme defect |
| Journal Title: | Annals of Oncology |
| Volume: | 24 |
| Issue: | 1 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2013-01-01 |
| Start Page: | 252 |
| End Page: | 257 |
| Language: | English |
| DOI: | 10.1093/annonc/mds275 |
| PROVIDER: | scopus |
| PUBMED: | 22898035 |
| PMCID: | PMC4023320 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 February 2013" - "Art. No.: mds275" - "CODEN: ANONE" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work