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


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 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.
Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. dicksonm@mskcc.org
M A
MA
Dickson
S H
SH
Okuno
M L
ML
Keohan
R G
RG
Maki
D R
DR
D'Adamo
T J
TJ
Akhurst
C R
CR
Antonescu
G K
GK
Schwartz
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D019788:Fluorodeoxyglucose F18; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; D018841:HSP90 Heat-Shock Proteins; D011725:Pyridines; D019788:Fluorodeoxyglucose F18; D000225:Adenine