Study of Hsp90 Inhibitor AUY922 for the Treatment of Patients With Refractory Gastrointestinal Stromal Tumor

Preclinical data have shown that Hsp90 inhibition can lead to decrease in tumor growth of
GIST tumors that are both imatinib-sensitive and imatinib-resistant (Bauer 2006). A recently
reported phase I trial evaluated Hsp90 inhibitor IPI-504 for the treatment of patients with
GIST refractory to tyrosine kinase inhibitors (Wagner 2008). In this study, 100% of patients
had been previously exposed to imatinib and 93% to sunitinib. For 36 patients treated on
this trial, the partial response (PR) rate was 3% and stable disease (SD) was 67%, with a
median PFS of 12 weeks. This is significantly improved over a placebo median PFS of 6 weeks
for patients treated with sunitinib versus placebo who were refractory for imatinib (Demetri
2006).

Inclusion Criteria:

1. Pts with histologically-confirmed metastatic or unresectable GIST who have progressed
on, are intolerant of, or are not a candidate for imatinib and sunitinib therapy. Pts
must not have received prior treatment with Hsp90 inhibitors.

2. Must have an ECOG Performance Status of 0-1.

3. Must have a life expectancy of ≥3 mos.

4. Must have at least one unidimensional measurable lesion definable by MRI or CT scan.
Disease must be measurable per RECIST v1.1.

5. Must have normal serum phosphorus and magnesium ≥ the lower limit of normal prior to
trial entry.

6. Normal bone marrow function defined as: ANC ≥1500/μL Hgb ≥9 g/dL Plt ≥100,000/L

7. Adequate hepatic function defined as: AST or ALT and ALP must be 2.5 x ULN, or ≤5 x
ULN in pts with liver mets Total bilirubin ≤1.5 x the institutional ULN

8. Renal function defined as: Serum creatinine ≤1.5 x ULN or 24-hour CrCl 50 mL/min

9. Women of childbearing potential (WOCP) must have a negative serum or urine pregnancy
test performed ≤7 days prior to start of treatment.

10. Must be accessible for treatment and follow-up.

11. Must be able to understand the investigational nature of this study and give written
informed consent prior to study entry

Exclusion Criteria:

1. Currently receiving or have received cancer therapies ≤21 days of initiating study
therapy. For pts receiving small molecule targeted therapy, study treatment may begin
≥21 days after last dose or ≥5 half lives of previous treatment, whichever is
shorter. The patient must have recovered from or come to a new chronic stable
baseline from all treatment-related toxicities.

2. Use of any non-approved or investigational agent ≤30 days of administration of the
first dose of study drug. Pts may not receive any other investigational or
anti-cancer treatments while participating in this study.

3. Uncontrolled brain mets. Pts with treated brain mets (resection or radiotherapy) are
eligible if brain mets have responded to treatment as documented by CT or MRI scan
obtained at ≥2 wks after completion of RT, neurologic symptoms are absent, and
steroids have been discontinued.

4. Treatment with therapeutic doses of coumadin-type anticoagulants (maximum daily dose
of 1 mg allowed for port line patency permitted).

5. Impaired cardiac function with any one of the following: History (or family history)
of prolong QT syndrome. Mean QTc ≥450 msec on baseline ECG. History of clinically
manifested IHD ≤6 mos prior to study start. History of heart failure or any history
of left ventricular (LV) dysfunction (LVEF ≤45%) by MUGA or ECHO. Clinically
significant ECG abnormalities including 1 or more of the following: left bundle
branch block, right bundle branch block with left anterior hemiblock. ST segment
elevation or depression >1 mm, or 2nd (Mobitz II) or 3rd degree AV block. History or
presence of A-Fib, atrial flutter or ventricular arrhythmias including ventricular
tachycardia or Torsades de Pointes. Other clinically significant heart disease.
Clinically significant resting bradycardia (<50 beats per minute). Currently
receiving treatment with any medication which has a relative risk of prolonging the
QTcF interval or inducing Torsades de Pointes and cannot be switched to an
alternative drug or discontinued prior to commencing AUY922. Obligate use of a
cardiac pacemaker.

6. Known diagnosis of HIV, Hep C virus, or acute or chronic Hep B infection.

7. Concurrent severe, intercurrent illness including, but not limited to, ongoing or
active infection, or psychiatric illness/social situations that would limit
compliance with study requirements.

8. Women who are pregnant or lactating.

9. Any condition that would prevent patient comprehension of the nature of, and risk
associated with, the study, and the inability to comply with study and/or follow-up
procedures.

10. Other malignancies ≤3 years, with the exception of adequately treated basal or
squamous cell carcinomas of the skin, carcinoma in situ of the cervix, or localized
prostate cancer with a current PSA of <1.0 mg/dL on 2 successive evaluations, at
least 3 mos apart, with the most recent evaluation no more than 4 wks prior to entry.