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

• response rate (RR) in patients by repeat scans [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Confirmation of response by repeat scans Every 6 wks (Cycles 1-4) then every 9 wks.
• Overall survival (OS) of patients will be analyzed using Kaplan-Meier methods. [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Determine the Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  The analyses of safety will be based on the frequency of Adverse Events (AEs) and their severity for patients who received at least one dose of study treatment. Worst toxicity grades per patient will be tabulated for select AEs and laboratory measurements by using NCI CTCAE criteria v4.0.

This is a multicenter, non-randomized, single agent, Phase II study of AUY922 in patients with refractory Gastrointestinal Stromal Tumor (GIST). The primary endpoint of this study is to determine progression-free survival (PFS) for patients with GIST receiving AUY922 intravenously (IV) on Days 1, 8, and 15 of a 21-day treatment cycle with restaging at 6 and 12 weeks and then every 9 weeks thereafter. Patients may continue treatment until evidence of disease progression.

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 PR rate was 3% and 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 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.