HSP90 Inhibitor, AUY922, in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), and Refractory PV/ET

Recruitment & Eligibility

Inclusion Criteria

Eligible patients must have myeloproliferative neoplasms, specifically, primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), and PV/ET that are refractory to hydroxyurea, phlebotomy and anagrelide or not a candidate for standard therapies.
≥ 18 years of age
ECOG performance status of 0-2
Acceptable pre-study organ function during screening as defined as:

Hematologic:

Biochemistry:

Potassium within normal limits
Total calcium (corrected for serum albumin) and phosphorus within normal limits
Magnesium above LLN or correctable with supplements Liver and Kidney Functions
AST/SGOT and ALT/SGPT ≤ 1.5 x Upper Limit of Normal (ULN) if AP > 2.5 X ULN
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5
Serum bilirubin ≤ 1.5 x ULN (Unless attributable to Gilbert's disease)
Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 ml/min
Negative serum pregnancy test. The serum pregnancy test must be obtained prior to the first administration of AUY922 (≤ 72 hours prior to dosing) in all pre-menopausal women and women <2 years after the onset of menopause
Patients who previously received JAK2 inhibitors will be eligible as long as they have been off the drug for more than 4 weeks.
Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria

Requiring ongoing therapy with either G- or GM-CSF, or long-acting versions of these molecules
Active medical condition such as infection or cancer that is actively requiring treatment.
Unresolved diarrhea ≥ CTCAE (v4.02) grade 1
Prior anti-neoplastic treatment with any HSP90 or HDAC inhibitor compound
Patients who have undergone any major surgery ≤ 2 weeks prior to starting study drug or have not recovered from the side effects of such therapy.
Patient must be ≥ 4 weeks since last chemotherapy or treatment with another systemic anticancer agent with the exception of hydroxyurea. Hydroxyurea must be discontinued at least 48 hours prior to the initiation of AUY922. Patients must have recovered (CTC ≤ 1) from acute toxicities of any previous therapy (with the exception of alopecia).
Active anticoagulation with warfarin.
Pregnant or lactating women
Fertile women of childbearing potential (WCBP) not using double-barrier methods of contraception (abstinence, oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile). Male patients whose partners are WCBP not using double-barrier methods of contraception.

Impaired cardiac function, including any one of the following:

History (or family history) of long QT syndrome
Mean QTc ≥ 450 msec on baseline ECG
History of clinically manifested ischemic heart disease (including myocardial infarction, stable or unstable angina pectoris, coronary arteriography or cardiac stress testing/imaging with findings consistent with infarction or clinically significant coronary occlusion) ≤ 6 months prior to study start
History of heart failure or 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 (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or 3rd degree AV block.

History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes

Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
Clinically significant resting bradycardia (< 50 beats per minute)
Patients who are 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 or discontinued to an alternative drug prior to commencing AUY922.
Obligate use of a cardiac pacemaker

Study & Design

Arm && Interventions

Group	Intervention	Description
AUY922	AUY922	This is an open-label phase II trial to assess the efficacy of the HSP90 inhibitor, AUY922, in patients with PMF, post-PV MF, post-ET MF, and with PV/ET who are refractory to hydroxyurea, phlebotomy or anagrelide.

Primary Outcome Measures

Name	Time	Method
Overall Objective Response	6 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

Name	Time	Method

Recruitment & Eligibility