A Phase II Study of the 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
- 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:
- Absolute Neutrophil Count (ANC) ≥1.5x109/L
- Hemoglobin (Hgb) ≥ 8 g/dl (may be supported with transfusion)
- Platelets (plt) ≥75x10^9/L
- 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 ULN
- Serum bilirubin ≤ 1.5 x ULN
- 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.
- Requiring ongoing therapy with either G- or GM-CSF, or long-acting versions of these
- Active medical condition such as infection or cancer that is actively requiring
- 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
- 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
- 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