Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis

Inclusion Criteria

• Subject has a confirmed diagnosis of myelofibrosis, including PMF, post-PV MF, and post-ET MF.
• Subject has been receiving ruxolitinib therapy for intermediate or high-risk myelofibrosis for >6 months prior to enrollment with no more than 1 dose reduction of ruxolitinib in the 2-8 weeks prior to enrollment and a stable daily dose ≥5 mg twice daily (BID) >2 months prior to enrollment.
• Subject has MF with evidence of persistent disease despite ruxolitinib monotherapy treatment, consisting of:
• Persistent or worsening disease-related symptoms, including but not limited to fatigue, pruritus, night sweats, early satiety, and other symptoms as determined by a MPN-SAF TSS score of >20 points; AND
• Documented splenomegaly of at least 5 cm below the costal margin as measured on inspiration by physical exam.
• Subject has an Eastern Cooperative Oncology Group performance status of 0-2.
• Acceptable pre-study organ function during screening defined as:
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Hemoglobin (hgb) ≥ 8.0 g/dL (may be supported with transfusion)
• Platelets (plt) ≥ 75,000/uL
• AST/SGOT and ALT/SGPT ≤2 x Upper Limit of Normal (ULN)
• Direct serum bilirubin ≤ 1.5 x ULN
• Creatinine clearance >50 mL/min/1.73 m2 based on Cockcroft Gault equation.

Exclusion Criteria

• Subject has known active liver disease, including viral hepatitis or cirrhosis.
• Subject has known or suspected HIV or other active infections requiring acute or chronic treatment with systemic antibiotics. Conditions requiring topical antibiotics are acceptable.
• Subject has a QTcF > 480 ms (corrected) in the screening or baseline ECG.
• Subject has left ventricular ejection fraction (LVEF) ≤ 50%, or below institution's lower limit of normal (whichever is lower) by echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
• Subject has a history (or family history) of long QT syndrome.
• Subject has coronary artery disease with an ischemic event within 6 months prior to enrollment.
• Subject has a permanent cardiac pacemaker.
• Subject has history of a second primary malignancy within the past 2 year except for the following (if appropriately treated and considered cured): stage I endometrial, surgically treated cervical or prostate carcinoma, and non-melanoma skin cancer.
• Subject has significant uncontrolled medical condition within 6 months prior to enrollment, as determined by the investigator.
• Subject has concurrent participation in any interventional studies within 14 days of first dose of study drug.
• Subject has uncontrolled diabetes mellitus, in the judgment of the Principal Investigator.
• Subject has an active ocular condition that in the opinion of the investigator may alter visual acuity during the course of the study (i.e., ocular inflammatory disease etc.) or a history or anticipation of major ocular surgery (including cataract extraction, intraocular surgery, etc.) during the study.