A Phase Ib Study of Ruxolitinib in Combination With PU-H71 for the Treatment of Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV MF), and Post-EssentialThrombocythemia MF (Post-ET MF)
This is a multicenter 2-part, Phase 1b study designed to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PU-H71 in subjects taking concomitant ruxolitinib. The first part (Dose Escalation) will employ a standard 3+3 dose escalation design to determine Maximum Tolerated Dose (MTD). The second part of the study (Dose Confirmation) will confirm the recommended Phase 2 dose (RP2D) in an expanded population.
• 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.