Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
• Patient must be diagnosed with JAK2V617F-positive primary or secondary MF.
• Dose-escalation and Expansion parts: Patients with a < 35% reduction in spleen volume by MRI/CT or < 50% reduction in spleen size by physical exam, with or without corresponding symptomatic improvement, after at least 6 months of treatment with single agent ruxolitinib at an optimal dose level in line with the label recommendations. Expansion parts only: Ruxolitinib-naive patients and patients who have been previously treated with single agent ruxolitinib and are relapsed and/or refractory.
• Patients must have splenomegaly measuring at least 5 cm by MRI at baseline.
• Have adequate bone marrow function:

• Platelets ≥ 100,000 mm3 without the assistance of growth factors or platelet transfusions
• Absolute Neutrophil Count (ANC) ≥ 1500/mm3 without growth factor support within 7 days prior to testing
• Hemoglobin ≥ 9 g/dL.

Exclusion criteria

• Systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
• Major surgery within 2 weeks before the first dose of either study drug.
• Patients who have had splenic irradiation within 2 weeks prior to Screening or prior splenectomy.
• Patients with AML, MDS, or peripheral blasts ≥ 10 %
• Prior autologous or allogeneic stem cell transplant at any time.
• Patients who are currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment:

• substrates of CYP3A4/5, CYP2B6 or CYP2D6 that have a narrow therapeutic window
• strong inhibitors of CYP3A4/5 or CYP2D6
• potent inducers of CYP3A4/5 or CYP2D6
• Serum total bilirubin > 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome who are excluded if the total bilirubin is > 3.0 x ULN or direct bilirubin > 1.5 x ULN, or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (SGPT) > 3 x ULN, except in patients with MF involvement of the liver who are excluded if AST or ALT > 5 x ULN.
• Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 60 ml/min according to Cockcroft-Gault equation
• Electrolyte abnormalities CTCAE grade ≥ 2 (e.g. serum potassium, magnesium and calcium) unless they can be repleted during screening and are deemed not clinically significant by the Investigator.