PIM447: This phase I trial is evaluating the investigational agent, PIM447, in combination with ruxolitinib (a targetted therapy) and LEE011 (an oral drug) for the treatment of MyelofibrosisA Phase Ib, Multi-center, Open-label, Dose-escalation Study of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 Administered Orally in Patients With Myelofibrosis

Exclusion

• 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.