This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Each regimen will be assessed for safety, tolerability, pharmacokinetics (PK) and pharmacodynamic effects, and preliminary anti-myelofibrosis activity, including changes in spleen volume, JAK2V617F allele burden, and hematologic response.

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.