Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)

A UK Open-label, Multicentre, Exploratory Phase II Study of INC424 for Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)

The primary objective of this study is to evaluate the efficacy of INC424 in patients with PMF, PPV MF, or PET-MF using a composite measure of either an objective endpoint (> 50% reduction in splenomegaly using palpitation at 48 weeks) and/or a subjective endpoint (>50% reduction in total symptom score at 48 weeks).

Inclusion Criteria:

• Patients must not be eligible for another ongoing INC424 clinical trial.

• Patients must be diagnosed with PMF, PPV MF or PET-MF, according to the 2008 revised World Health Organization criteria irrespective of JAK2 mutation status.

• Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 (1 prognostic factor, no more) with an enlarged spleen. The prognostic factors, defined by the International Working Group are:

  1. Age > 65 years;
  2. Presence of constitutional symptoms (weight loss, fever, night sweats); marked anemia (Hgb < 10g/dL)*;
  3. Leukocytosis (history of WBC > 25 x109/L);
  4. Circulating blasts > 1%. • A hemoglobin value < 10 g/dL must be demonstrated during the Screening Visit for patients who are not transfusion dependent. Patients receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of evaluation of risk factors.

• Patients with Intermediate-1 disease and splenomegaly must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.

• Patients must have a peripheral blood blast count of < 10%.

• Patients with adequate liver function defined as direct bilirubin ≤ 2.0 x ULN and ALT ≤ 2.5 x ULN.

• Patients with adequate renal function defined as serum creatinine ≤ 2 x ULN.

• Patients with an ECOG performance status of 0, 1, or 2 (Appendix 5).

Exclusion criteria:

• Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).

• Patients with history of malignancy in past 3 years except for treated, early-stage squamous or basal cell carcinoma in situ.

• Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e., erythropoietin [Epo], granulocyte colony stimulating factor (GCSF [Neupogen; Neulasta], romiplostim, eltrombopag) at any time within 2 weeks prior to Screening or 4 weeks prior to Baseline.

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).

• Patients with cardiac disease which in the Investigator's opinion may jeopardize the safety of the patient or the compliance with the protocol.

• Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.

• Patients with known active hepatitis A, B, C or who are HIV-positive.

• Patients with inadequate bone marrow reserve as demonstrated by:

  1. Absolute neutrophil count (ANC) that is ≤ 1000/µL.
  2. Platelet count that is < 100,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.

• Patients with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.

• Patients with coagulation parameters (PT, PTT, INR) ≥ 1.5.

• Patients with known hypersensitivity to INC424 or other JAK1/2 inhibitors, or to their excipients.

• Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days of screening.

• Patients with any concurrent condition that, in the Investigator's opinion would jeopardize the safety of the patient or compliance with the protocol.

Other protocol-defined inclusion/exclusion criteria may apply.