exploratory phase ii study of inc424 patients with primary myelofibrosis (pmf) or post polycythaemia myelofibrosis (ppv mf) or post essential thrombocythaemia myelofibrosis (pet-mf)

Conditions: Primary Myelofibrosis (PMF); Post Polycythaemia Myelofibrosis (PPV MF); Post Essential Thrombocythaemia Myelofibrosis (PET-MF)

Summary: 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).


Eligibility criteria:
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.

Keywords: ruxolitinib inc424 myelofibrosis pmf post polycythemia myelofibrosis ppv mf post-essential thrombocythemia myelofibrosis pet-mf primary myelofibrosis polycythemia thrombocythemia essential thrombocytosis myeloproliferative disorders bone marrow diseases haematologic diseases blood coagulation disorders blood platelet disorders haemorrhagic disorders