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

Study Overview
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Brief Summary
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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).

Official Title
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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)

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

Intervention / Treatment
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* Drug: INC424


Participation Criteria
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Eligibility Criteria
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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: Age > 65 years; Presence of constitutional symptoms (weight loss, fever, night sweats); marked anemia (Hgb < 10g/dL)*; Leukocytosis (history of WBC > 25 x109/L); 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: Absolute neutrophil count (ANC) that is ≤ 1000/µL. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INC424<br>Patients diagnosed with PMF, PPV MF, or PET-MF were treated with oral INC424 at a dose of 15 - 20 mg (dose based on Baseline platelet count) twice daily. | Drug: INC424<br>* Ruxolitinib was provided in 5 mg tablets, packaged in bottles. 15 - 20 mg (dose based on Baseline platelet count) twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment Success | Treatment success was defined as a 50% or greater reduction in palpable spleen length versus baseline at 48 weeks and/or a 50% or greater improvement in total symptom score (derived from the MF symptom assessment form (MFSAF) questionnaire) versus baseline at the week 48 time point. The MFSAF assesses the following symptoms (all scored from absent (0) to worst imaginable (10)): general fatigue, abdominal pain (and discomfort), inactivity (ability to move and walk around), cough, night sweats, itching (pruritus), bone pain (diffuse not joint pain or arthritis), fever, change in appetite/unintentional weight loss (or gain) in past 6 months, overall quality of life (QoL). | 48 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Best Overall Response | Response to treatment and disease progression was assessed by physical examination, specifically assessing changes in spleen size by palpation. Disease response and progression was evaluated using the International Working Group for myelofibrosis Research and Treatment Response Criteria. | week 48 | 
| Change From Baseline in Myelofibrosis Symptoms Assessment Form (MF-SAF) | The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions are scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6, which together comprise a Total Symptom Score (TSS), investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asks patients to report levels of inactivity. The TSS reflects the sum of the scores of these symptoms excluding inactivity, with the maximum possible score being 60 (most severe symptom experienced). | Baseline, week 4, week 12, week 24, week 48 | 
| Change From Baseline in EQ5D Preference Index (5 Level EuroQol Questionnaire Determining Quality of Life) From Baseline | The EQ-5D is a standardized instrument used for measuring health outcomes in a wide range of health conditions and treatment. It consists of a descriptive system and a visual analogue scale (EQ-VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The EQ-VAS records the participant's self-rated health on a vertical, VAS where the endpoints are labeled 'best imaginable health state' and 'worst imaginable health state'. The EQ-5D health state was converted to a single summary index by applying a formula that attaches a weight to each of the levels in each dimension. The final EQ5D preference index scores range from 0 to 1 with higher scores indicating better health. | Baseline, week 4, week 12, week 24, week 48 | 
| Number of Hospitalizations | Medical resource utilization (MRU) was assessed according to the number of hospitalizations. | week 12, week 24, week 26, week 48 | 
| Duration of Hospitalizations | MRU was assessed according to the mean duration of hospitalization visits. | week 48 | 
| Number of Accident & Emergency Visits From Baseline | MRU was assessed according to the number of accidents and emergency room visits. | baseline to week 12, week 12 to week 24, week 24 to week 36, week 36 to week 48 | 
| Number of General Practitioner (GP), Specialists' and Urgent Care Visits | MRU was assessed according to the number of GP, specialists', and urgent care visits. | baseline to week 12, week 12 to, week 24, week 24 to week 36, week 36 to week 48 | 
| Percentage of Participants With Transfusion Dependency Status | Transfusion dependency status from baseline through the end of study was assessed. New onset of transfusion dependency was defined as the use of 2 or more units of red blood cell products during the 8 weeks prior to a study visit. New onset of transfusion independency was defined as the use of 0 or 1 unit of red blood cell products during the 8 weeks prior to a study visit. | baseline (BL), end of treatment (up to 28 days post last treatment) (EOT) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PMF, Ruxolitinib, INC424, myelofibrosis, 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