Open Label Ruxolitinib (INCB018424) in Patients With Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

Study Overview
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Brief Summary
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To determine the safety, tolerability and effectiveness of ruxolitinib (INCB018424), administered orally to patients with Primary Myelofibrosis (PMF), Post Polycythemia Vera Myelofibrosis (PPV-MF) and Essential Thrombocythemia Myelofibrosis (PET-MF).

Detailed Description
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This is a multicenter, open-label, non-randomized, dose escalation study of ruxolitinib, a small molecule Janus kinase (JAK) inhibitor, administered orally to patients with PMF, PPEV-MF or PET-MF. The study is comprised of 3 parts: Part 1: Dose escalation and determination of maximum tolerated dose (complete). Part 2: Exploration of alternative dosing schedules (complete). Part 3: Further evaluation of selected dose regimens, including additional response measures to explore effect of ruxolitinib on symptoms and other parameters including daily physical activity and long-term survival (ongoing).

Official Title
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A Phase 1/2, Open-Label Study of the JAK2 Inhibitor INCB018424 Administered Orally to Patients With Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Post-PV/ET)

Conditions
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Myelofibrosis, Polycythemia Vera, Thrombocytosis

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with PMF or Post-PV/ET MF Patients with myelofibrosis requiring therapy Adequate bone marrow reserve Exclusion Criteria: Received anti-cancer medications or investigational therapy in the past 14 days

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: Ruxolitinib<br>All participants received oral ruxolitinib. Patients began treatment with either 10 mg twice a day (bid), 15 mg bid, 25 mg bid, 50 mg bid, 25 mg once a day (qd), 50 mg qd, 100 mg qd, or 200 mg qd, depending on the time period when they entered the study. The doses were titrated based on efficacy and safety to a maximum of 25 mg bid for patients who entered the study after sufficient dosing information had been obtained to define the maximum dose for patients in the study. Patients could continue receiving treatment indefinitely if receiving benefit at a dose that continues to maintain benefit but does not exceed a maximum dose of 25 mg BID. | Drug: Ruxolitinib<br>* 5 and 25 mg tablets with a daily dosing range from 10 to 200 mg qd or bid.<br>* Other names: Jakafi(TM);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | Treatment-Emergent AEs are events occurring after first drug administration or worsened from baseline. Treatment-Related AEs are those with a definite, probable, possible or missing causality. A serious AE is a medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is a medical event requiring intervention to prevent 1 of the above. A severe or life-threatening AE is based on intensity, according to National Cancer Institute-Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) v3.0. | From Baseline to the interim clinical cut-off date (31 December 2009). The median time on study was 14.8 months, with a range of 26 days to 29.7 months. As of March 1, 2011 the total exposure to ruxolitinib was 269 patient-years. | 
| Percentage of Participants With Clinical Improvement (CI) Over Time | Clinical improvement was defined according to the International Working Group Myelofibrosis Research and Treatment criteria, and required 1 of the following: A ≥ 2 g/dL increase in Hemoglobin level or becoming transfusion independent; Either a ≥ 50% reduction in palpable splenomegaly if spleen was ≥ 10 cm at Baseline or a spleen palpable at > 5 cm at Baseline becomes not palpable; A ≥ 100% increase in platelet count and an absolute platelet count of ≥ 50,000 x 10^9/L or A ≥ 100% increase in absolute neutrophil count (ANC) and an ANC of ≥ 0.5 x 10^9/L. | Week 12, 24, 36, 48 and 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Spleen Palpation Length Over Time | For each visit, patients who had a missing value at the visit, dropped out of the study due to any reasons prior to the visit or had non-palpable spleen at baseline and then became palpable at the time of the visit were all considered as having not achieved the ≥ 50% reduction in spleen palpation length. | Baseline and Weeks 4, 8, 12, 24, 36, 48 and 60 | 
| Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume Over Time | Spleen volume was assessed in a subgroup of 27 patients using magnetic resonance imaging (MRI) scans (or computed tomography (CT) scans in patients who were not candidates for MRI) of the abdomen in order to allow objective measurement of spleen volume using standard estimation techniques. For each visit, patients who had a missing value at the visit or dropped out of the study due to any reason prior to the visit were considered as not having achieved the ≥35% reduction in spleen volume. | Baseline, Weeks 4, 12, 24 and 48 | 
| Change From Baseline in Myelofibrosis Total Symptom Score at Week 24 | Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF). Abdominal discomfort, itching, muscle or bone pain, and night sweats are prominent and troubling symptoms in patients with MF. Therefore, the MFSAF-derived responses for these symptoms were analyzed as a total symptom score. Each symptom was assessed on a scale from 0 (absent), 1 (most favorable) to 10 (worst). The total symptom score is a sum of the individual scores and ranges from 0-40. A higher score indicates worse symptoms hence a negative change from baseline indicates improvement. | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Health-Related Quality of Life | Health-related Quality of Life was assessed using the Global Health Status/Quality of Life Scale of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). This scale ranges from 0 to 100, with higher scores indicating higher quality of life. | Baseline and Week 24 | 
| Change From Baseline in Body Weight Over Time |  | Baseline and Weeks 4, 8, 12, 24, 36, 48 and 60. | 
| Change From Baseline to Week 24 in Eastern Cooperative Oncology Group (ECOG) Performance Status | The ECOG performance status measures patients' functional status on the following scale: 0=Fully active, no restrictions; 1=Restricted in physically strenuous activity but ambulatory, able to carry out light work; 2=Ambulatory and capable of all selfcare, unable to carry out any work activities; Up and about > 50% of waking hours; 3=Limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Totally confined to bed or chair; 5=Dead. Data reported indicate the number of participants with a change from Baseline score of -2, -1, 0 and 1. | Baseline and Week 24 |