Ruxolitinib (INCB018424) in Participants With Primary Myelofibrosis (PMF), Post Essential Thrombocythemia-myelofibrosis and Post Polycythemia Vera-myelofibrosis (PPV-MF)

Study Overview
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Brief Summary
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To evaluate the effects of treatment with ruxolitinib (INCB018424) on spleen volume, symptoms and potential side effects in participants with PMF, PPV-MF and PET-MF who have platelet counts of 50 x 10^9/L to 100 x 10^9/L. It is anticipated that individualized dose optimization from the starting ruxolitinib level of 5 mg bid will be associated with reductions in splenomegaly, MF-associated symptoms and inflammatory cytokine levels.

Official Title
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An Open-Label Assessment of Safety and Efficacy of Ruxolitinib (INCB018424) in Subjects With Primary Myelofibrosis, Post- Essential Thrombocythemia Myelofibrosis, and Post-Polycythemia Vera Myelofibrosis Who Have Platelet Counts of 50 × 10^9/L to 100 × 10^9/L

Conditions
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MPN (Myeloproliferative Neoplasms)

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, PPV-MF or PET-MF as confirmed by bone marrow biopsy Discontinuation of all drugs used to treat underlying MF disease at least 14 days prior to baseline visit INR <= 1.5 or PTT value < 1.5 x upper limit of normal (ULN) at study entry Hemoglobin level at least 6.5 g/dL at Screening visit Willingness to be transfused to treat low hemoglobin levels Exclusion Criteria: Females who are pregnant, unable to comply with birth control use to avoid becoming pregnant or breastfeeding Males who cannot comply with birth control use to avoid fathering a child Platelet count < 50 x10^9/L or absolute neutrophil count (ANC) < 1 x10^9/L at the Screening visit Inadequate liver or renal function; Intracranial bleeds or invasive malignancy over the previous 2 years - international normalized ratio (INR) laboratory values cannot be > 1.5 x upper limit of normal at study entry.

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 5 mg<br>Participants began administration with 5 mg ruxolitinib twice daily (BID) orally. Beginning at the Week 4 visit, doses of ruxolitinib could be increased in 5 mg once a day (QD) increments every 4 weeks every 4 weeks not to exceed a dose of 25 mg BID. | Drug: Ruxolitinib<br>* Ruxolitinib (INCB018424), 5 mg bid<br>* Other names: INCB018424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Spleen Volume at Week 24 by Final Titrated Dose | Magnetic resonance imaging (MRI) of the upper and lower abdomen and pelvis was performed to assess spleen volumes. Computed tomography (CT) scan was performed if participant was not a candidate for MRI or if MRI was not readily available. MRI was performed with a body coil. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI (or CT scan in applicable participants) was performed on the first or second day of the baseline period (ie, Day -7 or Day -6), and the site radiologist sent the scan to the central imaging laboratory that same day. The CT scans were processed by the same central laboratory used for MRIs. | Baseline and Week 24 | 
| Percent Change From Baseline in Total Symptom Score (TSS) as Measured by the Modified Myelofibrosis Symptom Assessment Form (MFSAF) V2.0 Diary at Week 24 by Final Titrated Dose | Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF) Version 2.0 diary. Using the diary, patients rated the following symptoms on a scale from 0 (absent) to 10 (worst imaginable): night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), and muscle/bone pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms. | Baseline and Week 24 | 
| Percentage of Participants With Treatment-emergent Adverse Events (TEAE) | TEAE was defined as adverse events that began or worsened from baseline after the first administration of the study drug. Participants were analyzed based on the number of subjects who received a dose within the dose group. The percentages for each column are calculated using this N. Participants who had more than 1 event in an AE category (eg, treatment-related TEAE) are counted once at each dose level the event occurred. | Up to Week 156 | 
| Percentage of Participants With New Onset Grade 4 Thrombocytopenia Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE V4.03) | Participants with platelet count between 50 and 100 × 10^9/L at the screening and/or baseline visit were enrolled in the study. Thrombocytopenia is defined as a condition with low blood platelet count. Grade 4 thrombocytopenia was platelet count < 25 × 10^9/L. Participants were analyzed based on the number of subjects who received a dose within the dose group. The percentages for each column are calculated using this N. Participants who had more than 1 event in an AE category (eg, treatment-related TEAE) are counted once at each dose level the event occurred. | Up to Week 156 | 
| Percentage of Participants With New Onset Grade 2 or Higher Hemorrhage as Assessed by CTCAE V4.03 | Hemorrhages were defined as any lower level terms by MedDRA included in the Standardized MedDRA Query (SMQ) for hemorrhage terms. Participants were analyzed based on the number of subjects who received a dose within the dose group. The percentages for each column are calculated using this N. Participants who had more than 1 event in an AE category (eg, treatment-related TEAE) are counted once at each dose level the event occurred. | Up to Week 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Spleen Volume at Week 24 Compared to Baseline | MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. CT scan was performed if participant was not a candidate for MRI, or if MRI was not readily available. MRI was performed with a body coil. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI (or CT scan in applicable participants) was performed on the first or second day of the baseline period (ie, Day -7 or Day -6), and the site radiologist sent the scan to the central imaging laboratory that same day. The CT scans were processed by the same central laboratory used for MRIs. | Baseline and Week 24 | 
| Percent Change in Total Symptom Score as Measured by the Modified MFSAF V2.0 Diary at Week 24 Compared to Baseline | Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF) Version 2.0 diary. Using the diary, patients rated the following symptoms on a scale from 0 (absent) to 10 (worst imaginable): night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), and muscle/bone pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms.. | Baseline and Week 24 | 
| Percentage of Participants With ≥ 35% Reduction in Spleen Volume at Week 24 Compared to Baseline | MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. CT scan was performed if participant is not a candidate for MRI, or if MRI is not readily available. MRI was performed with a body coil. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI (or CT scan in applicable participants) was performed on the first or second day of the baseline period (ie, Day -7 or Day -6), and the site radiologist sent the scan to the central imaging laboratory that same day. The CT scans were processed by the same central laboratory used for MRIs. | Baseline and Week 24 | 
| Percentage of Participants With ≥10% Reduction in Spleen Volume at Week 24 Compared to Baseline | MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. CT scan was performed if participant is not a candidate for MRI, or if MRI is not readily available. MRI was performed with a body coil. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI (or CT scan in applicable participants) was performed on the first or second day of the baseline period (ie, Day -7 or Day -6), and the site radiologist sent the scan to the central imaging laboratory that same day. The CT scans were processed by the same central laboratory used for MRIs. | Baseline and Week 24 | 
| Percentage of Participants With ≥ 50% Improvement in Total Symptom Score as Measured by the Modified MFSAF V2.0 Diary at Week 24 Compared to Baseline | Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF) Version 2.0 diary. Using the diary, patients rated the following symptoms on a scale from 0 (absent) to 10 (worst imaginable): night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), and muscle/bone pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms. | Baseline and Week 24 | 
| Change in Spleen Length Measured by Palpation | Measurement of spleen length below the left costal margin was measured by palpation at each study visit. Investigators were provided with a soft centimeter ruler so that palpable spleen length was measured in centimeters and not in finger breadths. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. | Up to Week 156 | 
| Percent Change From Baseline in Spleen Length Measured by Palpation | Measurement of spleen length below the left costal margin was measured by palpation at each study visit. Investigators were provided with a soft centimeter ruler so that palpable spleen length was measured in centimeters and not in finger breadths. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. | Up to Week 156 | 
| Patient Global Impression of Change (PGIC) Score at Each Visit | Symptoms of myelofibrosis were assessed using the PGIC questionnaire. Using the questionnaire, patients rated the overall sense of treatment effect on their symptoms on a scale of 1 (very much improved)- 7(very much worse). The specific wording was: Since the start of the treatment you've received in this study, your myelofibrosis symptoms are: 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) No change, 5) Minimally worse, 6) Much worse, 7) Very much worse. A higher score indicates worse symptoms. | Up to Week 156 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PMF, PPV-MF, PET-MF