Alternative Dosing Strategy of Ruxolitinib in Patients With Myelofibrosis

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the effect of an alternative dosing strategy of ruxolitinib in subjects with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) and post essential thrombocythemia-myelofibrosis (PET-MF) in order to minimize the development of anemia and thrombocytopenia.

Detailed Description
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This pilot study was designed to explore an alternative dosing approach with the purpose of reducing anemia and thrombocytopenia. Subjects began dosing at 10 mg bid and had the opportunity for dose increases based on assessments of efficacy and overall hematologic status in a defined prior dosing interval. Dose increases were restricted to those patients who did not meet criteria for or have a dose hold over the prior 6 weeks, had a platelet count ≥100 x 10^9/L at week 12 or ≥150 x 10^9/L at week 18, and had a self-reported Patient's Global Impression of Change (PGIC) score of 3 (minimally improved) to 7 (very much worse) OR the subject's palpable spleen length below the costal margin had been reduced by less than 40% at that visit relative to Baseline. Dose increases were elective and not required. Subjects were permitted a dose increase of 5 mg BID to 15 mg BID at Week 12 and to a maximum of 20 mg BID at Week 18. There were also protocol-required dose decreases for thrombocytopenia (platelets <100 x 10^9/L) or protocol-defined anemia (decline in hemoglobin of at least 2 g/dL to a level < 8 g/dL, development of transfusion dependence, or a 50% increase in transfusion requirements for transfusion dependent subjects).This approach assumed that beginning at a low dose for initial therapy might have a positive impact on the rate of the initial hemoglobin decline and the nadir by decreasing the level of JAK-mediated inhibition of hematopoiesis. Specific dose modifications were described to minimize excursions of hemoglobin levels into the Grade 3 or Grade 4 range.

Official Title
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An Open-label Assessment of an Alternative Dosing Strategy of Ruxolitinib in Patients With Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, and Post-essential Thrombocythemia Myelofibrosis

Conditions
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Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) as confirmed by bone marrow biopsy. Must score at least 2 points on the Dynamic International Prognostic Scoring System (DIPSS) scale for prognostic risk factors. Peripheral blast count < 5% at both Screening and Baseline hematology assessments. Must discontinue all drugs used to treat underlying myelofibrosis (MF) disease no later than Day -1 (the day prior to starting ruxolitinib). Must have hemoglobin value ≥ 6.5 g/dL and be willing to receive blood transfusions. Platelet count ≥ 100*10^9/L. Must have a palpable spleen. Exclusion Criteria: Inadequate liver or bone marrow reserves, end stage renal disease on dialysis, clinically significant concurrent infections requiring therapy, or unstable cardiac function. Invasive malignancies over the previous 5 years (except treated early stage carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, and completely resected papillary thyroid and follicular thyroid cancers). Splenic irradiation within 6 months prior to receiving the first dose of study medication. Life expectancy less than 6 months.

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>Participants initially received ruxolitinib 10 mg twice a day (bid) for 24 weeks. Dose increases of 5 mg bid were possible at Weeks 12 and 18 up to a maximum dose of 20 mg bid. | Drug: Ruxolitinib<br>* Ruxolitinib was provided as 5 mg tablets. Dose increases were only permitted at wks 12 & 18 for lack of efficacy. Increases were restricted to patients who didn't meet criteria for a dose hold over the prior 6 wks, had a platelet count ≥ 100 x 10^9/L at wk 12 or ≥ 150 x 10^9/L at wk 18, and had a self-reported PGIC score of 3 (minimally improved) to 7 (very much worse) OR the subject's palpable spleen length below the costal margin was reduced by less than 40% relative to Baseline. Dose increases were elective and not required. Subjects were permitted a dose increase of 5 mg BID to 15 mg BID at wk 12 and to a maximum of 20 mg BID at wk 18. The protocol required dose decreases for thrombocytopenia (platelets <100 x 10^9/L) or protocol-defined anemia (decline in hemoglobin of at least 2 g/dL to a level < 8 g/dL, development of transfusion dependence, or a 50% increase in transfusion requirements for transfusion dependent subjects).<br>* Other names: INC424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percentage Change From Baseline in Spleen Volume at Week 24 | Spleen volume was measured using magnetic resonance imaging (MRI) or computed tomography (CT) scan. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. CT scans were performed if the participant was not a candidate for MRI. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for all visits for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. | Baseline to Week 24 | 
| Median Percent Change From Baseline in Spleen Volume at Week 24 | Spleen volume was measured using magnetic resonance imaging (MRI) or computed tomography (CT) scan. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. CT scans were performed if the participant was not a candidate for MRI. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for all visits for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percentage Change From Baseline in the Total Symptom Score at Week 24 | Symptoms of myelofibrosis were assessed using a symptom diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0). Participants were issued a hand-held device to record answers to queries regarding 7 symptoms of myelofibrosis each night from Baseline through Week 24. Symptoms assessed included night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), muscle/bone pain, and inactivity. The daily total symptom score (TSS) was the sum of the first 6 individual symptom scores (each on a scale of 0-10). Inactivity was not included in the total score. The Baseline TSS was the mean of daily total symptom scores from the last 7 consecutive days prior to the first study dose and ranged from 0 to 60. The Week 24 TSS was the mean of the daily total symptom scores from the last 28 consecutive days prior to the Week 24 visit and ranged from 0 to 60. A higher score indicates worse symptoms. A negative change score indicates improvement. | Baseline to Week 24 | 
| Median Percent Change From Baseline in the Total Symptom Score at Week 24 | Symptoms of myelofibrosis were assessed using a symptom diary, the modified MFSAF v2.0. Participants were issued a hand-held device to record answers to queries regarding 7 symptoms of myelofibrosis each night from Baseline through Week 24. Symptoms assessed included night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), muscle/bone pain, and inactivity. The daily TSS was the sum of the first 6 individual symptom scores (each on a scale of 0-10). Inactivity was not included in the total score. The Baseline total symptom score was the mean of daily total symptom scores from the last 7 consecutive days prior to the first study dose and ranged from 0 to 60. The Week 24 total symptom score was the mean of the daily total symptom scores from the last 28 consecutive days prior to the Week 24 visit and ranged from 0 to 60. A higher score indicates worse symptoms. A negative change score indicates improvement. | Baseline to Week 24 | 
| Percentage of Participants With a ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 | Spleen volume was measured using magnetic resonance imaging (MRI) or computed tomography (CT) scan. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. CT scans were performed if the participant was not a candidate for MRI. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for all visits for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. | Baseline to Week 24 | 
| Percentage of Participants With a ≥ 10% Reduction From Baseline in Spleen Volume at Week 24 | Spleen volume was measured using magnetic resonance imaging (MRI) or computed tomography (CT) scan. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. CT scans were performed if the participant was not a candidate for MRI. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for all visits for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. | Baseline to Week 24 | 
| Percentage of Participants With a ≥ 50% Improvement From Baseline in Total Symptom Score at Week 24 | Symptoms of myelofibrosis were assessed using a symptom diary, the modified MFSAF v2.0. Participants were issued a hand-held device to record answers to queries regarding 7 symptoms of myelofibrosis each night from Baseline through Week 24. Symptoms assessed included night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), muscle/bone pain, and inactivity. The daily total symptom score was the sum of the first 6 individual symptom scores (each on a scale of 0-10). Inactivity was not included in the total score. The Baseline total symptom score was the mean of daily total symptom scores from the last 7 consecutive days prior to the first study dose and ranged from 0 to 60. The Week 24 total symptom score was the mean of the daily total symptom scores from the last 28 consecutive days prior to the Week 24 visit and ranged from 0 to 60. A higher score indicates worse symptoms. A negative change score indicates improvement. | Baseline to Week 24 | 
| Mean Percentage Change From Baseline in Palpable Spleen Length at Week 24 | Spleen length was assessed by manual palpation. 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. | Baseline to Week 24 | 
| Median Percent Change From Baseline in Palpable Spleen Length at Week 24 | Spleen length was assessed by manual palpation. 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. | Baseline to Week 24 | 
| Percentage of Participants With a ≥ 50% Improvement From Baseline in Their Transfusion Status or With New Transfusion Independence Status for Those Participants Who Were Transfusion Dependent at Baseline | Transfusion dependence at Baseline is defined as subjects who received ≥ 2 units of red blood cell product(s) in the 12 consecutive weeks prior to the date of first dose. Transfusion independence On-Study is defined as subjects who received 0 units of red blood cell products over any 12-week period after starting dosing with ruxolitinib. Improvement in transfusion dependence On-Study is defined as a 50% or greater reduction in the frequency of red blood cell transfusions over any 12-week period after starting dosing with ruxolitinib. | Baseline to Week 24 | 
| Percentage of Participants With Clinically Notable Anemia | Clinically Notable Anemia was a pre-specified safety parameter examined at Weeks 12, 18 and 24 and defined as: 1) New onset Grade 3 or higher anemia in subjects who are transfusion independent at Baseline, 2) New onset transfusion dependence in subjects who are transfusion independent at Baseline, defined as receipt of ≥ 2 units in ≤ a 12-week interval, 3) 50% increase in transfusions compared to Baseline in subjects who are transfusion dependent at Baseline. | Baseline to Weeks 12, 18 and 24 | 
| Mean Percentage Change in Abdominal Symptom Scores at Week 24. | Symptoms of myelofibrosis were assessed using a symptom diary, the modified MFSAF v2.0. Participants were issued a hand-held device to record answers to queries regarding 7 symptoms of myelofibrosis each night from Baseline through Week 24. The abdominal symptom score was the sum of 3 individual symptom scores (abdominal discomfort, pain under ribs on left side, and feeling of fullness [early satiety]), each on a scale of 0 to 10. A higher score indicates worse symptoms. A negative change score indicates improvement. The Baseline abdominal symptom score was the mean of daily abdominal symptom scores from the last 7 consecutive days prior to the first study dose and ranged from 0 to 30. The Week 24 abdominal symptom score was the mean of the daily abdominal symptom scores from the last 28 consecutive days prior to the Week 24 visit and ranged from 0 to 30. | Week 24 | 
| Median Percentage Change in Abdominal Symptom Scores at Week 24. | Symptoms of myelofibrosis were assessed using a symptom diary, the modified MFSAF v2.0. Participants were issued a hand-held device to record answers to queries regarding 7 symptoms of myelofibrosis each night from Baseline through Week 24. The abdominal symptom score was the sum of 3 individual symptom scores (abdominal discomfort, pain under ribs on left side, and feeling of fullness [early satiety]). | Week 24 | 
| Number of Participants With Grade 3 or Grade 4 Adverse Events |  | Baseline to the end of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PMF, Myelofibrosis, Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, PPV-MF, Post-Essential Thrombocythemia Myelofibrosis, PET-MF, Open label, Ruxolitinib, 18424, Jak inhibitor