Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II: The COMFORT-II Trial

Study Overview
=================
Brief Summary
-----------------
This was an open label, randomized study comparing the efficacy and safety of randomized 2:1 Ruxolitinib tablets versus best-available therapy, as selected by the investigator. The purpose was to compare the efficacy, safety and tolerability of Ruxolitinib (INC424/INCB018424) given twice daily to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) or post essential thrombocythemia myelofibrosis (PET-MF).

Detailed Description
-----------------
This study included a randomized treatment phase, followed by an extension phase. The treatment phase lasted from Study Day 1 (day of randomization) to the occurrence of a protocol-specified progressive disease event or study conclusion, whichever came first. The extension phase (including crossover of control group patients) lasted from the progressive disease event until the earliest of the following events: a) the patient was no longer receiving clinical benefit, b) the patient chose to withdraw from the study, or c) the study ended. All patients received ruxolitinib in the extension phase of the study. Maximum individual patient duration was 5 years.

Official Title
-----------------
A Randomized Study of Ruxolitinib Tablets Compared to Best Available Therapy in Subjects With Primary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis

Conditions
-----------------
Myelofibrosis

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Drug: Best Available Therapy (BAT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must be diagnosed with PMF, PPV-MF or PET-MF according to the 2008 World Health Organization criteria Subjects with MF requiring therapy must be classified as high risk OR intermediate risk level 2 according to the prognostic factors defined by the International Working Group Subjects with an ECOG performance status of 0, 1, 2 or 3 Subjects with peripheral blood blast count of < 10%. Subjects who have not previously received treatment with a JAK inhibitor Exclusion Criteria: Subjects with a life expectancy of less than 6 months Subjects with inadequate bone marrow reserve as demonstrated by specific clinical laboratory counts Subjects 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 Subjects with inadequate liver or renal function Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy Subjects with an active malignancy over the previous 5 years except specific skin cancers Subjects with severe cardiac conditions Subjects who have had splenic irradiation within 12 months

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib<br>5 mg tablets administered orally in an outpatient setting according to the protocol-specified dosing schedule | Drug: Ruxolitinib<br>* 5 mg tablets packaged as 60-count in high-density polyethylene bottles<br>|
| Active Comparator: Best Available Therapy (BAT)<br>Commercially available therapy, oral or parenteral, per manufacturer's instructions and Investigator discretion. BAT included the option of no treatment. Patients randomized to BAT were eligible to cross over to receive open-label ruxolitinib after a qualifying progression event, if they met the safety criteria. After the primary analysis in January 2011, patients randomized to receive BAT were allowed to cross over to receive ruxolitinib and move to the extension phase of the study without a qualifying progression event. | Drug: Best Available Therapy (BAT)<br>* Prescribing and usage per respective package inserts<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 48 | The change in spleen volume from baseline to week 48 was measured by magnetic resonance imaging (MRI) (or by computer tomography (CT) for participants unable to undergo MRI) and was calculated only for participants who had an evaluable spleen volume at baseline. The percentage of participants achieving a greater than or equal to 35% reduction in spleen volume from baseline to week 48 was then calculated by treatment group. | Baseline, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Maintenance of Spleen Volume Reduction (Median) | DoMSR is defined as the interval between the first spleen volume measurement that is >=35% reduction from baseline and the first scan that is no longer = 35% reduction AND that is a >25% increase over nadir. It was evaluated using the Kaplan-Meier estimate for each treatment arm. The analysis was performed only for subjects who achieved greater than 35% reduction in spleen volume. | Baseline, up to Year 5 | 
| Duration of Maintenance of Spleen Volume Reduction (Kaplan-Meier Estimates) | This is defined as the interval between randomization and date of the first MRI showing a 35% reduction from baseline in spleen volume. The analysis was performed for participants who achieved a 35% reduction in spleen volume. | Baseline, up to Year 5 | 
| Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24 | The change in spleen volume from baseline to week 24 was measured by magnetic resonance imaging (MRI) (or by computer tomography (CT) for participants unable to undergo MRI) and was calculated only for participants who had an evaluable spleen volume at baseline. The percentage of participants achieving a greater than or equal to 35% reduction in spleen volume from baseline to week 24 was then calculated by treatment group. | Baseline, Week 24 | 
| Time to First at Least 35% Reduction in Spleen Volume From Baseline by Treatment (Primary Analysis) | This is defined as the interval between randomization and date of the first MRI showing at least 35% reduction from baseline in spleen volume. The analysis was performed for participants who achieved a 35% reduction in spleen volume | Time from randomization and date of the first MRI showing at least 35% reduction from baseline in spleen volume | 
| Progression-free Survival (PFS) | Median of time progression free survival (95% CI), years | Time from randomization and the earliest of either increase in spleen volume >=25% from on-study nadir, splenic irradiation, splenectomy, leukemic transformation or death | 
| Leukemia-free Survival (LFS) | Time from randomization and earliest of either (1) date of bone marrow blast count of 20% or greater; (2) date of first peripheral blast count of 20% or greater that was subsequently confirmed to sustain for at least 8 weeks; (3) date of death from any cause | Time from randomization and earliest of either leukemia or death | 
| Overall Survival (OS) | Defined as the interval between randomization and the date of the bone marrow blast count of 20% or greater OR the date of the first peripheral blast count of 20% or greater that was subsequently confirmed to have been sustained for at least 8 weeks OR the date of death from any cause, whichever occurs first. OS was summarized using Kaplan-Meier estimates for each treatment arm. The estimates were supplemented by tables of number of events and probability estimates at several timepoints | From randomization until death from any cause | 
| Percentage of Participants With Bone Marrow Histomorphology at Week 48 (Primary Analysis) | This was noted as fibrosis density and was tabulated by fibrosis grade at baseline and at week 48 (post-baseline). Descriptive statistics (participant percentages) were used. Fibrosis grades: 0 Scattered linear reticulin with no intersections corresponding to normal bone marrow ; 1 Loose network of reticulin with many intersections, especially in perivascular areas; 2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; 3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis | 48 weeks | 
| Bone Marrow Histomorphology | Shift table from baseline to last available postbaseline fibrosis grade by treatment The grade gives an indication of the activity or amount of inflammation and the stage represents the amount of fibrosis or scarring. The grade is assigned a number based on the degree of inflammation, which is usually scored from 0-4 with 0 being no activity and 3 or 4 considered severe activity | Baseline, once a year | 
| Duration of Follow-up by Treatment | Number of Participants with duration of Follow up | baseline, 260 weeks (end of study) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis