A Phase 3 interventional study of Ruxolitinib and Best Available Therapy (BAT) in Myelofibrosis, sponsored by Novartis Pharmaceuticals. Completed at 61 sites in 9 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-08-19.
Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment
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).
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.
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Exclusion Criteria:
5 mg tablets administered orally in an outpatient setting according to the protocol-specified dosing schedule
Drug: Ruxolitinib
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)
5 mg tablets packaged as 60-count in high-density polyethylene bottles
Prescribing and usage per respective package inserts
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.
Time frame: Baseline, Week 48
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.
Time frame: 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.
Time frame: 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.
Time frame: 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 frame: 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 frame: 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 frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, once a year
Duration of Follow-up by Treatment
Number of Participants with duration of Follow up
Time frame: baseline, 260 weeks (end of study)
Subjects were recruited from 9 countries located in Europe: Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, and United Kingdom.
| Milestone | Ruxolitinib | Best Available Therapy (BAT) | Ruxolitinib After BAT (Cross-over) |
|---|---|---|---|
| Started | 146 | 73 | 0 |
| Completed | 91 | 31 | 0 |
| Not completed | 55 | 42 | 0 |
| Withdrew: Adverse event | 12 | 4 | 0 |
| Withdrew: Withdrawal by subject | 2 | 9 | 0 |
| Withdrew: Protocol violation | 2 | 0 | 0 |
| Withdrew: Disease progression | 1 | 3 | 0 |
| Withdrew: Non-compliance with study medication | 2 | 0 | 0 |
| Withdrew: Non-compliance with study procedures | 0 | 1 | 0 |
| Withdrew: Other reasons | 7 | 7 | 0 |
| Withdrew: Entered extension phase | 29 | 18 | 0 |
| Milestone | Ruxolitinib | Best Available Therapy (BAT) | Ruxolitinib After BAT (Cross-over) |
|---|---|---|---|
| Started | 146 | 28 | 45 |
| Crossed over after qualifying event | 0 | 0 | 27 |
| Crossed over after amend 5 | 0 | 0 | 12 |
| Crossed over: other | 0 | 0 | 6 |
| Completed | 39 | 0 | 11 |
| Not completed | 107 | 28 | 34 |
| Withdrew: Including stem cell transplantation | 16 | 9 | 6 |
| Withdrew: Adverse event | 35 | 5 | 10 |
| Withdrew: Withdrawal by subject | 10 | 9 | 0 |
| Withdrew: Protocol violation | 2 | 0 | 5 |
| Withdrew: Disease progression | 32 | 4 | 7 |
| Withdrew: Noncompliance with study medication | 4 | 0 | 1 |
| Withdrew: Noncompliance with study procedures | 0 | 1 | 0 |
| Withdrew: Lack of efficacy | 8 | 0 | 5 |
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.
| Percentage of Participants | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 48 | 28.5 | 0 |
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.
| years | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Duration of Maintenance of Spleen Volume Reduction (Median) | 3.22 (1.65 to NA) | NA (NA to NA) |
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.
| probability of response | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| 1.0 year | 0.72 (.60 to .81) | NA (NA to NA) |
| 1.5 years | 0.67 (0.55 to 0.77) | NA (NA to NA) |
| 2.0 years | 0.63 (0.50 to 0.73) | NA (NA to NA) |
| 2.5 years | 0.54 (0.41 to 0.65) | NA (NA to NA) |
| 3.0 years | 0.51 (0.38 to 0.62) | NA (NA to NA) |
| 3.5 years | 0.48 (0.35 to 0.60) | NA (NA to NA) |
| 4.0 years | 0.48 (0.35 to 0.60) | NA (NA to NA) |
| 4.5 years | 0.48 (0.35 to 0.60) | NA (NA to NA) |
| 5.0 years | 0.48 (0.35 to 0.60) | NA (NA to NA) |
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.
| Percentage of Participants | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24 | 31.9 | 0 |
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
| probability of response | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| 12 weeks | 0.23 (0.14 to 0.34) | 0 (NA to NA) |
| 24 weeks | 0.67 (0.54 to 0.76) | 1 (NA to NA) |
| 36 weeks | 0.87 (0.76 to 0.93) | 1 (NA to NA) |
| 48 weeks | 0.97 (0.89 to 0.99) | 1 (NA to NA) |
Median of time progression free survival (95% CI), years
| years | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Progression-free Survival (PFS) | 1.6 (1.2 to 2.3) | 1.4 (1.1 to 1.9) |
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
| Years | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Leukemia-free Survival (LFS) | NA (NA to NA) | 4.1 (2.4 to NA) |
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
| Years | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Overall Survival (OS) | NA (NA to NA) | 4.1 (2.4 to NA) |
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
| Percentage of participants | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| Grade 0 | 2.7 | 0.0 |
| Grade 1 | 7.5 | 2.7 |
| Grade 2 | 8.9 | 6.8 |
| Grade 3 | 24.0 | 15.1 |
| Missing Grade | 56.8 | 75.3 |
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
| participants | Ruxolitinib | Ruxolitinib - Grade 1 | Ruxolitinib - Grade 2 | Ruxolitinib - Grade 3 | Ruxolitinib - Missing | Best Available Therapy (BAT) - Grade 0 | Best Available Therapy (BAT) - Grade 1 | Best Available Therapy (BAT) - Grade 2 | Best Available Therapy (BAT) - Grade 3 | Best Available Therapy - Missing |
|---|---|---|---|---|---|---|---|---|---|---|
| Postbaseline Grade 0 | 1 (41.8 to 2.3) | 1 (47.9 to 1.9) | 2 | 1 | 2 | 0 | 0 | 0 | 0 | 0 |
| Postbaseline Grade 1 | 0 | 10 | 9 | 2 | 0 | 0 | 1 | 0 | 1 | 0 |
| Postbaseline Grade 2 | 0 | 2 | 8 | 8 | 1 | 0 | 0 | 4 | 1 | 0 |
| Postbaseline Grade 3 | 0 | 6 | 19 | 28 | 2 | 0 | 0 | 4 | 8 | 3 |
| Postbaseline Missing | 2 | 2 | 17 | 20 | 3 | 2 | 2 | 19 | 24 | 4 |
Number of Participants with duration of Follow up
| participants | Ruxolitinib | Best Available Therapy (BAT) |
|---|---|---|
| <=1 year | 16 | 15 |
| >1 year - <=2 years | 21 | 10 |
| >2 years - <=3 years | 9 | 13 |
| >3 years - <=4 years | 12 | 5 |
| >4 years - <=5 years | 27 | 8 |
| 5 years | 61 | 22 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ruxolitinib Randomized | — | 51/146 (34.9%) | 145/146 (99.3%) |
| Ruxolitinib Randomized + Extension Phase | — | 85/146 (58.2%) | 145/146 (99.3%) |
| BAT Randomized | — | 22/73 (30.1%) | 64/73 (87.7%) |
| Ruxolitinib Cross-over | — | 20/45 (44.4%) | 42/45 (93.3%) |
| Event | Ruxolitinib Randomized | Ruxolitinib Randomized + Extension Phase | BAT Randomized | Ruxolitinib Cross-over |
|---|---|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 1/146 | 2/146 | 1/73 | 4/45 |
| PneumoniaInfections and infestations | 2/146 | 11/146 | 4/73 | 1/45 |
| AnaemiaBlood and lymphatic system disorders | 8/146 | 10/146 | 4/73 | 2/45 |
| Renal failure acuteRenal and urinary disorders | 3/146 | 4/146 | 1/73 | 3/45 |
| Escherichia urinary tract infectionInfections and infestations | 0/146 | 0/146 | 0/73 | 2/45 |
| Abdominal painGastrointestinal disorders | 3/146 | 6/146 | 2/73 | 1/45 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 2/146 | 4/146 | 3/73 | 0/45 |
| Cardiac failureCardiac disorders | 3/146 | 5/146 | 1/73 | 1/45 |
| PyrexiaGeneral disorders | 4/146 | 5/146 | 1/73 | 1/45 |
| Squamous cell carcinoma of skinNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 3/146 | 5/146 | 1/73 | 0/45 |
| Event | Ruxolitinib Randomized | Ruxolitinib Randomized + Extension Phase | BAT Randomized | Ruxolitinib Cross-over |
|---|---|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 67/146 | 77/146 | 10/73 | 21/45 |
| AnaemiaBlood and lymphatic system disorders | 61/146 | 71/146 | 8/73 | 19/45 |
| DiarrhoeaGastrointestinal disorders | 36/146 | 55/146 | 13/73 | 12/45 |
| Oedema peripheralGeneral disorders | 33/146 | 55/146 | 21/73 | 8/45 |
| NasopharyngitisInfections and infestations | 27/146 | 40/146 | 9/73 | 4/45 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 22/146 | 35/146 | 13/73 | 12/45 |
| AstheniaGeneral disorders | 28/146 | 38/146 | 9/73 | 10/45 |
| CoughRespiratory, thoracic and mediastinal disorders | 22/146 | 38/146 | 12/73 | 9/45 |
| BronchitisInfections and infestations | 15/146 | 37/146 | 5/73 | 3/45 |
| FatigueGeneral disorders | 23/146 | 36/146 | 8/73 | 8/45 |
| Age, Continuous(years) | Ruxolitinib | Best Available Therapy (BAT) | Total |
|---|---|---|---|
| Mean | 65.1 ± 9.74 | 65.2 ± 10.27 | 65.2 ± 9.89 |
| Sex: Female, Male(Participants) | Ruxolitinib | Best Available Therapy (BAT) | Total |
|---|---|---|---|
| Female | 63 | 31 | 94 |
| Male | 83 | 42 | 125 |
| Disease Profile - Type of Myelofibrosis (MF)(Participants) | Ruxolitinib | Best Available Therapy (BAT) | Total |
|---|---|---|---|
| Primary Myelofibrosis | 77 | 39 | 116 |
| Post-polycythemia vera-myelofibrosis | 48 | 20 | 68 |
| Post-essential thrombocythemia-myelofibrosis | 21 | 14 | 35 |
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