MPN (Myeloproliferative Neoplasms)
Conditions
Keywords
Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis
Brief summary
This was a randomized, double-blind study comparing the efficacy and safety of ruxolitinib (INCB018424) tablets to matching placebo tablets in patients diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).
Detailed description
Patients with spleen growth of greater than 25% based on an increase in spleen volume from Baseline were eligible for early unblinding, and for patients on placebo, cross over to ruxolitinib prior to the primary study endpoint being reached. If this spleen growth occurred before Week 24, it must have been accompanied by specific worsening of symptoms, based on worsening early satiety accompanied by weight loss or worsening pain requiring daily narcotic use. After Week 24, asymptomatic spleen growth alone was sufficient for early unblinding and potential cross over. Patients found to have been randomized to ruxolitinib after early unblinding prior to Week 24 were discontinued. When half of the patients remaining in the study completed the Week 36 visit and all patients enrolled completed Week 24 or discontinued, the database was frozen and the primary analysis was conducted. Once this was complete, all patients were unblinded and patients who had been randomized to placebo were given the opportunity to cross over to ruxolitinib treatment, provided hematology laboratory parameters were adequate; Patients receiving benefit could continue treatment until the later of marketing approval or when the last randomized patient remaining in the study had completed Week 144 (36 months).
Interventions
DRUGRuxolitinib
Ruxolitinib phosphate tablets 5 mg administered as oral doses.
DRUGPlacebo
Matching placebo tablets were administered as oral doses in the same manner as active drug.
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must be diagnosed with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF) according to the 2008 World Health Organization criteria * Subjects with myelofibrosis 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 Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3 * Subjects who have not previously received treatment with a Janus kinase (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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24 | Baseline and Week 24 | Spleen volume was assessed by magnetic resonance imaging (MRI) or by computed tomography (CT) scans if MRI was not suitable, and analyzed by a blinded central laboratory reader. Patients who withdrew, crossed over to ruxolitinib prior to the visit, or had a missing value at the visit were considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib | Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months). | The duration of ≥ 35% reduction from Baseline in spleen volume was defined as the longest duration of consecutive measurements of ≥ 35% reduction observed before the data cut-off date for patients who had at least one measured ≥ 35% reduction, and who either had at least one subsequent measurement or, who subsequently dropped out prior to another assessment. The duration of a ≥ 35% reduction from Baseline in spleen volume was analyzed using the Kaplan-Meier method. |
| Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24 | Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit. | 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. |
| Change From Baseline to Week 24 in Total Symptom Score | Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit. | 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 hence a negative change from baseline indicates improvement. |
| Overall Survival | From randomization to the data cut-off date (up to 14 months). | Overall survival is reported here by the number of deaths from randomization until the data cut-off. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. |
| Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib | Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months). | The maintenance of ≥ 35% reduction from Baseline in spleen volume was assessed up until the data cutoff date using the Kaplan-Meier method for patients who had at least one measured ≥ 35% reduction, and who either had at least one subsequent measurement or who subsequently dropped out prior to another assessment. |
| Overall Survival - Extended Data | From randomization to 4 months after the data cut-off date (up to 18 months). | Overall survival is reported here by the number of deaths from randomization until 01 March 2011. Patients were censored at this time or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. This outcome reports data from August 2009 through March 2011 to coincide with a pre-planned New Drug Application (NDA) 120-day safety update. |
| Overall Survival Time - Extended Data | From randomization to 4 months after the data cut-off date (up to 18 months). | Overall survival was assessed by the time to death or censoring up until 01 March 2011. Patients were censored at this time or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. This outcome reports data from August 2009 through March 2011 to coincide with a pre-planned New Drug Application (NDA) 120-day safety update. |
| Overall Survival at Week 144 | Week 144 | Overall survival is reported here by the number of deaths from randomization until the data cut-off. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of database cut-off. The survival time was analyzed using the Kaplan-Meier method. |
| Overall Survival Time at Week 144 | Week 144 | Overall survival was assessed by the time to death or censoring. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of database cut-off. The survival time was analyzed using the Kaplan-Meier method. |
| Overall Survival Time | From randomization to the data cut-off date (up to 14 months). | Overall survival was assessed by the time to death or censoring. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. |
Countries
Australia, Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ruxolitinib Participants began treatment with ruxolitinib 15 or 20 mg taken orally twice a day based on Baseline platelet count. The dose was adjusted by the Investigator based on efficacy and safety to a maximum of 25 mg twice daily. | 155 |
| Placebo Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting pre-specified requirements were given the opportunity to cross over to ruxolitinib treatment. | 154 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| All Participants | Adverse Event | 8 | 8 |
| All Participants | Data lost during site relocation | 0 | 1 |
| All Participants | Death | 9 | 9 |
| All Participants | Disease progression | 3 | 12 |
| All Participants | Withdrawal by Subject | 1 | 10 |
| Patients Who Crossed Over to Ruxolitinib | Adverse Event | 0 | 19 |
| Patients Who Crossed Over to Ruxolitinib | Disease progression | 0 | 15 |
| Patients Who Crossed Over to Ruxolitinib | Non-compliance to study medication | 0 | 2 |
| Patients Who Crossed Over to Ruxolitinib | Other Unspecified | 0 | 7 |
| Patients Who Crossed Over to Ruxolitinib | Withdrawal by Subject | 0 | 11 |
Baseline characteristics
| Characteristic | Ruxolitinib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.7 years STANDARD_DEVIATION 8.82 | 68.7 years STANDARD_DEVIATION 8.66 | 67.7 years STANDARD_DEVIATION 8.78 |
| Disease Subtype Missing | 0 participants | 1 participants | 1 participants |
| Disease Subtype Post-essential thrombocythemia-myelofibrosis | 35 participants | 22 participants | 57 participants |
| Disease Subtype Post-polycythemia vera-myelofibrosis | 50 participants | 47 participants | 97 participants |
| Disease Subtype Primary myelofibrosis | 70 participants | 84 participants | 154 participants |
| JAK2 V617F Mutation Status Negative | 40 participants | 27 participants | 67 participants |
| JAK2 V617F Mutation Status Positive | 113 participants | 123 participants | 236 participants |
| JAK2 V617F Mutation Status Unknown/Missing | 2 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 7 participants | 13 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 5 participants | 3 participants | 8 participants |
| Race/Ethnicity, Customized White | 138 participants | 139 participants | 277 participants |
| Sex/Gender, Customized Female | 76 participants | 65 participants | 141 participants |
| Sex/Gender, Customized Male | 79 participants | 88 participants | 167 participants |
| Spleen volume | 2745.7 cm˄3 STANDARD_DEVIATION 1247 | 2797.6 cm˄3 STANDARD_DEVIATION 1388.5 | 2771.5 cm˄3 STANDARD_DEVIATION 1317.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 150 / 155 | 147 / 151 |
| serious Total, serious adverse events | 43 / 155 | 53 / 151 |
Outcome results
Primary
Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24
Spleen volume was assessed by magnetic resonance imaging (MRI) or by computed tomography (CT) scans if MRI was not suitable, and analyzed by a blinded central laboratory reader. Patients who withdrew, crossed over to ruxolitinib prior to the visit, or had a missing value at the visit were considered non-responders.
Time frame: Baseline and Week 24
Population: Intent-to-treat (ITT) population included all subjects randomized in the study. Treatment groups for this population were defined according to the treatment assignment at randomization. One patient was not included in the analysis due to a missing baseline spleen volume value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib | Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24 | 65 participants |
| Placebo | Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24 | 1 participants |
Comparison: The primary endpoint analyzed with a 2-sided alpha of 0.05.p-value: <0.0001Fisher Exact
Secondary
Change From Baseline to Week 24 in Total Symptom Score
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 hence a negative change from baseline indicates improvement.
Time frame: Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit.
Population: This analysis only includes patients who had a non-missing change from Baseline to Week 24. Data collected after the date of treatment cross over were not included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ruxolitinib | Change From Baseline to Week 24 in Total Symptom Score | Baseline | 18.0 scores on a scale | Standard Deviation 10.9 |
| Ruxolitinib | Change From Baseline to Week 24 in Total Symptom Score | Week 24 | 9.4 scores on a scale | Standard Deviation 9.7 |
| Ruxolitinib | Change From Baseline to Week 24 in Total Symptom Score | Change from Baseline | -8.6 scores on a scale | Standard Deviation 10 |
| Placebo | Change From Baseline to Week 24 in Total Symptom Score | Baseline | 16.5 scores on a scale | Standard Deviation 11.5 |
| Placebo | Change From Baseline to Week 24 in Total Symptom Score | Week 24 | 19.7 scores on a scale | Standard Deviation 13.7 |
| Placebo | Change From Baseline to Week 24 in Total Symptom Score | Change from Baseline | 3.2 scores on a scale | Standard Deviation 9.4 |
Secondary
Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib
The duration of ≥ 35% reduction from Baseline in spleen volume was defined as the longest duration of consecutive measurements of ≥ 35% reduction observed before the data cut-off date for patients who had at least one measured ≥ 35% reduction, and who either had at least one subsequent measurement or, who subsequently dropped out prior to another assessment. The duration of a ≥ 35% reduction from Baseline in spleen volume was analyzed using the Kaplan-Meier method.
Time frame: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).
Population: Patients who had at least 1 measurement of ≥ 35% reduction from Baseline in spleen volume at any time during the study and had at least 1 subsequent measurement or withdrew prior to another assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib | Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib | 135.0 weeks |
Secondary
Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib
The maintenance of ≥ 35% reduction from Baseline in spleen volume was assessed up until the data cutoff date using the Kaplan-Meier method for patients who had at least one measured ≥ 35% reduction, and who either had at least one subsequent measurement or who subsequently dropped out prior to another assessment.
Time frame: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).
Population: Patients who had at least 1 measurement of ≥ 35% reduction from Baseline in spleen volume at any time during the study and had at least 1 subsequent measurement or withdrew prior to another assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib | Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib | Still Responder by 144 weeks | 0.27 proportion of participants |
| Ruxolitinib | Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib | Still Responder by 48 weeks | 0.76 proportion of participants |
| Ruxolitinib | Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib | Still Responder by 96 weeks | 0.67 proportion of participants |
Secondary
Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24
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.
Time frame: Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit.
Population: ITT evaluable population included patients with Baseline data and who did not have a 0 total score at both Baseline \& Week 24; data measured after the cross over date were excluded. Patients who withdrew, met cross over criteria prior to Week 24 or had a 0 Baseline score \& a nonzero/missing score at Week 24 were considered not meeting the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib | Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24 | 68 participants |
| Placebo | Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24 | 8 participants |
Secondary
Overall Survival
Overall survival is reported here by the number of deaths from randomization until the data cut-off. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method.
Time frame: From randomization to the data cut-off date (up to 14 months).
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib | Overall Survival | Death events | 10 participants |
| Ruxolitinib | Overall Survival | Censored events | 145 participants |
| Placebo | Overall Survival | Death events | 14 participants |
| Placebo | Overall Survival | Censored events | 140 participants |
Secondary
Overall Survival at Week 144
Overall survival is reported here by the number of deaths from randomization until the data cut-off. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of database cut-off. The survival time was analyzed using the Kaplan-Meier method.
Time frame: Week 144
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib | Overall Survival at Week 144 | Death events | 42 participants |
| Ruxolitinib | Overall Survival at Week 144 | Censored events | 113 participants |
| Placebo | Overall Survival at Week 144 | Death events | 54 participants |
| Placebo | Overall Survival at Week 144 | Censored events | 100 participants |
Secondary
Overall Survival - Extended Data
Overall survival is reported here by the number of deaths from randomization until 01 March 2011. Patients were censored at this time or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. This outcome reports data from August 2009 through March 2011 to coincide with a pre-planned New Drug Application (NDA) 120-day safety update.
Time frame: From randomization to 4 months after the data cut-off date (up to 18 months).
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib | Overall Survival - Extended Data | Death events | 13 participants |
| Ruxolitinib | Overall Survival - Extended Data | Censored events | 142 participants |
| Placebo | Overall Survival - Extended Data | Death events | 24 participants |
| Placebo | Overall Survival - Extended Data | Censored events | 130 participants |
Secondary
Overall Survival Time
Overall survival was assessed by the time to death or censoring. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method.
Time frame: From randomization to the data cut-off date (up to 14 months).
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib | Overall Survival Time | NA weeks |
| Placebo | Overall Survival Time | NA weeks |
Secondary
Overall Survival Time at Week 144
Overall survival was assessed by the time to death or censoring. Patients were censored at the time of database cut-off or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of database cut-off. The survival time was analyzed using the Kaplan-Meier method.
Time frame: Week 144
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib | Overall Survival Time at Week 144 | 0.74 probability |
| Placebo | Overall Survival Time at Week 144 | 0.61 probability |
Secondary
Overall Survival Time - Extended Data
Overall survival was assessed by the time to death or censoring up until 01 March 2011. Patients were censored at this time or the later of either the date of withdrawal or the date of last follow-up for patients who withdrew from study before the date of data cut. The survival time was analyzed using the Kaplan-Meier method. This outcome reports data from August 2009 through March 2011 to coincide with a pre-planned New Drug Application (NDA) 120-day safety update.
Time frame: From randomization to 4 months after the data cut-off date (up to 18 months).
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib | Overall Survival Time - Extended Data | NA weeks |
| Placebo | Overall Survival Time - Extended Data | NA weeks |