Myelofibrosis
Conditions
Keywords
myelofibrosis, myeloproliferative neoplasms, PMF, PET-MF, PPV-MF
Brief summary
The purpose of this study is to determine the safety and tolerability of ruxolitinib (INCB018424) sustained release (SR) formulation in participants with primary myelofibrosis (PMF), post-polycythemia vera MF (PPV-MF), and post-essential thrombocythemia MF (PET-MF).
Detailed description
The study will enroll approximately 40 participants with PMF, PPV-MF or PET-MF. Participants will take ruxolitinib SR once daily for 16 consecutive weeks and then transition to a comparable twice daily dose regimen of ruxolitinib using the immediate release (IR) tablets which have been under investigation in controlled Phase 1, 2, and 3 clinical trials. Participants receiving benefit from treatment with ruxolitinib may continue further participation with IR tablets up to the time when the last participant completed Week 36 or the commercial availability of ruxolitinib IR, whichever was earlier. Follow-up will occur at least 30 days following the last dose of ruxolitinib.
Interventions
DRUGRuxolitinib
Ruxolitinib was supplied as SR and IR formulated tablets.
Sponsors
Incyte Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants 18 years of age or older. * Participants must be diagnosed with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PPV-MF), or post-polycythemia vera myelofibrosis (PET-MF). * Participants with myelofibrosis requiring therapy must be classified as high risk (3 or more prognostic factors), intermediate risk level 2 (2 prognostic factors), or intermediate risk level 1 (1 prognostic factor)defined by International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). * Participants must have a palpable spleen measuring 5 cm or greater below the costal margin.
Exclusion criteria
* Participants with a life expectancy of less than 6 months. * Participants of childbearing potential who are unwilling to take appropriate precautions to avoid pregnancy or fathering a child. * Participants with inadequate bone marrow reserve. * Participants with history of platelet counts \< 50,000/μL, platelet transfusion(s), or an absolute neutrophil count \< 500/μL in the month prior to Screening. * Participants with inadequate liver or renal function at Screening and Baseline visits.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 1 Adverse Event From Baseline Through Week 16 | Baseline to Week 16 | — |
| Overall Response (OR) at Week 16 | Baseline to Week 16 | The investigator graded OR according to the International Working Group for Myelofibrosis Research and Therapy criteria for treatment response. As bone marrow biopsies were not taken after baseline, the best achievable response was clinical improvement which required 1 of the following in the absence of progressive disease (PD): (1) A ≥ 2 g/dL increase in hemoglobin level or (2) either a palpable ≥ 50% reduction of splenomegaly of a spleen ≥ 10 cm at baseline or a spleen palpable at \> 5 cm at baseline becoming not palpable. PD required 1 of the following: (1) Progressive splenomegaly defined by the appearance of previously absent splenomegaly that was palpable at \> 5 cm below the left costal margin or a ≥ 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a ≥ 50% increase in palpable distance for baseline splenomegaly of \> 10 cm or (2) an increase in peripheral blood blast percentage to ≥ 20% that lasted for ≥ 8 weeks. Stable disease: None of the above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥ 35% Reduction in Spleen Volume at Week 16 From Baseline | Baseline to Week 16 | Spleen volume was measured by magnetic resonance imaging (or by computed tomography \[CT\] in applicable participants). Scans were read by a central reader. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. |
| Change From Baseline in the Total Symptom Score at Week 16 | Baseline to Week 16 | Symptoms of myelofibrosis were assessed using the modified Myelofibrosis Symptom Assessment Form v2.0 diary that was to be completed by participants each night. The 7 symptoms (night sweats, itchiness, abdominal pain, pain under the ribs on left side, feeling of fullness \[early satiety\], bone/muscle pain, inactivity) were each rated on a scale from 0 (absent) to 10 (worst imaginable). The total symptom score was the sum of 6 of the 7 symptoms (inactivity was not included) and ranged from 0 to 60. A lower score indicated fewer symptoms. A negative change score indicated improvement. |
| Percentage of Participants With a ≥ 50% Reduction From Baseline in the Total Symptom Score at Week 16 | Baseline to Week 16 | Symptoms of myelofibrosis were assessed using the modified Myelofibrosis Symptom Assessment Form v2.0 diary that was to be completed by participants each night. The 7 symptoms (night sweats, itchiness, abdominal pain, pain under the ribs on left side, feeling of fullness \[early satiety\], bone/muscle pain, inactivity) were each rated on a scale from 0 (absent) to 10 (worst imaginable). The total symptom score was the sum of 6 of the 7 symptoms (inactivity was not included) and ranged from 0 to 60. A lower score indicated fewer symptoms. |
| Change From Baseline in Spleen Volume at Week 16 | Baseline to Week 16 | Spleen volume was measured by magnetic resonance imaging (or by computed tomography \[CT\] in applicable participants). Scans were read by a central reader. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Ruxolitinib 25 mg SR on Day 1 | Day 1 | Blood samples were collected prior to and at 0.5, 1, 2, 3, 4, 6, and 9 hours after administration of ruxolitinib 25 mg SR on Day 1 of the study. The concentration of ruxolitinib was determined in plasma samples by a validated LC/MS/MS assay. Standard noncompartmental pharmacokinetic methods were used to analyze the ruxolitinib plasma concentration data using WinNonlin® version 6.0.0 (Pharsight Corporation, Mountain View, CA). Tmax was taken directly from the observed plasma concentration data. |
| Area Under the Plasma Concentration-time Curve (AUC) of Ruxolitinib 25 mg SR on Day 1 | Day 1 | Blood samples were collected prior to and at 0.5, 1, 2, 3, 4, 6, and 9 hours after administration of ruxolitinib 25 mg SR on Day 1 of the study. The concentration of ruxolitinib was determined in plasma samples by a validated LC/MS/MS assay. The area under the plasma concentration-time curve (AUC) was derived from the plasma concentrations using a non-compartmental method and computed using the linear trapezoidal rule for increasing concentrations and the log-trapezoidal rule for decreasing concentrations with the software WinNonlin® version 6.0.0 (Pharsight Corporation, Mountain View, CA). |
| Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib 25 mg SR on Day 1 | Day 1 | Blood samples were collected prior to and at 0.5, 1, 2, 3, 4, 6, and 9 hours after administration of ruxolitinib 25 mg SR on Day 1 of the study. The concentration of ruxolitinib was determined in plasma samples by a validated LC/MS/MS assay. Standard non-compartmental pharmacokinetic methods were used to analyze the ruxolitinib plasma concentration data using WinNonlin® version 6.0.0 (Pharsight Corporation, Mountain View, CA). Cmax was taken directly from the observed plasma concentration data. |
| Change From Baseline in Spleen Length at Week 16 | Baseline to Week 16 | Spleen length was measured in centimeters by palpation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ruxolitinib Participants began administration with 25 mg ruxolitinib sustained release (SR) once daily (QD). After 8 weeks, if there was inadequate efficacy, the dose level could be titrated to 50 mg SR QD or 25 mg SR every other day (QOD) alternating with 50 mg SR QOD. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Commercial Supply per Sponsor | 12 |
| Overall Study | Consent Withdrawn | 2 |
Baseline characteristics
| Characteristic | Ruxolitinib |
|---|---|
| Age, Continuous | 67.2 years STANDARD_DEVIATION 7.94 |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 41 | 9 / 41 |
| serious Total, serious adverse events | 6 / 41 | 9 / 41 |
Outcome results
Primary
Overall Response (OR) at Week 16
The investigator graded OR according to the International Working Group for Myelofibrosis Research and Therapy criteria for treatment response. As bone marrow biopsies were not taken after baseline, the best achievable response was clinical improvement which required 1 of the following in the absence of progressive disease (PD): (1) A ≥ 2 g/dL increase in hemoglobin level or (2) either a palpable ≥ 50% reduction of splenomegaly of a spleen ≥ 10 cm at baseline or a spleen palpable at \> 5 cm at baseline becoming not palpable. PD required 1 of the following: (1) Progressive splenomegaly defined by the appearance of previously absent splenomegaly that was palpable at \> 5 cm below the left costal margin or a ≥ 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a ≥ 50% increase in palpable distance for baseline splenomegaly of \> 10 cm or (2) an increase in peripheral blood blast percentage to ≥ 20% that lasted for ≥ 8 weeks. Stable disease: None of the above.
Time frame: Baseline to Week 16
Population: Intent-to-treat population: All enrolled participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ruxolitinib | Overall Response (OR) at Week 16 | Clinical improvement | 17.1 Percentage of participants |
| Ruxolitinib | Overall Response (OR) at Week 16 | Stable disease | 80.5 Percentage of participants |
| Ruxolitinib | Overall Response (OR) at Week 16 | Progressive disease | 2.4 Percentage of participants |
Primary
Percentage of Participants With at Least 1 Adverse Event From Baseline Through Week 16
Time frame: Baseline to Week 16
Population: Safety population: All enrolled participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib | Percentage of Participants With at Least 1 Adverse Event From Baseline Through Week 16 | 78.0 Percentage of participants |
Secondary
Area Under the Plasma Concentration-time Curve (AUC) of Ruxolitinib 25 mg SR on Day 1
Blood samples were collected prior to and at 0.5, 1, 2, 3, 4, 6, and 9 hours after administration of ruxolitinib 25 mg SR on Day 1 of the study. The concentration of ruxolitinib was determined in plasma samples by a validated LC/MS/MS assay. The area under the plasma concentration-time curve (AUC) was derived from the plasma concentrations using a non-compartmental method and computed using the linear trapezoidal rule for increasing concentrations and the log-trapezoidal rule for decreasing concentrations with the software WinNonlin® version 6.0.0 (Pharsight Corporation, Mountain View, CA).
Time frame: Day 1
Population: Pharmacokinetic evaluable participants: All enrolled participants who received at least 1 dose of study medication and provided at least 1 plasma sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruxolitinib | Area Under the Plasma Concentration-time Curve (AUC) of Ruxolitinib 25 mg SR on Day 1 | 1550 nM*h | Standard Deviation 647 |
Secondary
Change From Baseline in Spleen Length at Week 16
Spleen length was measured in centimeters by palpation.
Time frame: Baseline to Week 16
Population: Intent-to-treat population: All enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruxolitinib | Change From Baseline in Spleen Length at Week 16 | -29.6 Percentage change | Standard Deviation 34.38 |
Secondary
Change From Baseline in Spleen Volume at Week 16
Spleen volume was measured by magnetic resonance imaging (or by computed tomography \[CT\] in applicable participants). Scans were read by a central reader. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares.
Time frame: Baseline to Week 16
Population: Intent-to-treat population: All enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruxolitinib | Change From Baseline in Spleen Volume at Week 16 | -22.3 Percentage change | Standard Deviation 20.79 |
Secondary
Change From Baseline in the Total Symptom Score at Week 16
Symptoms of myelofibrosis were assessed using the modified Myelofibrosis Symptom Assessment Form v2.0 diary that was to be completed by participants each night. The 7 symptoms (night sweats, itchiness, abdominal pain, pain under the ribs on left side, feeling of fullness \[early satiety\], bone/muscle pain, inactivity) were each rated on a scale from 0 (absent) to 10 (worst imaginable). The total symptom score was the sum of 6 of the 7 symptoms (inactivity was not included) and ranged from 0 to 60. A lower score indicated fewer symptoms. A negative change score indicated improvement.
Time frame: Baseline to Week 16
Population: Intent-to-treat population: All enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruxolitinib | Change From Baseline in the Total Symptom Score at Week 16 | -50.4 Percentage change | Standard Deviation 31.16 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib 25 mg SR on Day 1
Blood samples were collected prior to and at 0.5, 1, 2, 3, 4, 6, and 9 hours after administration of ruxolitinib 25 mg SR on Day 1 of the study. The concentration of ruxolitinib was determined in plasma samples by a validated LC/MS/MS assay. Standard non-compartmental pharmacokinetic methods were used to analyze the ruxolitinib plasma concentration data using WinNonlin® version 6.0.0 (Pharsight Corporation, Mountain View, CA). Cmax was taken directly from the observed plasma concentration data.
Time frame: Day 1
Population: Pharmacokinetic evaluable participants: All enrolled participants who received at least 1 dose of study medication and provided at least 1 plasma sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ruxolitinib | Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib 25 mg SR on Day 1 | 319 nM | Standard Deviation 119 |
Secondary
Percentage of Participants With ≥ 35% Reduction in Spleen Volume at Week 16 From Baseline
Spleen volume was measured by magnetic resonance imaging (or by computed tomography \[CT\] in applicable participants). Scans were read by a central reader. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares.
Time frame: Baseline to Week 16
Population: Intent-to-treat population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib | Percentage of Participants With ≥ 35% Reduction in Spleen Volume at Week 16 From Baseline | 26.8 Percentage of participants |
Secondary
Percentage of Participants With a ≥ 50% Reduction From Baseline in the Total Symptom Score at Week 16
Symptoms of myelofibrosis were assessed using the modified Myelofibrosis Symptom Assessment Form v2.0 diary that was to be completed by participants each night. The 7 symptoms (night sweats, itchiness, abdominal pain, pain under the ribs on left side, feeling of fullness \[early satiety\], bone/muscle pain, inactivity) were each rated on a scale from 0 (absent) to 10 (worst imaginable). The total symptom score was the sum of 6 of the 7 symptoms (inactivity was not included) and ranged from 0 to 60. A lower score indicated fewer symptoms.
Time frame: Baseline to Week 16
Population: Intent-to-treat population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ruxolitinib | Percentage of Participants With a ≥ 50% Reduction From Baseline in the Total Symptom Score at Week 16 | 43.9 Percentage of participants |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) of Ruxolitinib 25 mg SR on Day 1
Blood samples were collected prior to and at 0.5, 1, 2, 3, 4, 6, and 9 hours after administration of ruxolitinib 25 mg SR on Day 1 of the study. The concentration of ruxolitinib was determined in plasma samples by a validated LC/MS/MS assay. Standard noncompartmental pharmacokinetic methods were used to analyze the ruxolitinib plasma concentration data using WinNonlin® version 6.0.0 (Pharsight Corporation, Mountain View, CA). Tmax was taken directly from the observed plasma concentration data.
Time frame: Day 1
Population: Pharmacokinetic evaluable participants: All enrolled participants who received at least 1 dose of study medication and provided at least 1 plasma sample.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ruxolitinib | Time to Reach the Maximum Plasma Concentration (Tmax) of Ruxolitinib 25 mg SR on Day 1 | 2.0 h |