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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ruxolitinib 25 mg SR/10, 15, or 20 mg IR | Experimental | 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. At Week 16, participants transitioned to ruxolitinib 10, 15, or 20 mg immediate release (IR) orally twice daily. Participants who continued to demonstrate benefit in the opinion of the investigator could remain on ruxolitinib IR until the last participant completed Week 36 or the commercial availability of ruxolitinib IR, whichever was earlier; the dose received was based on platelet counts at the time of transition. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ruxolitinib | Drug | Ruxolitinib was supplied as SR and IR formulated tablets. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With at Least 1 Adverse Event From Baseline Through Week 16 | Baseline to Week 16 | |
| 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. | Baseline to Week 16 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline to Week 16 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Srdan Verstovsek, MD, PhD | M.D. Anderson Cancer Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Scottsdale | Arizona | United States | ||||
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. At Week 16, participants transitioned to ruxolitinib 10, 15, or 20 mg immediate release (IR) orally twice daily up to when the last participant completed Week 36 or the commercial availability of ruxolitinib IR, whichever was earlier; the dose received was based on platelet counts at the time of transition. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Intent-to-treat population: All enrolled participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants With at Least 1 Adverse Event From Baseline Through Week 16 | Safety population: All enrolled participants who took at least 1 dose of study drug. | Posted | Number | Percentage of participants | Baseline to Week 16 |
|
|
Adverse events were collected from Baseline through the end of the study
Safety population: All enrolled participants who took at least 1 dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ruxolitinib - Weeks 1-16 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Incyte Corporation | 855 463-3463 |
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| ID | Term |
|---|---|
| D055728 | Primary Myelofibrosis |
| D009196 | Myeloproliferative Disorders |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C540383 | ruxolitinib |
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| Change From Baseline in Spleen Length at Week 16 | Spleen length was measured in centimeters by palpation. | Baseline to Week 16 |
| 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. | Baseline to Week 16 |
| 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. | Baseline to Week 16 |
| 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. | Baseline to Week 16 |
| 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. | Day 1 |
| 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. | Day 1 |
| 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). | Day 1 |
| Winter Park |
| Florida |
| United States |
| Houston | Texas | TX | United States |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
| 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. | Intent-to-treat population: All enrolled participants. | Posted | Number | Percentage of participants | Baseline to Week 16 |
|
|
|
| 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. | Intent-to-treat population: All enrolled participants. | Posted | Mean | Standard Deviation | Percentage change | Baseline to Week 16 |
|
|
|
| Secondary | Change From Baseline in Spleen Length at Week 16 | Spleen length was measured in centimeters by palpation. | Intent-to-treat population: All enrolled participants. | Posted | Mean | Standard Deviation | Percentage change | Baseline to Week 16 |
|
|
|
| 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. | Intent-to-treat population: All enrolled participants. | Posted | Number | 95% Confidence Interval | Percentage of participants | Baseline to Week 16 |
|
|
|
| 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. | Intent-to-treat population: All enrolled participants. | Posted | Mean | Standard Deviation | Percentage change | Baseline to Week 16 |
|
|
|
| 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. | Intent-to-treat population: All enrolled participants. | Posted | Number | 95% Confidence Interval | Percentage of participants | Baseline to Week 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. | Pharmacokinetic evaluable participants: All enrolled participants who received at least 1 dose of study medication and provided at least 1 plasma sample. | Posted | Mean | Standard Deviation | nM | Day 1 |
|
|
|
| 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. | Pharmacokinetic evaluable participants: All enrolled participants who received at least 1 dose of study medication and provided at least 1 plasma sample. | Posted | Median | Full Range | h | Day 1 |
|
|
|
| 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). | Pharmacokinetic evaluable participants: All enrolled participants who received at least 1 dose of study medication and provided at least 1 plasma sample. | Posted | Mean | Standard Deviation | nM*h | Day 1 |
|
|
|
| 6 |
| 41 |
| 27 |
| 41 |
| EG001 | Ruxolitinib - After Week 16 | At Week 16, participants transitioned to ruxolitinib 10, 15, or 20 mg immediate release (IR) orally twice daily up to when the last participant completed Week 36 or the commercial availability of ruxolitinib IR, whichever was earlier; the dose received was based on platelet counts at the time of transition. | 9 | 41 | 9 | 41 |
| Cardiac arrest | Cardiac disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Cardiac failure congestive | Cardiac disorders | MedDRA 14.1 | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Gastrointestinal hemorrhage | Gastrointestinal disorders | MedDRA 14.1 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 14.1 | Systematic Assessment |
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| Generalized edema | General disorders | MedDRA 14.1 | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA 14.1 | Systematic Assessment |
|
| Clostridium difficile colitis | Infections and infestations | MedDRA 14.1 | Systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA 14.1 | Systematic Assessment |
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| Herpes zoster | Infections and infestations | MedDRA 14.1 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 14.1 | Systematic Assessment |
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| Prostate infection | Infections and infestations | MedDRA 14.1 | Systematic Assessment |
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| Hip fracture | Injury, poisoning and procedural complications | MedDRA 14.1 | Systematic Assessment |
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| Patella fracture | Injury, poisoning and procedural complications | MedDRA 14.1 | Systematic Assessment |
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| Dehydration | Metabolism and nutrition disorders | MedDRA 14.1 | Systematic Assessment |
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| Acute myeloid leukemia | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 14.1 | Systematic Assessment |
|
| Nephrolithiasis | Renal and urinary disorders | MedDRA 14.1 | Systematic Assessment |
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| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA 14.1 | Systematic Assessment |
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| Pulmonary edema | Respiratory, thoracic and mediastinal disorders | MedDRA 14.1 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 14.1 | Systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA 14.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (Unspecified) | Systematic Assessment |
|
Following the first publication, the Institution and/or Principal Investigator may publish data or results from the Study, provided, however, that the Institution and/or Principal Investigator submits the proposed publication to the Sponsor for review at least thirty (30) days prior to the date of the proposed publication. Sponsor may remove from the proposed publication any information that is considered confidential and/or proprietary other than Study data and results.
| Title | Measurements |
|---|---|
|