Clinical Trial: Study of Ruxolitinib (INCB018424) Sustained Release Formulation in Myelofibrosis Patients

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: An Open-label Assessment of Once-daily Dosing of a Sustained Release (SR) Formulation of INCB018424 in Patients With Primary Myelofibrosis, Post-essential Thrombocythemia

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 Summary:

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.

Current Primary Outcome:

• Percentage of Participants With at Least 1 Adverse Event From Baseline Through Week 16 [ Time Frame: Baseline to Week 16 ]
• Overall Response (OR) at Week 16 [ Time Frame: 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.

Original Primary Outcome: Change in platelet count from Baseline to each visit where platelet count is measured duing the treatment phase of the study. [ Time Frame: Baseline and every 1-2 weeks through the Week 16 Visit or until early termination from the study. ]

Current Secondary Outcome:

• Change From Baseline in Spleen Volume at Week 16 [ Time Frame: 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 Spleen Length at Week 16 [ Time Frame: Baseline to Week 16 ]
  Spleen length was measured in centimeters by palpation.
• Percentage of Participants With ≥ 35% Reduction in Spleen Volume at Week 16 From Baseline [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
• Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib 25 mg SR on Day 1 [ Time Frame: 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 to Reach the Maximum Plasma Concentration (Tmax) of Ruxolitinib 25 mg SR on Day 1 [ Time Frame: 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 [ Time Frame: 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).

Original Secondary Outcome: Change in spleen volume measured by MRI/CT and change in spleen length measured by palpation during the Treatment Phase of the study. [ Time Frame: Spleen Volume - Baseline and Week 16; Spleen Palpation - Baseline and every 2-4 weeks thereafter until Week 16 Visit or early termination from the study. ]

Information By: Incyte Corporation

Dates:
Date Received: April 21, 2011
Date Started: March 2011
Date Completion:
Last Updated: February 5, 2014
Last Verified: December 2013