Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II: The COMFORT-II Trial

A Randomized Study of Ruxolitinib Tablets Compared to Best Available Therapy in Subjects With Primary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis

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).

Study Overview

• Status: Completed
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Best Available Therapy (BAT)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 219
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Novartis Investigative Site
  • Linz, Austria, 4010
    • Novartis Investigative Site
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Vienna, Austria, A-1090
    • Novartis Investigative Site
• Belgium
  • Antwerp, Belgium, 2020
    • Novartis Investigative Site
  • Antwerp, Belgium, 2060
    • Novartis Investigative Site
  • Brugge, Belgium, 8000
    • Novartis Investigative Site
  • Brussel, Belgium, 1200
    • Novartis Investigative Site
  • Hasselt, Belgium, 3500
    • Novartis Investigative Site
  • Kortrijk, Belgium, 8500
    • Novartis Investigative Site
  • La Louvière, Belgium, 7100
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Roeselare, Belgium, 8800
    • Novartis Investigative Site
  • Yvoir, Belgium, 5530
    • Novartis Investigative Site
• France
  • Amiens cedex 1, France, 80054
    • Novartis Investigative Site
  • Caen Cedex, France, 14033
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Lens Cedex, France, 62307
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Lyon, France, 69437
    • Novartis Investigative Site
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Nimes, France, 30029
    • Novartis Investigative Site
  • Paris, France, 75014
    • Novartis Investigative Site
  • Paris, France, 75010
    • Novartis Investigative Site
  • Paris, France, 75012
    • Novartis Investigative Site
  • Pessac, France, 33600
    • Novartis Investigative Site
  • Poitiers Cedex, France, 86021
    • Novartis Investigative Site
  • Rennes, France, F-35043
    • Novartis Investigative Site
  • Strasbourg, France, 67091
    • Novartis Investigative Site
  • Toulouse Cedex, France, 31059
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Frankfurt/M, Germany, 60590
    • Novartis Investigative Site
  • Köln, Germany, 50937
    • Novartis Investigative Site
  • Magdeburg, Germany, 39120
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Stuttgart, Germany, 70376
    • Novartis Investigative Site
  • Tuebingen, Germany, 72076
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Italy
  • Florence, Italy, 50134
    • Novartis Investigative Site
  • Orbassano, Italy, 10043
    • Novartis Investigative Site
  • Pavia, Italy, 27100
    • Novartis Investigative Site
  • (pv)
    • Pavia, (pv), Italy, 27100
      • Novartis Investigative Site
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081
    • Novartis Investigative Site
  • Den Haag, Netherlands, 2545 CH
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Maastricht, Netherlands, 5800
    • Novartis Investigative Site
  • Nijmegen, Netherlands, 6500 MB
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Novartis Investigative Site
• Sweden
  • Göteborg, Sweden, SE-413 45
    • Novartis Investigative Site
  • Stockholm, Sweden, SE-118 83
    • Novartis Investigative Site
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Novartis Investigative Site
  • Cambridge, United Kingdom, CB2 2QQ
    • Novartis Investigative Site
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX37LJ
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects must be diagnosed with PMF, PPV-MF or PET-MF according to the 2008 World Health Organization criteria
• Subjects with MF 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 ECOG performance status of 0, 1, 2 or 3
• Subjects with peripheral blood blast count of < 10%.
• Subjects who have not previously received treatment with a 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 any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ruxolitinib; 5 mg tablets administered orally in an outpatient setting according to the protocol-specified dosing schedule	Drug: Ruxolitinib; 5 mg tablets packaged as 60-count in high-density polyethylene bottles
Active Comparator: Best Available Therapy (BAT); 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); Prescribing and usage per respective package inserts

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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 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 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 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	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	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	Baseline, once a year
Duration of Follow-up by Treatment	Number of Participants with duration of Follow up	baseline, 260 weeks (end of study)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Verstovsek S, Gotlib J, Mesa RA, Vannucchi AM, Kiladjian JJ, Cervantes F, Harrison CN, Paquette R, Sun W, Naim A, Langmuir P, Dong T, Gopalakrishna P, Gupta V. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017 Sep 29;10(1):156. doi: 10.1186/s13045-017-0527-7.
• McMullin MF, Harrison CN, Niederwieser D, Demuynck H, Jakel N, Gopalakrishna P, McQuitty M, Stalbovskaya V, Recher C, Theunissen K, Gisslinger H, Kiladjian JJ, Al-Ali HK. The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis. Exp Hematol Oncol. 2015 Sep 15;4:26. doi: 10.1186/s40164-015-0021-2. eCollection 2015.
• Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, Sarlis NJ, Peng W, Sandor V, Gopalakrishna P, Hmissi A, Stalbovskaya V, Gupta V, Harrison C, Verstovsek S; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015 Sep;100(9):1139-45. doi: 10.3324/haematol.2014.119545. Epub 2015 Jun 11.
• Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G, Harrison CN, Knoops L, Gisslinger H; COMFORT-II investigators. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013 Dec 12;122(25):4047-53. doi: 10.1182/blood-2013-02-485888. Epub 2013 Oct 30. Erratum In: Blood. 2016 Dec 22;128(25):3013.
• Wilkins BS, Radia D, Woodley C, Farhi SE, Keohane C, Harrison CN. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica. 2013 Dec;98(12):1872-6. doi: 10.3324/haematol.2013.095109. Epub 2013 Sep 20.
• Mesa RA, Kiladjian JJ, Verstovsek S, Al-Ali HK, Gotlib J, Gisslinger H, Levy R, Siulnik A, Gupta V, Khan M, DiPersio JF, McQuitty M, Catalano JV, Hunter DS, Knoops L, Deininger M, Cervantes F, Miller C, Vannucchi AM, Silver RT, Barbui T, Talpaz M, Barosi G, Winton EF, Mendeson E, Harvey JH Jr, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Sun W, Sandor V, Kantarjian HM, Harrison C. Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies. Haematologica. 2014 Feb;99(2):292-8. doi: 10.3324/haematol.2013.087650. Epub 2013 Aug 2.
• Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, McQuitty M, Hunter DS, Levy R, Knoops L, Cervantes F, Vannucchi AM, Barbui T, Barosi G. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):787-98. doi: 10.1056/NEJMoa1110556.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2009
• Primary Completion (Actual): March 4, 2015
• Study Completion (Actual): March 4, 2015

Study Registration Dates

• First Submitted: July 6, 2009
• First Submitted That Met QC Criteria: July 7, 2009
• First Posted (Estimate): July 8, 2009

Study Record Updates

• Last Update Posted (Actual): August 19, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Myelofibrosis; Post-Essential Thrombocythemia Myelofibrosis; Post-Polycythemia Vera Myelofibrosis
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Primary Myelofibrosis; Polycythemia Vera
• Other Study ID Numbers: CINC424A2352; CINCB 18424-352 (Other Identifier: INCYTE); 2009-009858-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No