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

Primary Purpose

Myelofibrosis

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Ruxolitinib

Best Available Therapy (BAT)

About this trial

This is an interventional treatment trial for Myelofibrosis focused on measuring Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ruxolitinib

Best Available Therapy (BAT)

Arm Description

5 mg tablets administered orally in an outpatient setting according to the protocol-specified dosing schedule

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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

Progression-free Survival (PFS)

Median of time progression free survival (95% CI), years

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

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

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

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

Duration of Follow-up by Treatment

Number of Participants with duration of Follow up

Full Information

NCT ID

NCT00934544

First Posted

July 6, 2009

Last Updated

July 11, 2019

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00934544

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

July 1, 2009 (Actual)

Primary Completion Date

March 4, 2015 (Actual)

Study Completion Date

March 4, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelofibrosis

Keywords

Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

219 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ruxolitinib

Arm Type

Experimental

Arm Description

5 mg tablets administered orally in an outpatient setting according to the protocol-specified dosing schedule

Arm Title

Best Available Therapy (BAT)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ruxolitinib

Intervention Description

5 mg tablets packaged as 60-count in high-density polyethylene bottles

Intervention Type

Drug

Intervention Name(s)

Best Available Therapy (BAT)

Intervention Description

Prescribing and usage per respective package inserts

Primary Outcome Measure Information:

Title

Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 48

Description

Time Frame

Baseline, Week 48

Secondary Outcome Measure Information:

Title

Duration of Maintenance of Spleen Volume Reduction (Median)

Description

Time Frame

Baseline, up to Year 5

Title

Duration of Maintenance of Spleen Volume Reduction (Kaplan-Meier Estimates)

Description

Time Frame

Baseline, up to Year 5

Title

Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24

Description

Time Frame

Baseline, Week 24

Title

Time to First at Least 35% Reduction in Spleen Volume From Baseline by Treatment (Primary Analysis)

Description

Time Frame

Time from randomization and date of the first MRI showing at least 35% reduction from baseline in spleen volume

Title

Progression-free Survival (PFS)

Description

Median of time progression free survival (95% CI), years

Time Frame

Time from randomization and the earliest of either increase in spleen volume >=25% from on-study nadir, splenic irradiation, splenectomy, leukemic transformation or death

Title

Leukemia-free Survival (LFS)

Description

Time Frame

Time from randomization and earliest of either leukemia or death

Title

Overall Survival (OS)

Description

Time Frame

From randomization until death from any cause

Title

Percentage of Participants With Bone Marrow Histomorphology at Week 48 (Primary Analysis)

Description

Time Frame

48 weeks

Title

Bone Marrow Histomorphology

Description

Time Frame

Baseline, once a year

Title

Duration of Follow-up by Treatment

Description

Number of Participants with duration of Follow up

Time Frame

baseline, 260 weeks (end of study)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Innsbruck

ZIP/Postal Code

6020

Country

Austria

Facility Name

Novartis Investigative Site

City

Linz

ZIP/Postal Code

4010

Country

Austria

Facility Name

Novartis Investigative Site

City

Salzburg

ZIP/Postal Code

5020

Country

Austria

Facility Name

Novartis Investigative Site

City

Vienna

ZIP/Postal Code

A-1090

Country

Austria

Facility Name

Novartis Investigative Site

City

Antwerp

ZIP/Postal Code

2020

Country

Belgium

Facility Name

Novartis Investigative Site

City

Antwerp

ZIP/Postal Code

2060

Country

Belgium

Facility Name

Novartis Investigative Site

City

Brugge

ZIP/Postal Code

8000

Country

Belgium

Facility Name

Novartis Investigative Site

City

Brussel

ZIP/Postal Code

1200

Country

Belgium

Facility Name

Novartis Investigative Site

City

Hasselt

ZIP/Postal Code

3500

Country

Belgium

Facility Name

Novartis Investigative Site

City

Kortrijk

ZIP/Postal Code

8500

Country

Belgium

Facility Name

Novartis Investigative Site

City

La Louvière

ZIP/Postal Code

7100

Country

Belgium

Facility Name

Novartis Investigative Site

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

Novartis Investigative Site

City

Roeselare

ZIP/Postal Code

8800

Country

Belgium

Facility Name

Novartis Investigative Site

City

Yvoir

ZIP/Postal Code

5530

Country

Belgium

Facility Name

Novartis Investigative Site

City

Amiens cedex 1

ZIP/Postal Code

80054

Country

France

Facility Name

Novartis Investigative Site

City

Caen Cedex

ZIP/Postal Code

14033

Country

France

Facility Name

Novartis Investigative Site

City

Grenoble

ZIP/Postal Code

38043

Country

France

Facility Name

Novartis Investigative Site

City

Lens Cedex

ZIP/Postal Code

62307

Country

France

Facility Name

Novartis Investigative Site

City

Lille

ZIP/Postal Code

59037

Country

France

Facility Name

Novartis Investigative Site

City

Lyon

ZIP/Postal Code

69437

Country

France

Facility Name

Novartis Investigative Site

City

Marseille

ZIP/Postal Code

13273

Country

France

Facility Name

Novartis Investigative Site

City

Nimes

ZIP/Postal Code

30029

Country

France

Facility Name

Novartis Investigative Site

City

Paris

ZIP/Postal Code

75010

Country

France

Facility Name

Novartis Investigative Site

City

Paris

ZIP/Postal Code

75012

Country

France

Facility Name

Novartis Investigative Site

City

Paris

ZIP/Postal Code

75014

Country

France

Facility Name

Novartis Investigative Site

City

Pessac

ZIP/Postal Code

33600

Country

France

Facility Name

Novartis Investigative Site

City

Poitiers Cedex

ZIP/Postal Code

86021

Country

France

Facility Name

Novartis Investigative Site

City

Rennes

ZIP/Postal Code

F-35043

Country

France

Facility Name

Novartis Investigative Site

City

Strasbourg

ZIP/Postal Code

67091

Country

France

Facility Name

Novartis Investigative Site

City

Toulouse Cedex

ZIP/Postal Code

31059

Country

France

Facility Name

Novartis Investigative Site

City

Villejuif Cedex

ZIP/Postal Code

94805

Country

France

Facility Name

Novartis Investigative Site

City

Berlin

ZIP/Postal Code

13353

Country

Germany

Facility Name

Novartis Investigative Site

City

Frankfurt/M

ZIP/Postal Code

60590

Country

Germany

Facility Name

Novartis Investigative Site

City

Köln

ZIP/Postal Code

50937

Country

Germany

Facility Name

Novartis Investigative Site

City

Magdeburg

ZIP/Postal Code

39120

Country

Germany

Facility Name

Novartis Investigative Site

City

Mainz

ZIP/Postal Code

55131

Country

Germany

Facility Name

Novartis Investigative Site

City

Muenster

ZIP/Postal Code

48149

Country

Germany

Facility Name

Novartis Investigative Site

City

Stuttgart

ZIP/Postal Code

70376

Country

Germany

Facility Name

Novartis Investigative Site

City

Tuebingen

ZIP/Postal Code

72076

Country

Germany

Facility Name

Novartis Investigative Site

City

Ulm

ZIP/Postal Code

89081

Country

Germany

Facility Name

Novartis Investigative Site

City

Pavia

State/Province

(pv)

ZIP/Postal Code

27100

Country

Italy

Facility Name

Novartis Investigative Site

City

Monza

State/Province

ZIP/Postal Code

20900

Country

Italy

Facility Name

Novartis Investigative Site

City

Milano

State/Province

ZIP/Postal Code

20162

Country

Italy

Facility Name

Novartis Investigative Site

City

Florence

ZIP/Postal Code

50134

Country

Italy

Facility Name

Novartis Investigative Site

City

Orbassano

ZIP/Postal Code

10043

Country

Italy

Facility Name

Novartis Investigative Site

City

Pavia

ZIP/Postal Code

27100

Country

Italy

Facility Name

Novartis Investigative Site

City

Amsterdam

ZIP/Postal Code

1081

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Den Haag

ZIP/Postal Code

2545 CH

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Groningen

ZIP/Postal Code

9713 GZ

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Maastricht

ZIP/Postal Code

5800

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Nijmegen

ZIP/Postal Code

6500 MB

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Rotterdam

ZIP/Postal Code

3015 CE

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Catalunya

ZIP/Postal Code

08036

Country

Spain

Facility Name

Novartis Investigative Site

City

Valencia

State/Province

Comunidad Valenciana

ZIP/Postal Code

46010

Country

Spain

Facility Name

Novartis Investigative Site

City

Majadahonda

State/Province

Madrid

ZIP/Postal Code

28222

Country

Spain

Facility Name

Novartis Investigative Site

City

Göteborg

ZIP/Postal Code

SE-413 45

Country

Sweden

Facility Name

Novartis Investigative Site

City

Stockholm

ZIP/Postal Code

SE-118 83

Country

Sweden

Facility Name

Novartis Investigative Site

City

Belfast

ZIP/Postal Code

BT9 7AB

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Cambridge

ZIP/Postal Code

CB2 2QQ

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

London

ZIP/Postal Code

SE1 9RT

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Oxford

ZIP/Postal Code

OX37LJ

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

28962635

Citation

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.

Results Reference

derived

PubMed Identifier

26380150

Citation

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.

Results Reference

derived

PubMed Identifier

26069290

Citation

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.

Results Reference

derived

PubMed Identifier

24174625

Citation

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.

Results Reference

derived

PubMed Identifier

24056820

Citation

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.

Results Reference

derived

PubMed Identifier

23911705

Citation

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.

Results Reference

derived

PubMed Identifier

22375970

Citation

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.

Results Reference

derived

Learn more about this trial

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

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

Myelofibrosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial