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

Myelofibrosis Clinical 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00934544
• Other study ID #: CINC424A2352
• Secondary ID: CINCB 18424-3522
• Status: Completed
• Phase: Phase 3
• Start date: July 1, 2009
• Est. completion date: March 4, 2015

Study information

• Verified date: July 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 219
• Est. completion date: March 4, 2015
• Est. primary completion date: March 4, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelofibrosis
• Polycythemia Vera
• Primary Myelofibrosis

Intervention

Drug:
• Ruxolitinib
5 mg tablets packaged as 60-count in high-density polyethylene bottles
• Best Available Therapy (BAT)
Prescribing and usage per respective package inserts

Locations

Country	Name	City	State
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Antwerp
Belgium	Novartis Investigative Site	Antwerp
Belgium	Novartis Investigative Site	Brugge
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Hasselt
Belgium	Novartis Investigative Site	Kortrijk
Belgium	Novartis Investigative Site	La Louvière
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Roeselare
Belgium	Novartis Investigative Site	Yvoir
France	Novartis Investigative Site	Amiens cedex 1
France	Novartis Investigative Site	Caen Cedex
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Lens Cedex
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Nimes
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Pessac
France	Novartis Investigative Site	Poitiers Cedex
France	Novartis Investigative Site	Rennes
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Toulouse Cedex
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Frankfurt/M
Germany	Novartis Investigative Site	Köln
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Stuttgart
Germany	Novartis Investigative Site	Tuebingen
Germany	Novartis Investigative Site	Ulm
Italy	Novartis Investigative Site	Florence
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Orbassano
Italy	Novartis Investigative Site	Pavia
Italy	Novartis Investigative Site	Pavia	(pv)
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Maastricht
Netherlands	Novartis Investigative Site	Nijmegen
Netherlands	Novartis Investigative Site	Rotterdam
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Majadahonda	Madrid
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Stockholm
United Kingdom	Novartis Investigative Site	Belfast
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Oxford

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Duration of Follow-up by Treatment	Number of Participants with duration of Follow up	baseline, 260 weeks (end of study)