Clinical trial NCT00952289: COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial
Official title: A Randomized, Double-blind, Placebo-controlled Study of the JAK Inhibitor INCB018424 Tablets Administered Orally to Subjects With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: MPN (Myeloproliferative Neoplasms)
Keywords: Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2009-08-06
Enrollment: 309
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a randomized, double-blind study comparing the efficacy and safety of ruxolitinib (INCB018424) tablets to matching placebo tablets in patients diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Detailed description: Patients with spleen growth of greater than 25% based on an increase in spleen volume from Baseline were eligible for early unblinding, and for patients on placebo, cross over to ruxolitinib prior to the primary study endpoint being reached. If this spleen growth occurred before Week 24, it must have been accompanied by specific worsening of symptoms, based on worsening early satiety accompanied by weight loss or worsening pain requiring daily narcotic use. After Week 24, asymptomatic spleen growth alone was sufficient for early unblinding and potential cross over. Patients found to have been randomized to ruxolitinib after early unblinding prior to Week 24 were discontinued.

When half of the patients remaining in the study completed the Week 36 visit and all patients enrolled completed Week 24 or discontinued, the database was frozen and the primary analysis was conducted. Once this was complete, all patients were unblinded and patients who had been randomized to placebo were given the opportunity to cross over to ruxolitinib treatment, provided hematology laboratory parameters were adequate; Patients receiving benefit could continue treatment until the later of marketing approval or when the last randomized patient remaining in the study had completed Week 144 (36 months).

Eligibility criteria: Inclusion Criteria:

* Subjects must be diagnosed with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF) according to the 2008 World Health Organization criteria
* Subjects with myelofibrosis 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 Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3
* Subjects who have not previously received treatment with a Janus kinase (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 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

Primary outcomes:
measure: Number of Participants Achieving ≥ 35% Reduction in Spleen Volume From Baseline to Week 24
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib
timeFrame: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).
measure: Duration of Maintenance of a ≥ 35% Reduction From Baseline in Spleen Volume Among Patients Initially Randomized to Receive Ruxolitinib
timeFrame: Baseline Visit and every 12 weeks until the data cut-off date (up to 14 months).
measure: Number of Participants With a ≥ 50% Reduction in Total Symptom Score From Baseline to Week 24
timeFrame: Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit.
measure: Change From Baseline to Week 24 in Total Symptom Score
timeFrame: Baseline and Week 24. Baseline total score was the average of the daily total scores for the last 7 days prior to randomization. The Week 24 total score was the average of daily total scores from the 28 days prior to the Week 24 visit.
measure: Overall Survival
timeFrame: From randomization to the data cut-off date (up to 14 months).
measure: Overall Survival Time
timeFrame: From randomization to the data cut-off date (up to 14 months).
measure: Overall Survival - Extended Data
timeFrame: From randomization to 4 months after the data cut-off date (up to 18 months).
measure: Overall Survival Time - Extended Data
timeFrame: From randomization to 4 months after the data cut-off date (up to 18 months).
measure: Overall Survival at Week 144
timeFrame: Week 144
measure: Overall Survival Time at Week 144
timeFrame: Week 144
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Scottsdale
country: United States
state: Arizona
city: Baldwin Park
country: United States
state: California
city: Bellflower
country: United States
state: California
city: Beverly Hills
country: United States
state: California
city: Corona
country: United States
state: California
city: Fullerton
country: United States
state: California
city: Highland
country: United States
state: California
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Orange
country: United States
state: California
city: Palo Alto
country: United States
state: California
city: Panorama City
country: United States
state: California
city: Rancho Cucamonga
country: United States
state: California
city: Riverside
country: United States
state: California
city: Sacramento
country: United States
state: California
city: San Diego
country: United States
state: California
city: West Covina
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Denver
country: United States
state: Colorado
city: Fort Collins
country: United States
state: Colorado
city: Norwalk
country: United States
state: Connecticut
city: Washington
country: United States
state: District of Columbia
city: Boynton Beach
country: United States
state: Florida
city: Gainesville
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Augusta
country: United States
state: Georgia
city: Honolulu
country: United States
state: Hawaii
city: Boise
country: United States
state: Idaho
city: Meridian
country: United States
state: Idaho
city: Twin Falls
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Beech Grove
country: United States
state: Indiana
city: Indianapolis
country: United States
state: Indiana
city: Ames
country: United States
state: Iowa
city: Iowa City
country: United States
state: Iowa
city: Sioux City
country: United States
state: Iowa
city: Waterloo
country: United States
state: Iowa
city: Louisville
country: United States
state: Kentucky
city: Alexandria
country: United States
state: Louisiana
city: New Orleans
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Ann Arbor
country: United States
state: Michigan
city: Detroit
country: United States
state: Michigan
city: Novi
country: United States
state: Michigan
city: Southfield
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Rochester
country: United States
state: Minnesota
city: Saint Louis Park
country: United States
state: Minnesota
city: New Albany
country: United States
state: Mississippi
city: Saint Louis
country: United States
state: Missouri
city: Billings
country: United States
state: Montana
city: Denville
country: United States
state: New Jersey
city: Hackensack
country: United States
state: New Jersey
city: Morristown
country: United States
state: New Jersey
city: Somerville
country: United States
state: New Jersey
city: Albuquerque
country: United States
state: New Mexico
city: East Setauket
country: United States
state: New York
city: New York
country: United States
state: New York
city: Valhalla
country: United States
state: New York
city: Durham
country: United States
state: North Carolina
city: Hickory
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Bismarck
country: United States
state: North Dakota
city: Akron
country: United States
state: Ohio
city: Canton
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Dayton
country: United States
state: Ohio
city: Dover
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Germantown
country: United States
state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: New Braunfels
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Burlington
country: United States
state: Vermont
city: Everett
country: United States
state: Washington
city: Seattle
country: United States
state: Washington
city: Milwaukee
country: United States
state: Wisconsin
city: Darlinghurst
country: Australia
state: New South Wales
city: Kogarah
country: Australia
state: New South Wales
city: Randwick
country: Australia
state: New South Wales
city: St Leonards
country: Australia
state: New South Wales
city: Brisbane
country: Australia
state: Queensland
city: Douglas
country: Australia
state: Queensland
city: Herston
country: Australia
state: Queensland
city: Milton
country: Australia
state: Queensland
city: Woolloongabba
country: Australia
state: Queensland
city: Bedford Park
country: Australia
state: South Australia
city: Box Hill
country: Australia
state: Victoria
city: Clayton
country: Australia
state: Victoria
city: Frankston
country: Australia
state: Victoria
city: Ringwood East
country: Australia
state: Victoria
city: Fremantle
country: Australia
state: Western Australia
city: Perth
country: Australia
state: Western Australia
city: Vancouver
country: Canada
state: British Columbia
city: St. John's
country: Canada
state: Newfoundland and Labrador
city: Halifax
country: Canada
state: Nova Scotia
city: London
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Levis
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Srdan Verstovsek, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Verstovsek S, Mesa R, Gotlib J, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK1/2 inhibitor INCB18424 (424) vs placebo (PB) for patients with myelofibrosis (MF). The 47th Annual ASCO meeting, Chicago, IL. J Clin Oncol 2011; 29 (suppl; abstract 6500). Verstovsek S, Mesa R, Gotlib J, et al. Results of COMFORT-I, a randomized, double-blind phase III trial of the JAK1 and JAK2 inhibitor ruxolitinib (INCB018424) versus placebo for patients with myelofibrosis. The 16th Annual EHA meeting, London, UK. Haematologica 2011; 96 (suppl 2; abstract 0505).
citation: Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger M, Miller C, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner E, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Koumenis IL, Sun W, Sandor V, Kantarjian HM. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799-807. doi: 10.1056/NEJMoa1110557.
citation: Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S, Sun W, Sandor V, Kantarjian HM. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 2013 Dec;98(12):1865-71. doi: 10.3324/haematol.2013.092155. Epub 2013 Sep 13.
citation: Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Raza A, Vaddi K, Sun W, Peng W, Sandor V, Kantarjian H; COMFORT-I investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015 Apr;100(4):479-88. doi: 10.3324/haematol.2014.115840. Epub 2015 Jan 23.
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.
citation: Miller CB, Komrokji RS, Mesa RA, Sun W, Montgomery M, Verstovsek S. Practical Measures of Clinical Benefit With Ruxolitinib Therapy: An Exploratory Analysis of COMFORT-I. Clin Lymphoma Myeloma Leuk. 2017 Aug;17(8):479-487. doi: 10.1016/j.clml.2017.05.015. Epub 2017 May 12.
citation: Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Jones M, Kornacki D, Sun K, Kantarjian H; COMFORT-I investigators. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017 Feb 22;10(1):55. doi: 10.1186/s13045-017-0417-z.
citation: Deininger M, Radich J, Burn TC, Huber R, Paranagama D, Verstovsek S. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood. 2015 Sep 24;126(13):1551-4. doi: 10.1182/blood-2015-03-635235. Epub 2015 Jul 30.
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.
citation: Mesa RA, Verstovsek S, Gupta V, Mascarenhas JO, Atallah E, Burn T, Sun W, Sandor V, Gotlib J. Effects of ruxolitinib treatment on metabolic and nutritional parameters in patients with myelofibrosis from COMFORT-I. Clin Lymphoma Myeloma Leuk. 2015 Apr;15(4):214-221.e1. doi: 10.1016/j.clml.2014.12.008. Epub 2014 Dec 27.
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.
citation: Mesa RA, Gotlib J, Gupta V, Catalano JV, Deininger MW, Shields AL, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH, Hare T, Erickson-Viitanen S, Sun W, Sandor V, Levy RS, Kantarjian HM, Verstovsek S. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013 Apr 1;31(10):1285-92. doi: 10.1200/JCO.2012.44.4489. Epub 2013 Feb 19.