Clinical trial NCT01178281: Study of Pomalidomide in Persons With Myeloproliferative-Neoplasm-Associated Myelofibrosis and RBC-Transfusion-Dependence
Official title: A Phase-3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Compare Efficacy and Safety of Pomalidomide in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Red Blood Cell-Transfusion-Dependence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Primary Myelofibrosis
MPN-associated Myelofibrosis
Keywords: Myelofibrosis
Post-polycythemia vera myelofibrosis
Post-essential thrombocythemia myelofibrosis
RBC-transfusion-dependence
Primary Myelofibrosis
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2010-08-10
Enrollment: 267
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: The objective of this study is to determine whether pomalidomide is safe and effective in reversing red blood cell (RBC)-transfusion-dependence in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis (global study) and in reversing anemia in Chinese with MPN-associated myelofibrosis and severe anemia not receiving RBC-transfusions (China extension study only)

Detailed description: The multicenter global study was conducted in 15 countries including Australia, Austria, Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Russia, Spain, Sweden, the United Kingdom, and the United States. The global study enrolled participants with myeloproliferative neoplasm (MPN)-associated myelofibrosis and RBC-transfusion-dependence. Participants were randomly assigned to receive pomalidomide or placebo in a blinded fashion.

In most countries participating in the global study, RBC-transfusions are typically given for a hemoglobin level \<80-90 g/L. In China, RBC-transfusions are rarely given unless the hemoglobin level is \<60 g/L. Consequently, few Chinese with MPN-associated myelofibrosis meet RBC-transfusion-dependence criteria of the global study. A China-specific extension was developed to test the ability of pomalidomide to improve severe anemia (defined as a hemoglobin \< 80 g/L for ≥ 84 days in persons not receiving RBC-transfusions).

The China-specific extension study consisted of a single-arm, open-label study in adults with MPN-associated myelofibrosis and severe anemia not receiving RBC transfusions with the objective of describing the frequency of anemia response.

The Global (intent-to-treat \[ITT\] and safety) population in the main study and the China extension (ITT and safety) population are mutually exclusive.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Myeloproliferative-neoplasm (MPN)-associated myelofibrosis
* RBC-transfusion-dependence (global study):

  * Average RBC-transfusion frequency ≥ 2 units/28 days over at least the 84 days immediately prior to randomization. There must be no interval \> 42 days without ≥ 1 RBC-transfusion.
  * Only RBC-transfusions given when the hemoglobin ≤ 90 g/L³ are scored in

determining eligibility.

* RBC-transfusions due to bleeding are not scored in determining eligibility.
* RBC-transfusions due to chemotherapy-induced anemia are not scored in determining eligibility.

  * Severe anemia (China-specific extension):
* ≥ 2 hemoglobin concentrations ≤ 80 g/L for ≥ 84 days immediately before the day of enrollment.
* No RBC-transfusion within 6 months prior to enrollment.

  * Hemoglobin ≤ 130 g/L at randomization (global study); ≤ 80 g/L at enrollment in the China-specific extension.
  * Bone marrow biopsy within 6 months (global study only).
  * Inappropriate to receive blood cell or bone marrow allotransplant, erythropoietin and androgenic steroids
  * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  * Agree to follow pregnancy precautions as required by the protocol.
  * Agree to receive counseling related to teratogenic and other risks of pomalidomide.
  * Agree not to donate blood or semen.

Exclusion Criteria:

* Prior blood cell or bone marrow allotransplant.
* Use of drugs to treat MPN-associated myelofibrosis ≤ 30 days before starting study drug.
* Treatment with erythropoietin or androgenic steroids ≤ 84 days before starting study drug.
* Anemia due to reasons other than MPN-associated myelofibrosis.
* Pregnant or lactating females.
* More than 10% blasts by bone marrow examination or more than 10% blasts in blood in consecutive measurements spanning at least 8 weeks
* Prior history of malignancies,other than the disease being studied, unless the subject has been free of the malignancy for ≥ 5 years with the following exceptions:

  * Carcinoma in situ of the cervix
  * Carcinoma in situ of the breast
  * Incidental histologic finding of prostate cancer (T 1a or T 1b using TNM \[tumor, nodes, metastasis\] clinical staging system)
* Human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections.
* Prior treatment with pomalidomide.
* Allergic reaction or rash after treatment with thalidomide or lenalidomide
* Any of the following laboratory abnormalities:

  * Neutrophils \< 0.5x10\^9 /L
  * Platelets \< 25 x 10\^9 /L
  * Estimated glomerular filtration rate (kidney function) \< 30 mL/min/1.73 m²
  * Aspartate aminotransferase (AST) and alanine transaminase (ALT) \> 3.0 x upper limit of normal (ULN)
  * Total bilirubin ≥ 4 x ULN;
* Uncontrolled hyperthyroidism or hypothyroidism.
* Deep venous thrombosis (DVT) or pulmonary embolus (PE) \< 6 months before starting study drug
* Clinically-important heart disease within the past 6 months

Primary outcomes:
measure: Percentage of Participants Who Achieved RBC-Transfusion Independence
timeFrame: 168 days
measure: China Extension: Number of Participants Achieving a Hemoglobin Increase of ≥ 15 g/L Compared to Baseline for ≥ 84 Consecutive Days
timeFrame: From the first dose of study drug until treatment discontinuation; median treatment duration was 24.0 weeks.
Secondary outcomes:
measure: Overall Survival
timeFrame: From first dose of study drug up to end of study; median follow-up time was 19.1 months in the pomalidomide 0.5 mg arm and 17.6 months in the placebo arm.
measure: Duration of RBC-Transfusion Independence
timeFrame: From first dose of study drug up to 28 days after last dose, as of the data cut-off date of 16 Jan 2013; median treatment duration was 23.6 weeks in the pomalidomide arm and 23.9 weeks in the placebo arm.
measure: Time to RBC-Transfusion Independence
timeFrame: 168 days
measure: Number of Participants With Treatment-emergent Adverse Events (TEAE)
timeFrame: From the first dose of study drug until 28 days after last dose; median treatment duration was 23.7 weeks in the pomalidomide arm, 23.9 weeks in the placebo arm, and 24.0 weeks in the China extension pomalidomide arm.
measure: Healthcare Resource Utilization
timeFrame: From first dose of study drug up to 28 days after last dose, as of the data cut-off date of 16 Jan 2013; median treatment duration was 23.6 weeks in the pomalidomide arm and 23.9 weeks in the placebo arm.
measure: Change From Baseline in EuroQoL-5D (EQ-5D) Health Index Score
timeFrame: Baseline and Days 85 and 169
measure: Change From Baseline in EuroQoL-5D (EQ-5D) Visual Analog Scale
timeFrame: Baseline and Days 85 and 169
measure: Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Total Score
timeFrame: Baseline and Days 85 and 169
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Brooklyn
country: United States
facility: Mount Sinai School of Medicine Brookdale University Hospital
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: New York
country: United States
facility: Ruttenberg Treatment Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Medicine Taussig Cancer Institute
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Hematology and Transplant
state: South Dakota
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Graz
country: Austria
facility: Medizinische Universitatklinik Graz
city: Innsbruck
country: Austria
facility: Medizinische Universitat Innsbruck
city: Vienna
country: Austria
facility: Medizinische Universitat Wien
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuis Leuven Gathuisberg
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal,
country: Canada
facility: Centre Hospitalier de L'Universite de Montreal
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Jiangsu
country: China
facility: Jiangsu Province Hospital
city: Shanghai
country: China
facility: Shanghai Ruijin Hospital
city: Sichuan
country: China
facility: West China Hospital, Sichuan University
city: Tianjin
country: China
facility: Blood Disease Hospital Chinese Academy of Medical Sciences
city: La Tronche
country: France
facility: Hopital Albert Michallon
city: Lille
country: France
facility: Hopital Saint Vincent de Paul
city: Limoges
country: France
facility: CHU Dupuytren
city: Paris
country: France
facility: Hopital Saint-Louis
city: Pessac
country: France
facility: CHRU - Hopital du Haut Leveque
city: Strasbourg
country: France
facility: Hopitaux Universitaires de Strasbourg, CHU Haute-Pierre
city: Toulouse
country: France
facility: Hopital Purpan
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Aachen
country: Germany
facility: Universitatsklinikum Aachen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Bari
country: Italy
facility: Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II di Napoli
city: Orbassano
country: Italy
facility: Azienda Ospedaliera San Luigi Gonzaga
city: Pavia
country: Italy
facility: IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Centro per lo Studio della Mielofibrosi
city: Pavia
country: Italy
facility: IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Ematologia
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi Varese
city: Bunkyou-ku
country: Japan
facility: Juntendo University Hospital
city: Fukuoka City
country: Japan
facility: Kyushu University Hospital
city: Isehara City
country: Japan
facility: Tokai University Hospital
city: Kyoto City
country: Japan
facility: Kyoto University Hospital
city: Nagasaki City
country: Japan
facility: Nagasaki University Hospital
city: Shinjuku
country: Japan
facility: Tokyo Medical University Hospital
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medish Centrum
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Rzeszow
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. F.Chopina
city: Szczecin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 PAM
city: Warsaw
country: Poland
facility: Centralny Szpital Kliniczny MSWiA
city: Moscow
country: Russian Federation
facility: Russian Scientific Haematology Centre
city: Saint-Petersburg
country: Russian Federation
facility: Federal State Institution Russian Scientific-research Institute of Hematology and Transfusiology of Federal Medical-Biological Agency of Russia
city: Saint-Petersburg
country: Russian Federation
facility: State Pavlov Medical University
city: Saint-Petersburg
country: Russian Federation
facility: Federal State Institution "Federal Centre of Heart, Blood and Endocrinology of Rosmedtechnologies named after V.A. Almazov"
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial de Barcelona
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta De Hierro Majadahonda
city: Salamanca
country: Spain
facility: Hospital Clinico de Salamanca
city: Valencia
country: Spain
facility: Hospital Clinico de Valencia
city: Lund
country: Sweden
facility: Skane University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Glasgow
country: United Kingdom
facility: Beatson Oncology Centre
city: Headington
country: United Kingdom
facility: John Radcliffe Hospital NHS Trust
city: London
country: United Kingdom
facility: St. Thomas Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
Study officials:
affiliation: Celgene Corporation
name: Robert Peter P Gale, MD, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Tefferi A, Al-Ali HK, Barosi G, Devos T, Gisslinger H, Jiang Q, Kiladjian JJ, Mesa R, Passamonti F, McMullin MF, Ribrag V, Schiller G, Vannucchi AM, Zhou D, Reiser D, Zhong J, Gale RP. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017 Apr;31(4):896-902. doi: 10.1038/leu.2016.300. Epub 2016 Oct 24.
citation: Begna KH, Pardanani A, Mesa R, Litzow MR, Hogan WJ, Hanson CA, Tefferi A. Long-term outcome of pomalidomide therapy in myelofibrosis. Am J Hematol. 2012 Jan;87(1):66-8. doi: 10.1002/ajh.22233. Epub 2011 Nov 12.