Study of Pomalidomide in Persons With Myeloproliferative-Neoplasm-Associated Myelofibrosis and RBC-Transfusion-Dependence
- Conditions
- Primary MyelofibrosisMPN-associated Myelofibrosis
- Interventions
- Registration Number
- NCT01178281
- Lead Sponsor
- Celgene
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 267
-
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.
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants received placebo taken by mouth once daily for at least 168 days unless there were unacceptable side effects or disease progression. Participants who were RBC-transfusion independent or experienced clinical benefit could continue to receive placebo until loss of RBC- transfusion independence response or clinical benefit, or other criteria for treatment discontinuation applied. China Extension: Pomalidomide 0.5 mg Pomalidomide Participants received pomalidomide 0.5 mg/day by mouth for at least 168 days unless there were unacceptable side effects, disease progression, or they received a RBC-transfusion. Participants who experienced anemia response could continue treatment until the response was lost or other criteria for treatment discontinuation applied. Pomalidomide 0.5 mg Pomalidomide 0.5 mg Participants received pomalidomide 0.5 mg/day by mouth for at least 168 days unless there were unacceptable side effects or disease progression. Participants who were RBC-transfusion independent or experienced clinical benefit (defined as a reduction from Baseline of ≥ 50% in RBC-transfusion frequency during the prior 84-day interval) could continue to receive pomalidomide until loss of RBC-transfusion independence response or clinical benefit, or other criteria for treatment discontinuation applied.
- Primary Outcome Measures
Name Time Method Percentage of Participants Who Achieved RBC-Transfusion Independence 168 days RBC-transfusion independence was defined as the absence of RBC transfusions for any consecutive 84-day interval.
China Extension: Number of Participants Achieving a Hemoglobin Increase of ≥ 15 g/L Compared to Baseline for ≥ 84 Consecutive Days From the first dose of study drug until treatment discontinuation; median treatment duration was 24.0 weeks. A response in the China extension study was defined as an increase in hemoglobin ≥ 15 g/L above baseline value (in the absence of RBC transfusion) for ≥ 84 consecutive days.
- Secondary Outcome Measures
Name Time Method Duration of RBC-Transfusion Independence 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. The duration of RBC-transfusion independence is the time from the date at which the first RBC-transfusion independence started to the date of another RBC-transfusion given at least 84 days after the time the transfusion independence started. The duration of the RBC-transfusion independence was analyzed using the Kaplan-Meier method. Data were censored at the end of the treatment phase for participants who had not received another RBC-transfusion after the start of transfusion independence by the end of treatment phase.
Change From Baseline in EuroQoL-5D (EQ-5D) Visual Analog Scale Baseline and Days 85 and 169 EQ-5D is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D includes 2 components: the EQ-5D health state profile (descriptive system) and the EQ-5D visual analog scale (VAS). On the VAS the participant rates his/her health state on a line from 0 (worst imaginable health) to 100 (best imaginable health).
Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Total Score Baseline and Days 85 and 169 The FACT-An is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire measuring the four general domains of QoL (physical, social/family, emotional and functional well-being), and an additional 20-item anemia questionnaire (FACT-An Anemia subscale) that measures 13 fatigue-associated items (FACT-F Fatigue subscale) and seven non-fatigue-related items. Each item is scored using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a bit; and 4 = Very much). FACT-An total score is calculated by adding all the FACT-An subscales together. The total score ranges from 0-188 with higher scores representing better QOL.
Number of Participants With Treatment-emergent Adverse Events (TEAE) 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. A TEAE is an adverse event (AE) that starts on or after the first dose of study drug. The severity of each AE was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE),Version 4.0 and according to the following scale: Grade 1 = Mild (transient or mild discomfort; no limitation in activity; no medical intervention/therapy required); Grade 2 = Moderate (mild to moderate limitation in activity, some assistance may be needed; minimal medical intervention/therapy required); Grade 3 = Severe (marked limitation in activity, assistance usually required; medical intervention/therapy required, hospitalization possible); Grade 4 = Life-threatening (extreme limitation in activity, significant assistance or medical intervention/therapy required, hospitalization or hospice care probable); Grade 5 = Death Drug-related (related) AEs are those suspected by the Investigator as being related to administration of study drug
Healthcare Resource Utilization 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. Overall Survival 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. The time from randomization to the death or to the latest date when participants are known to be alive. Overall survival was analyzed using Kaplan-Meier method; participants who were alive or lost to follow-up were censored at the latest date they were known to be alive.
Time to RBC-Transfusion Independence 168 days Time to response was measured from first dose of study drug to the start of the first response. The start date of the response was defined as one day after the last date of an RBC-transfusion for participants who received a RBC-transfusion after the first dose, and as the date of the first dose of study drug for participants who received no RBC-transfusions during the 84 days after the first dose of study drug.
Change From Baseline in EuroQoL-5D (EQ-5D) Health Index Score Baseline and Days 85 and 169 EQ-5D is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D includes 2 components: the EQ-5D health state profile (descriptive system) and the EQ-5D visual analog scale (VAS). For the health state profile participants rate their perceived health state today on 5 dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression on a Likert-type scale from 1 to 3, where 1 = "no problems," 2 = "some problems," and 3 = "extreme problems." The EQ-5D Health Utility Index (HUI) was generated from the five health state domain scores, and ranges from -0.594 (worst) and 1 (best) imaginable health state, with -0.594 representing an "unconscious" health state.
Trial Locations
- Locations (85)
Centralny Szpital Kliniczny MSWiA
🇵🇱Warsaw, Poland
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Universitaire Ziekenhuis Leuven Gathuisberg
🇧🇪Leuven, Belgium
UCLA School of Medicine
🇺🇸Los Angeles, California, United States
Wojewodzki Szpital Specjalistyczny im. F.Chopina
🇵🇱Rzeszow, Poland
Algemeen Ziekenhuis Sint-Jan
🇧🇪Brugge, Belgium
Universitatsklinikum Leipzig
🇩🇪Leipzig, Germany
CHRU - Hopital du Haut Leveque
🇫🇷Pessac, France
Avera Hematology and Transplant
🇺🇸Sioux Falls, South Dakota, United States
West China Hospital, Sichuan University
🇨🇳Sichuan, China
Frankston Hospital
🇦🇺Frankston, Victoria, Australia
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Centre Hospitalier de L'Universite de Montreal
🇨🇦Montreal,, Canada
Medizinische Universitat Innsbruck
🇦🇹Innsbruck, Austria
Medizinische Universitat Wien
🇦🇹Vienna, Austria
Grand Hopital de Charleroi
🇧🇪Charleroi, Belgium
Jiangsu Province Hospital
🇨🇳Jiangsu, China
Ospedale di Circolo e Fondazione Macchi Varese
🇮🇹Varese, Italy
University of Utah
🇺🇸Salt Lake City, Utah, United States
Tokyo Medical University Hospital
🇯🇵Shinjuku, Japan
CHU Dupuytren
🇫🇷Limoges, France
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari
🇮🇹Bari, Italy
Azienda Ospedaliera Universitaria Federico II di Napoli
🇮🇹Napoli, Italy
Universitatsklinikum Ulm
🇩🇪Ulm, Germany
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States
Blood Disease Hospital Chinese Academy of Medical Sciences
🇨🇳Tianjin, China
Johannes Wesling Klinikum Minden
🇩🇪Minden, Germany
Hopitaux Universitaires de Strasbourg, CHU Haute-Pierre
🇫🇷Strasbourg, France
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Kyushu University Hospital
🇯🇵Fukuoka City, Japan
Nagasaki University Hospital
🇯🇵Nagasaki City, Japan
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Peking Union Medical College Hospital
🇨🇳Beijing, China
Russian Scientific Haematology Centre
🇷🇺Moscow, Russian Federation
Ospedali Riuniti di Bergamo
🇮🇹Bergamo, Italy
Hopital Saint Vincent de Paul
🇫🇷Lille, France
Hopital Purpan
🇫🇷Toulouse, France
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
University of Florida Shands Cancer Center
🇺🇸Gainesville, Florida, United States
University of Illinois at Chicago
🇺🇸Chicago, Illinois, United States
Medicine Taussig Cancer Institute
🇺🇸Cleveland, Ohio, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Weill Medical College of Cornell University
🇺🇸New York, New York, United States
Ruttenberg Treatment Center
🇺🇸New York, New York, United States
Mount Sinai School of Medicine Brookdale University Hospital
🇺🇸Brooklyn, New York, United States
Gosford Hospital
🇦🇺Gosford, New South Wales, Australia
Royal North Shore Hospital
🇦🇺St. Leonards, New South Wales, Australia
Shanghai Ruijin Hospital
🇨🇳Shanghai, China
Peking University People's Hospital
🇨🇳Beijing, China
Hopital Albert Michallon
🇫🇷La Tronche, France
Hopital Saint-Louis
🇫🇷Paris, France
Institut Gustave Roussy
🇫🇷Villejuif, France
IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Centro per lo Studio della Mielofibrosi
🇮🇹Pavia, Italy
Universitatsklinikum Aachen
🇩🇪Aachen, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Azienda Ospedaliera San Luigi Gonzaga
🇮🇹Orbassano, Italy
IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Ematologia
🇮🇹Pavia, Italy
Juntendo University Hospital
🇯🇵Bunkyou-ku, Japan
Kyoto University Hospital
🇯🇵Kyoto City, Japan
Tokai University Hospital
🇯🇵Isehara City, Japan
Erasmus Medish Centrum
🇳🇱Rotterdam, Netherlands
VU University Medical Center
🇳🇱Amsterdam, Netherlands
Federal State Institution Russian Scientific-research Institute of Hematology and Transfusiology of Federal Medical-Biological Agency of Russia
🇷🇺Saint-Petersburg, Russian Federation
State Pavlov Medical University
🇷🇺Saint-Petersburg, Russian Federation
Samodzielny Publiczny Szpital Kliniczny Nr 1 PAM
🇵🇱Szczecin, Poland
Federal State Institution "Federal Centre of Heart, Blood and Endocrinology of Rosmedtechnologies named after V.A. Almazov"
🇷🇺Saint-Petersburg, Russian Federation
Hospital Clinico de Valencia
🇪🇸Valencia, Spain
Hospital Clinic I Provincial de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Puerta De Hierro Majadahonda
🇪🇸Majadahonda, Spain
Hospital Clinico de Salamanca
🇪🇸Salamanca, Spain
Skane University Hospital
🇸🇪Lund, Sweden
Karolinska University Hospital Huddinge
🇸🇪Stockholm, Sweden
Belfast City Hospital
🇬🇧Belfast, United Kingdom
Beatson Oncology Centre
🇬🇧Glasgow, United Kingdom
Hammersmith Hospital
🇬🇧London, United Kingdom
St. Thomas Hospital
🇬🇧London, United Kingdom
John Radcliffe Hospital NHS Trust
🇬🇧Headington, United Kingdom
Freeman Hospital
🇬🇧Newcastle upon Tyne, United Kingdom
Royal Hallamshire Hospital
🇬🇧Sheffield, United Kingdom
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Medizinische Universitatklinik Graz
🇦🇹Graz, Austria
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands