Study of Pomalidomide in Persons With Myeloproliferative-Neoplasm-Associated Myelofibrosis and RBC-Transfusion-Dependence

Primary Myelofibrosis Clinical Trial

— RESUME  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01178281
• Other study ID #: CC-4047-MF-002
• Secondary ID: 2010-018965-42
• Status: Completed
• Phase: Phase 3
• Start date: September 8, 2010
• Est. completion date: May 15, 2018

Study information

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

Clinical Trial 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)

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 information / eligibility

• Status: Completed
• Enrollment: 267
• Est. completion date: May 15, 2018
• Est. primary completion date: January 1, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• MPN-associated Myelofibrosis
• Myeloproliferative Disorders
• Neoplasms
• Primary Myelofibrosis

Intervention

Drug:
• Pomalidomide 0.5 mg
Pomalidomide 0.5 mg capsule taken by mouth once daily. Immunomodulatory agent with demonstrated efficacy in the treatment of subjects with RBC-transfusion-dependence associated with MNP-associated myelofibrosis.
• Placebo
Placebo Comparator to active drug; Placebo capsule taken by mouth once daily
• Pomalidomide
Pomalidomide 0.5 mg capsule taken by mouth once daily.

Locations

Country	Name	City	State
Australia	Frankston Hospital	Frankston	Victoria
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Austria	Medizinische Universitatklinik Graz	Graz
Austria	Medizinische Universitat Innsbruck	Innsbruck
Austria	Medizinische Universitat Wien	Vienna
Belgium	Algemeen Ziekenhuis Sint-Jan	Brugge
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	Universitaire Ziekenhuis Leuven Gathuisberg	Leuven
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Centre Hospitalier de L'Universite de Montreal	Montreal,
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
China	Peking Union Medical College Hospital	Beijing
China	Peking University People's Hospital	Beijing
China	Jiangsu Province Hospital	Jiangsu
China	Shanghai Ruijin Hospital	Shanghai
China	West China Hospital, Sichuan University	Sichuan
China	Blood Disease Hospital Chinese Academy of Medical Sciences	Tianjin
France	Hopital Albert Michallon	La Tronche
France	Hopital Saint Vincent de Paul	Lille
France	CHU Dupuytren	Limoges
France	Hopital Saint-Louis	Paris
France	CHRU - Hopital du Haut Leveque	Pessac
France	Hopitaux Universitaires de Strasbourg, CHU Haute-Pierre	Strasbourg
France	Hopital Purpan	Toulouse
France	Institut Gustave Roussy	Villejuif
Germany	Universitatsklinikum Aachen	Aachen
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinikum Leipzig	Leipzig
Germany	Johannes Wesling Klinikum Minden	Minden
Germany	Universitatsklinikum Ulm	Ulm
Italy	Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari	Bari
Italy	Ospedali Riuniti di Bergamo	Bergamo
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Azienda Ospedaliera Universitaria Federico II di Napoli	Napoli
Italy	Azienda Ospedaliera San Luigi Gonzaga	Orbassano
Italy	IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Centro per lo Studio della Mielofibrosi	Pavia
Italy	IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Ematologia	Pavia
Italy	Ospedale di Circolo e Fondazione Macchi Varese	Varese
Japan	Juntendo University Hospital	Bunkyou-ku
Japan	Kyushu University Hospital	Fukuoka City
Japan	Tokai University Hospital	Isehara City
Japan	Kyoto University Hospital	Kyoto City
Japan	Nagasaki University Hospital	Nagasaki City
Japan	Tokyo Medical University Hospital	Shinjuku
Netherlands	VU University Medical Center	Amsterdam
Netherlands	Erasmus Medish Centrum	Rotterdam
Netherlands	University Medical Center Utrecht	Utrecht
Poland	Wojewodzki Szpital Specjalistyczny im. F.Chopina	Rzeszow
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1 PAM	Szczecin
Poland	Centralny Szpital Kliniczny MSWiA	Warsaw
Russian Federation	Russian Scientific Haematology Centre	Moscow
Russian Federation	Federal State Institution "Federal Centre of Heart, Blood and Endocrinology of Rosmedtechnologies named after V.A. Almazov"	Saint-Petersburg
Russian Federation	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
Spain	Hospital Clinic I Provincial de Barcelona	Barcelona
Spain	Hospital Universitario Puerta De Hierro Majadahonda	Majadahonda
Spain	Hospital Clinico de Salamanca	Salamanca
Spain	Hospital Clinico de Valencia	Valencia
Sweden	Skane University Hospital	Lund
Sweden	Karolinska University Hospital Huddinge	Stockholm
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Beatson Oncology Centre	Glasgow
United Kingdom	John Radcliffe Hospital NHS Trust	Headington
United Kingdom	Hammersmith Hospital	London
United Kingdom	St. Thomas Hospital	London
United Kingdom	Freeman Hospital	Newcastle upon Tyne
United Kingdom	Royal Hallamshire Hospital	Sheffield
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Mount Sinai School of Medicine Brookdale University Hospital	Brooklyn	New York
United States	University of Illinois at Chicago	Chicago	Illinois
United States	Medicine Taussig Cancer Institute	Cleveland	Ohio
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic	Jacksonville	Florida
United States	UCLA School of Medicine	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Ruttenberg Treatment Center	New York	New York
United States	Weill Medical College of Cornell University	New York	New York
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Mayo Clinic	Scottsdale	Arizona
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Avera Hematology and Transplant	Sioux Falls	South Dakota

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  China,  France,  Germany,  Italy,  Japan,  Netherlands,  Poland,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieved RBC-Transfusion Independence	RBC-transfusion independence was defined as the absence of RBC transfusions for any consecutive 84-day interval.	168 days
Primary	China Extension: Number of Participants Achieving a Hemoglobin Increase of = 15 g/L Compared to Baseline for = 84 Consecutive Days	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.	From the first dose of study drug until treatment discontinuation; median treatment duration was 24.0 weeks.
Secondary	Overall Survival	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.	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.
Secondary	Duration of RBC-Transfusion Independence	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.	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.
Secondary	Time to RBC-Transfusion Independence	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.	168 days
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAE)	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	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.
Secondary	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.
Secondary	Change From Baseline in EuroQoL-5D (EQ-5D) Health Index Score	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.	Baseline and Days 85 and 169
Secondary	Change From Baseline in EuroQoL-5D (EQ-5D) Visual Analog Scale	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).	Baseline and Days 85 and 169
Secondary	Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Total Score	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.	Baseline and Days 85 and 169