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

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

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)

Study Overview

• Status: Completed
• Conditions: Primary Myelofibrosis; MPN-associated Myelofibrosis
• Intervention / Treatment: Drug: Pomalidomide 0.5 mg; Drug: Placebo; Drug: Pomalidomide

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.

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • St. Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Frankston Hospital
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Austria
  • Graz, Austria, A-8036
    • Medizinische Universitatklinik Graz
  • Innsbruck, Austria, A-6020
    • Medizinische Universität Innsbruck
  • Vienna, Austria, A-1190
    • Medizinische Universität Wien
• Belgium
  • Brugge, Belgium, 8000
    • Algemeen Ziekenhuis Sint-Jan
  • Charleroi, Belgium, 6000
    • Grand Hopital de Charleroi
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuis Leuven Gathuisberg
• Canada
  • Montreal,, Canada
    • Centre Hospitalier de l'Universite de Montreal
  • Alberta
    • Edmonton, Alberta, Canada, T6G lz2
      • Cross Cancer Institute
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• China
  • Beijing, China, 100044
    • Peking University People's Hospital
  • Beijing, China, 100730
    • Peking Union Medical College Hospital
  • Jiangsu, China, 210029
    • Jiangsu Province Hospital
  • Shanghai, China, 200025
    • Shanghai Ruijin Hospital
  • Sichuan, China, 610041
    • West China Hospital, Sichuan University
  • Tianjin, China, 300041
    • Blood Disease Hospital Chinese Academy of Medical Sciences
• France
  • La Tronche, France, 38043
    • Hopital Albert Michallon
  • Lille, France, 59020
    • Hopital Saint Vincent De Paul
  • Limoges, France, 87042
    • Chu Dupuytren
  • Paris, France, 75475
    • Hôpital Saint-Louis
  • Pessac, France, 33604
    • CHRU - Hôpital du Haut Lévêque
  • Strasbourg, France, 67098
    • Hopitaux Universitaires de Strasbourg, CHU Haute-Pierre
  • Toulouse, France, 31059
    • Hôpital Purpan
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Aachen, Germany, 52074
    • Universitätsklinikum Aachen
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Leipzig, Germany, 04103
    • Universitatsklinikum Leipzig
  • Minden, Germany, 32429
    • Johannes Wesling Klinikum Minden
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Italy
  • Bari, Italy, 70124
    • Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari
  • Bergamo, Italy, 24128
    • Ospedali Riuniti di Bergamo
  • Firenze, Italy, 50134
    • Azienda Ospedaliera Universitaria Careggi
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria Federico II di Napoli
  • Orbassano, Italy, 10043
    • Azienda Ospedaliera San Luigi Gonzaga
  • Pavia, Italy, 27100
    • IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Centro per lo Studio della Mielofibrosi
  • Pavia, Italy, 27100
    • IRCCS Fondazione Policlinico San Matteo, Universita di Pavia, Ematologia
  • Varese, Italy, 21100
    • Ospedale di Circolo e Fondazione Macchi Varese
• Japan
  • Bunkyou-ku, Japan, 113-8431
    • Juntendo University Hospital
  • Fukuoka City, Japan, 812-8582
    • Kyushu University Hospital
  • Isehara City, Japan, 259-1193
    • Tokai University Hospital
  • Kyoto City, Japan, 606-8507
    • Kyoto University Hospital
  • Nagasaki City, Japan, 852-8501
    • Nagasaki University Hospital
  • Shinjuku, Japan, 160-0023
    • Tokyo Medical University Hospital
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus Medish Centrum
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• Poland
  • Rzeszow, Poland, 35-055
    • Wojewodzki Szpital Specjalistyczny im. F.Chopina
  • Szczecin, Poland, 71-242
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 PAM
  • Warsaw, Poland, 02-507
    • Centralny Szpital Kliniczny Mswia
• Russian Federation
  • Moscow, Russian Federation, 125167
    • Russian Scientific Haematology Centre
  • Saint-Petersburg, Russian Federation, 191024
    • Federal State Institution Russian Scientific-research Institute of Hematology and Transfusiology of Federal Medical-Biological Agency of Russia
  • Saint-Petersburg, Russian Federation, 196022
    • State Pavlov Medical University
  • Saint-Petersburg, Russian Federation, 197341
    • Federal State Institution "Federal Centre of Heart, Blood and Endocrinology of Rosmedtechnologies named after V.A. Almazov"
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Salamanca, Spain, 37007
    • Hospital Clinico De Salamanca
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
• Sweden
  • Lund, Sweden, 22185
    • Skåne University Hospital
  • Stockholm, Sweden, 14185
    • Karolinska University Hospital Huddinge
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Belfast City Hospital
  • Glasgow, United Kingdom, G12 0YN
    • Beatson Oncology Centre
  • Headington, United Kingdom, OX3 9DU
    • John Radcliffe Hospital NHS Trust
  • London, United Kingdom, W12 ONN
    • Hammersmith Hospital
  • London, United Kingdom, SE1 9RT
    • St. Thomas Hospital
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
  • California
    • Los Angeles, California, United States, 90095
      • UCLA School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • Brooklyn, New York, United States, 11212
      • Mount Sinai School of Medicine Brookdale University Hospital
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10021
      • Weill Medical College of Cornell University
    • New York, New York, United States, 10029
      • Ruttenberg Treatment Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Medicine Taussig Cancer Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Hematology and Transplant
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	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.; Other Names: CC-4047; Pomalyst; Imnovid
PLACEBO_COMPARATOR: 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.	Drug: Placebo; Placebo Comparator to active drug; Placebo capsule taken by mouth once daily
EXPERIMENTAL: China Extension: Pomalidomide 0.5 mg; 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.	Drug: Pomalidomide; Pomalidomide 0.5 mg capsule taken by mouth once daily.; Other Names: Pomalyst; Imnovid; CC-4047

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
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
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.
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.
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
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
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

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Robert Peter P Gale, MD, Ph.D., Celgene Corporation

Publications and helpful links

General Publications

• 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. Erratum In: Leukemia. 2017 May;31(5):1252.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 8, 2010
• Primary Completion (ACTUAL): January 1, 2013
• Study Completion (ACTUAL): May 15, 2018

Study Registration Dates

• First Submitted: July 15, 2010
• First Submitted That Met QC Criteria: August 9, 2010
• First Posted (ESTIMATE): August 10, 2010

Study Record Updates

• Last Update Posted (ACTUAL): July 17, 2019
• Last Update Submitted That Met QC Criteria: June 24, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Myelofibrosis; Primary Myelofibrosis; Post-essential thrombocythemia myelofibrosis; Post-polycythemia vera myelofibrosis; RBC-transfusion-dependence
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Neoplasms; Primary Myelofibrosis; Myeloproliferative Disorders; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Thalidomide; Pomalidomide
• Other Study ID Numbers: CC-4047-MF-002; 2010-018965-42 (EUDRACT_NUMBER)