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

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)

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.

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