Clinical Trials /

Pegylated Interferon Alfa-2a Salvage Therapy in High Risk Polycythemia Vera (PV) or Essential Thrombocythemia (ET)

NCT01259817

Description:

The aim of this research is to look at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots. It is important for patients with ET or PV who are at risk of blood clots to receive drugs which will minimize the risks of developing these blood clots but at the moment the investigators are not sure which drugs will best control the disorder. The purpose of this study is to look at the effectiveness of giving patients who have been diagnosed with ET and PV a study drug regimen using Aspirin and PEGASYS (also known as Pegylated interferon alfa-2a, instead of the standard treatment drug called Hydroxyurea (or hydroxycarbamide or Hydroxyurea), for whom this drug may not be suitable. The drug may not be suitable either because it is not adequately controlling the number of blood cells or some specific side effects occur.

Related Conditions:
  • Essential Thrombocythemia
  • Polycythemia Vera
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Pegylated Interferon Alfa-2a Salvage Therapy in High Risk Polycythemia Vera (PV) or Essential Thrombocythemia (ET)

Title

  • Brief Title: Pegylated Interferon Alfa-2a Salvage Therapy in High Risk Polycythemia Vera (PV) or Essential Thrombocythemia (ET)
  • Official Title: Single Arm Salvage Therapy With Pegylated Interferon Alfa-2a for Patients With High Risk Polycythemia Vera or High Risk Essential Thrombocythemia Who Are Either Hydroxyurea Resistant or Intolerant or Have Had Abdominal Vein Thrombosis
  • Clinical Trial IDs

    NCT ID: NCT01259817

    ORG ID: GCO 09-1300 001

    NCI ID: P01CA108671

    Trial Conditions

    High Risk Polycythemia Vera

    High Risk Essential Thrombocythemia

    Trial Interventions

    Drug Synonyms Arms
    PEGASYS Pegylated Interferon Alfa-2a PEGASYS
    Aspirin acetylsalicylic acid Aspirin

    Trial Purpose

    The aim of this research is to look at two conditions, Essential Thrombocythemia (ET) and
    Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets
    and PV causes too many platelets and red blood cells to be made. Platelets are particles
    which circulate in the blood stream and normally prevent bleeding and bruising. Having too
    many platelets in the blood increases the risk of developing blood clots, which can result
    in life threatening events like heart attacks and strokes. When the number of red blood
    cells is increased in PV this will slow the speed of blood flow in the body and increases
    the risk of developing blood clots.

    It is important for patients with ET or PV who are at risk of blood clots to receive drugs
    which will minimize the risks of developing these blood clots but at the moment the
    investigators are not sure which drugs will best control the disorder.

    The purpose of this study is to look at the effectiveness of giving patients who have been
    diagnosed with ET and PV a study drug regimen using Aspirin and PEGASYS (also known as
    Pegylated interferon alfa-2a, instead of the standard treatment drug called Hydroxyurea (or
    hydroxycarbamide or Hydroxyurea), for whom this drug may not be suitable. The drug may not
    be suitable either because it is not adequately controlling the number of blood cells or
    some specific side effects occur.

    Detailed Description

    Myeloproliferative disorders (MPDs) are clonal hematologic diseases characterized by the
    excess production of one or more lineages of mature blood cells, a predisposition to
    bleeding and thrombotic complications, extramedullary hematopoiesis, and a variable
    progression to acute leukemia. The classical Philadelphia chromosome-negative MPDs are
    polycythemia vera (PV), characterized by an expansion in red blood cell production;
    essential thrombocythemia (ET), characterized by an isolated elevation in the platelet
    count; and myelofibrosis, distinguished by a fibrotic bone marrow and peripheral blood
    cytopenias, and accompanied by the highest risk of leukemic transformation. Myelofibrosis
    can arise de novo, as primary myelofibrosis (PMF), or can evolve out of PV or ET as those
    diseases progress (so called post-PV MF and post-ET MF). Amongst the MPDs, those
    characterized by myelofibrosis (PMF together with post-PV and post-ET MF) carry the worst
    prognosis, with a median survival on the order of 3 to 5 years. Patients typically present
    with anemia, often requiring transfusions, symptomatic splenomegaly and severe
    constitutional symptoms. Donor stem cell transplantation is the only potentially curative
    therapy. To date there is no therapy for myelofibrosis that has been shown to offer a
    survival benefit, and all other therapies for myelofibrosis are palliative.

    In 2005, a major breakthrough in understanding the pathophysiology of MPDs came when 4
    groups described a recurrent somatic mutation in Janus kinase 2 (JAK2) in the majority of
    patients with MPDs. The point mutation in JAK2 encodes a valine to phenylalanine change at
    position 617 (JAK2 V617F), and confers constitutive tyrosine kinase activity. Introducing
    the mutation into the bone marrow of mouse models recapitulates the PV phenotype (complete
    with evolution to bone marrow fibrosis) and inhibitors of JAK2 attenuate the growth of cell
    lines bearing the mutation in vitro and in vivo, suggesting that JAK2 V617F is a
    pathophysiologically relevant therapeutic target. It is estimated that 95% of PV cases carry
    JAK2 V617F, while 50 to 60% of ET and PMF cases are JAK2 V617F+. The discovery of the
    JAK2V617F mutation in nearly all patients with PV and half those with ET and PMF have
    redefined the classification and possibly the management of MPNs.

    Despite the discovery of the JAK2V617F mutation, many of the clinical questions in the
    management of MPNs remain unanswered. In PV, for example, cardiovascular mortality remains
    1.4 to 1.6 times that of the reference normal population with leukemia and myelofibrosis
    rates many times increased over baseline. Debate continues over the role of venesection
    versus cytoreduction as first-line therapy, and whether hydroxycarbamide (Hydroxyurea) is
    associated with better thrombotic prophylaxis and/or a higher rate of leukemic
    transformation. Interferons may produce molecular responses in PV patients. In high-risk
    ET, while Hydroxyurea and aspirin appear to be more optimal than anagrelide and aspirin,
    vascular complications remain the most significant cause of mortality and morbidity,
    suggesting that targeting vascular risk factors may be worthwhile.

    Furthermore while Hydroxyurea is regarded as the first-choice therapy in most of high risk
    patients with ET and PV; up to 10% of the patients do not attain the desired reduction of
    platelet number or hematocrit with the recommended dose of the drug, exhibiting clinical
    resistance, whereas some will develop unacceptable side effects, demonstrating clinical
    intolerance.

    Quantitation of the JAK2V617F allele burden provides for the first time the opportunity to
    monitor the effect of potential therapeutic agents on the malignant clone in patients with
    PV. Great enthusiasm has been expressed for the use of small molecule inhibitors of JAK2 for
    the treatment of patients with MPN. Phase 1/2 trials have indicated greater than expected
    toxicity, non specificity of action and an inability of these compounds to dramatically
    alter the JAK2V617F allele burden. Interferon (rIFN -2b), is a drug that appears to be
    non-leukemogenic (contrary to 32P, alkylating agents, and possibly Hydroxyurea), and may
    have a preferential activity on the malignant clone in PV, as suggested by cytogenetic
    remissions obtained in patients treated with rIFN -2b.

    This trial was designed as open-label phase 2 study conducted in two strata of patients with
    high risk PV or ET who were intolerant of hydroxyurea. Patients with ET or PV with
    Splanchnic Vein Thrombosis (regardless of prior hydroxyurea) are enrolled in separate
    strata.

    Trial Arms

    Name Type Description Interventions
    PEGASYS Experimental Patient will start at 45 micrograms per week and gradually increase to 180 micrograms per week. Pegasys will be supplied in prefilled syringes and are to be given subcutaneously. PEGASYS
    Aspirin Active Comparator 81 or 100 mg daily. Aspirin

    Eligibility Criteria

    Inclusion Criteria:

    A diagnosis of ET or PV shall be made in accordance with the WHO (2008) criteria (Swerdlow
    2008) as shown below (Values below are at the time of diagnosis, not study entry):

    - Polycythemia Vera (2 major criteria required)

    1. Hb >18.5g/dl () or 16.5g/dl () or HCT >99 percentile reference range or
    Elevated red cell mass (>25% above mean predicted value) or Hb >17g/dl () or
    15g/dl () if associated with a sustained rise from baseline with no apparent
    cause (e.g. treated iron deficiency).

    2. Presence of JAK2V617F

    - If source documentation of diagnostic criterion #1 cannot be obtained, then
    diagnosis can be made with (1) the addition of an erythropoietin level
    below the reference range of normal AND (2) bone marrow biopsy showing
    hypercellularity for age with trilineage (panmyelosis) with prominent
    erythroid, granulocytic, and megakaryocytic proliferation.

    - Essential Thrombocythemia (all 6 criteria required)

    1. Platelets count 450 x 10 to 9/L

    2. Megakaryocyte proliferation with large and mature morphology. No or
    little granulocyte or erythroid proliferation. Patients may have up to and
    including 2+ marrow reticulin fibrosis.

    3. Not meeting WHO criteria for CML, PV, MDS, PMF or over myeloid neoplasm

    4. Demonstration of clonal cytogenetic marker or no evidence for a reactive
    thrombocytosis.

    5. Absence of a leukoerythroblastic blood picture.

    6. May participate in study without presence of JAK2V617F.

    - Patients must have high risk disease as defined below:

    High risk PV ANY ONE of the following:

    - Age 60 years

    - Previous documented thrombosis, erythromelalgia or migraine (severe, recurrent,
    requiring medications, and felt to be secondary to the MPN) either after diagnosis or
    within 10 years before diagnosis and considered to be disease related

    - Significant (i.e. 5cm below costal margin on palpation) or symptomatic splenomegaly
    (splenic infarcts or requiring analgesia)

    - Platelets 1000 x 10 to 9/L

    - Diabetes or hypertension requiring pharmacological therapy for 6 months

    High risk ET ANY ONE of the following:

    - Age 60 years

    - Platelet count 1500 x 10 to 9/L

    - Previous documented thrombosis, erythromelalgia or migraine (severe, recurrent,
    requiring medications, and felt to be secondary to the MPN) either after diagnosis or
    within 10 years before diagnosis and considered to be disease related

    - Previous hemorrhage related to ET

    - Diabetes or hypertension requiring pharmacological therapy for 6 months

    In addition patients must EITHER be intolerant or resistant to Hydroxyurea according to
    established criteria as follows:

    Any ONE of the following:

    - Platelet count 600 x 10 to 9/L after 3 months of at least 2 g/day of Hydroxyurea
    (2.5 g/day in patients with a body weight>80 kg)

    - WBC < 2.5 x 109/L or Hgb < 11g/dl at any dose of hydroxyurea not to exceed 2g/day.

    - Progressive splenomegaly or hepatomegaly (> 5cm from initiation of hydroxyurea) or
    the appearance of new splenomegaly or hepatomegaly while on MTD of hydroxyurea.

    - Not achieving a Hct < 45% in order to eliminate the need for supplemental
    phlebotomies after 3 months of at least 2g/day or MTD of hydroxyurea.

    - Not achieving a WBC of < 10 x 109/L after 3 months of at least 2g/day or MTD of
    hydroxyurea.

    - Having a platelet count < 100 x 109/L on hydroxyurea at any dose without eliminating
    the need for supplemental phlebotomy or having progressive splenomegaly as defined
    above.

    - Development of a major thrombotic episode (CVA, myocardial infarction, severe
    migraines requiring medication, abdominal vein thrombosis, deep vein thrombosis)
    while being treated with maximal tolerated doses of hydroxyurea.

    - Presence of leg ulcers or other unacceptable Hydroxyurea-related non-hematological
    toxicities, such as unacceptable mucocutaneous manifestations, gastrointestinal
    symptoms, pneumonitis or fever at any dose of Hydroxyurea.

    OR have Splanchnic Vein Thrombosis (SVT) (includes Budd-Chiari, abdominal vein thrombosis,
    portal vein thrombosis, splenic vein thrombosis). For these patients the following
    additional inclusion/exclusion criteria apply:

    - > 3 months since onset of SVT

    - SVT treated with oral anticoagulants but no aspirin

    - Liver enzymes not > 2 times the normal value

    - Absence of encephalopathy, refractory or infected ascites, esophageal varicose of
    grade > 1 at time of trial entry

    - Bone marrow biopsy confirmed diagnosis of PV or ET

    - JAK2-V617F mutations present

    - These patients may have a normal blood count at trial entry

    - Age over 18 years (no upper age limit)

    - Able and willing to comply with study criteria

    - Signed and informed consent to participant in this study

    - Willing to participate in associated correlative science biomarker study

    - Serum creatinine < 1.5 x upper limit of normal

    - AST and ALT < 2 x upper limit of normal

    - Total bilirubin within normal limits

    Exclusion Criteria:

    - Patients cannot have any other form of chemotherapy for their MPD (other than
    hydroxyurea). Specifically prior interferon or JAK2 inhibitors are prohibited.

    - If a patient has received prior hydroxyurea, they should be tapered off hydroxyurea
    over a period of the first 2 months of Pegylated interferon alfa-2a therapy. Taper is
    at the treating physician's discretion, but must be absent (completed) by the start
    of the third month.

    - Patients with a prior malignancy within the last 5 years (except for basal or
    squamous cell carcinoma, or in situ cancer of the cervix)

    - Presence of any life-threatening co-morbidity

    - History of active substance or alcohol abuse within the last year

    - Any contraindications to pegylated or non-pegylated interferon

    - Subjects who have a positive pregnancy test, are pregnant, lactating or of
    reproductive potential and not practicing an effective means of contraception

    - History of psychiatric disorder (e.g. depression; suicidal ideation; psychosis)
    Subjects with a history of mild depression may be considered for entry into this
    study, provided that a pretreatment assessment of the subject's affective status
    supports that the subject is clinically stable based on the investigator's normal
    practice for such subject.

    - History of autoimmune disorder (e.g. hepatitis; ITP; scleroderma; severe psoriasis
    affecting > 10% of the body, rheumatoid arthritis requiring more than intermittent
    NSAID for management)

    - Hypersensitivity to IFN-

    - HBV or untreated systemic infection

    - Known HIV disease

    - Evidence of severe retinopathy (e.g. CMV retinitis, macular degeneration) or
    clinically relevant ophthalmological disorder (e.g. due to diabetes mellitus or
    hypertension)

    - History or other evidence of decompensated liver disease

    - History or other evidence of chronic pulmonary disease associated with functional
    limitation

    - Thyroid dysfunction not adequately controlled

    - Any investigational drug <6 weeks prior to the first dose of study drug or not
    recovered from effects of prior investigational agent.

    - Presence of JAK2 exon 12 mutation

    - Patients should not meet criteria for post PV or post ET-MF (see appendix B)

    - Previous exposure to any formulation of interferon

    - Subjects with any other medical condition, which in the opinion of the investigator
    would compromise the results of the study by deleterious effects of treatment.

    - History of major organ transplantation

    - History of uncontrolled severe seizure disorder

    - Inability to give informed written consent

    - Serum creatinine > 1.5 x upper limit of normal

    - AST and ALT > 2 x upper limit of normal

    - Total bilirubin > 1.5 mg/ml

    - No detectable PNH (paroxysmal nocturnal hemoglobinuria) clone where tested

    - Concurrent hormonal contraceptive use

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Evaluate the ability of Pegylated Interferon Alfa-2a to achieve Complete Response or Partial Response in patients with (1) high risk polycythemia vera or (2) high risk essential thrombocythemia or (3) splanchnic vein thrombosis

    Secondary Outcome Measures

    To evaluate the toxicity and tolerability of therapy Pegylated Interferon Alfa-2a in each of the 3 strata by recording the number of adverse events that occur during the study by using CTC 4.0 as the guide.

    To measure the impact of Pegylated Interferon Alfa-2a on key biomarkers of the disease(s)by measuring the JAK2 allele burden.

    To evaluate specific pre-defined toxicity and tolerance of Pegylated Interferon Alfa-2a through a sequential structured symptom assessment package of patient reported outcome instruments.

    To estimate survival, and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation during therapy Pegylated Interferon Alfa-2a.

    Estimate the observed incidence of major cardiovascular events during therapy Pegylated Interferon Alfa-2a.

    To measure the impact of Pegylated Interferon Alfa-2a on JAK2-V617F, CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

    Trial Keywords

    Polycythemia Vera

    Essential Thrombocythemia

    Hydroxyurea Resistant

    Abdominal Vein Thrombosis

    PEGASYS