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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Mount Sinai School of Medicine
Sponsor:
Collaborators:
Myeloproliferative Disorders-Research Consortium
Roche Pharma AG
QIAGEN Marseille
Information provided by (Responsible Party):
Ronald Hoffman, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01259817
First received: December 6, 2010
Last updated: June 11, 2014
Last verified: June 2014
  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.


Condition Intervention Phase
High Risk Polycythemia Vera
High Risk Essential Thrombocythemia
Drug: PEGASYS
Drug: Aspirin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

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 [ Time Frame: 4 years ] [ Designated as safety issue: No ]

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. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
  • To measure the impact of Pegylated Interferon Alfa-2a on key biomarkers of the disease(s)by measuring the JAK2 allele burden. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
    Improvement in disease symptoms will be measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study.

  • To estimate survival, and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after Pegylated Interferon Alfa-2a. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    We plan to capture the rate of disease progression to a more advanced myeloid malignancy.

  • Estimate the observed incidence of major cardiovascular events after therapy Pegylated Interferon Alfa-2a. [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
    Capture and record the cardiovascular events that occur during the study.

  • To measure the impact of Pegylated Interferon Alfa-2a on JAK2-V617F, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.


Estimated Enrollment: 188
Study Start Date: September 2011
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PEGASYS
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.
Drug: PEGASYS
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.
Other Name: Pegylated Interferon Alfa-2a
Active Comparator: Aspirin
81 or 100 mg daily.
Drug: Aspirin
81 or 100 mg daily.
Other Name: acetylsalicylic acid

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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)
  • Platelet count>400 x 10 to 9/L and WBC less than 2.5 x 10 to 9/L at any dose of Hydroxyurea (for a period of at least 2 months). Platelet count>400 x 10 to 9/L and Hb less than10 g/dl at any dose of Hydroxyurea (for a period of at least 2 months) Progressive splenomegaly or hepatomegaly (>5cm or appearance of new splenomegaly or hepatomegaly) in a patient being treated for splenomegaly In patients with baseline splenomegaly an increase by > 5 cm over baseline
  • Not achieving the desired reduction of HCT with the addition of Hydroxyurea in patients who do not tolerate enough frequent venesections after 3 months of at least 2 g/day of Hydroxyurea (2.5 g/day in patients with a body weight>80 kg)
  • Not achieving the desired stable reduction of WBC when leukocytes are a target of therapy after 3 months of at least 2 g/day of Hydroxyurea (2.5 g/day in patients with a body weight>80 kg)
  • 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.
  • 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)
  • 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-α
  • 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)
  • No 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01259817

  Show 28 Study Locations
Sponsors and Collaborators
Ronald Hoffman
Myeloproliferative Disorders-Research Consortium
Roche Pharma AG
QIAGEN Marseille
Investigators
Principal Investigator: John Mascarenhas, MD Mount Sinai School of Medicine
Principal Investigator: Richard Silver, MD Myeloproliferative Disorders-Research Consortium
Principal Investigator: Claire Harrison, MD Myeloproliferative Disorders-Research Consortium
Principal Investigator: Alessandro Rambaldi, MD Myeloproliferative Disorders-Research Consortium
  More Information

No publications provided

Responsible Party: Ronald Hoffman, Professor of Medicine, Hematology and Medical Oncology, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01259817     History of Changes
Other Study ID Numbers: GCO 09-1300 001, P01CA108671, MPD-RC 111
Study First Received: December 6, 2010
Last Updated: June 11, 2014
Health Authority: United States: Food and Drug Administration
Canada: Canadian Regulatory Authority
Italy: European Union Drug Regulatory Authorities
France: European Union Drug Regulatory Authorities
United Kingdom: European Union Drug Regulatory Authorities
Netherlands: European Union Drug Regulatory Authorities
Belgium: European Union Drug Regulatory Authorities
Sweden: European Union Drug Regulatory Authorities

Keywords provided by Mount Sinai School of Medicine:
Polycythemia Vera
Essential Thrombocythemia
Hydroxyurea Resistant
Abdominal Vein Thrombosis
PEGASYS

Additional relevant MeSH terms:
Thrombocythemia, Essential
Thrombocytosis
Polycythemia
Polycythemia Vera
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Aspirin
Hydroxyurea
Interferon-alpha
Interferons
Peginterferon alfa-2a
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Hematologic Agents

ClinicalTrials.gov processed this record on August 18, 2014