Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)

Study Overview
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Brief Summary
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This research is looking 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. The purpose of this study is to look at the effectiveness of giving participants who have been diagnosed with ET or PV one of two different study regimens over time. The study subject will be followed for their condition for about 5 years. The subject will be randomized into one of two study regimens, either Pegylated Interferon Alfa-2a (PEGASYS) or Aspirin and Hydroxyurea (also called Hydroxycarbamide). The subject must be newly diagnosed or already receiving treatment for either PV or ET. Each of the study drugs used in this study is already being used to treat subjects with ET or PV currently, but the investigators are unsure which study drug is better.

Detailed Description
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The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are a group of clonal hematological malignancies that are characterized by a chronic course which can be punctuated by a number of disease related events including thrombosis, hemorrhage, pruritis and leukemic transformation. These disorders include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PM). Recently an acquired somatic mutation in the intracellular kinase, JAK2 (JAK2V617F) has been observed in 95% of patients with PV, 50% of patients with ET and 50% of patients with primary myelofibrosis. At present the chemotherapeutic agent hydroxyurea is the standard of care for high risk patients with PV. Concern exists about prolonged use of this drug leading to leukemia and the inability of hydroxyurea to eliminate the malignant clone. Interferon (rIFN -2b), is a drug that appears to be non-leukemogenic, and may have a preferential activity on the malignant clone in PV, as suggested by cytogenetic remissions obtained in patients treated with rIFN -2b. Several investigators recently reported that patients with PV treated with rIFN -2b had lower JAK2V617F allele burdens as compared to a control group that included patients treated with phlebotomy, hydroxyurea, or anagrelide, or who remained untreated. The results confirm the hypothesis that rIFN -2b preferentially targets the malignant clone in PV and raises the possibility that the JAK2V617F allele burden, and a reversion of clonal hematopoiesis monitored in females by expression of X-chromosome polymorphic alleles maybe useful in monitoring minimal residual disease in PV patients. Pegylated Interferon Alfa-2a (PEGASYS) has been demonstrated in phase II trials of patients with PV and ET to have clinical efficacy as measured by normalization of myeloproliferation, lack of vascular events while on therapy, and a decrease in the JAK2V617F allele burden. Overall the tolerability of the therapy was good, with each of these trials having a dropout rate secondary to toxicity of less than 10% of those enrolled. Although dropout rates for toxicity were low, that is not to say the therapy was without symptomatic toxicity, and indeed a spectrum of toxicities might be encountered and need to be weighed in the analysis of the net clinical benefit patients experience on a clinical trial with Pegylated Interferon Alfa-2a. A new MPN assessment form will be utilized in this study. This 19 item instrument includes a previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. The instrument yields an independent result for each symptom (fatigue is a composite score), as this methodology (of linear analog scale assessment [LASA]) has proven very valid in the past. This instrument was validated prospectively (by comparison to a panel of instruments each containing an aspect of the MPN-SAF) for administration at a single time point. This is a randomized trial between hydroxyurea and Pegylated Interferon Alfa-2a, it is an open label clinical trial in two independent disease strata: (1) high risk polycythemia vera and (2) high risk essential thrombocythemia.

Official Title
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Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)

Conditions
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High Risk Polycythemia Vera, High Risk Essential Thrombocythemia

Intervention / Treatment
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* Drug: PEGASYS
* Drug: Hydroxyurea
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of Essential Thrombocythemia (ET) or Polycythemia Vera (PV) shall be made in accordance with the WHO (2008)criteria (Swerdlow 2008) as shown below. Diagnosis < 5 years prior to entry. Polycythemia Vera (2 major criteria required) 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). 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) Platelets count ≥ 450 x 10 to 9/L Megakaryocyte proliferation with large and mature morphology. No significant increase or left shift of neutrophil granulopoiesis or erythropoiesis. Patients may have up to and including 2+ marrow reticulin fibrosis (0, 1 or 2 on scale 0 -4). Not meeting WHO criteria for CML, PV, MDS, PMF or other myeloid neoplasm Demonstration of clonal cytogenetic marker or no evidence of reactive thrombocytosis. Absence of a leukoerythroblastic blood picture. 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 splenomegaly (> 5cm below the left costal margin on palpitation) 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 headaches (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 Other Inclusion criteria (Both Strata) Diagnosed less than 5 years prior to entry on trial Never treated with cytoreductive drugs except hydroxyurea for up to 3 months maximum (phlebotomy, aspirin allowed, anagrelide allowed) Age: ≥ 18 years (no upper limit) Ability and willingness to comply with all study requirements Signed informed consent to participate in this study. Willing to participate in associated correlative science biomarker study Serum creatinine ≤ 1.5 x upper limit of normal ST and ALT ≤ 2 x upper limit of normal No known PNH (paroxysmal nocturnal hemoglobinuria) clone No concurrent hormonal oral contraceptive use Exclusion Criteria: (ANY of the following, both strata) Known to meet the criteria for primary myelofibrosis (as opposed to ET) by WHO 2008 Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix) Any contraindications to pegylated interferon or hydroxyurea Presence of any life-threatening co-morbidity History of active substance or alcohol abuse within the last year Subjects who are pregnant, lactating or of reproductive potential and not practicing an effective means of contraception History of psychiatric disorder (e.g. depression) 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) Hypersensitivity to interferon alfa Hepatitis B or C infection (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 Neutrophil count <1.5 x 10 to 9/L JAK2 exon 12 mutation: PV that lacks the JAK2V617F mutation but is characterized by the exon 12 mutation. Meets criteria for post PV or post ET-MF 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. Previous exposure to any formulation of pegylated interferon History of major organ transplantation History of uncontrolled severe seizure disorder Inability to give informed written consent Total bilirubin >1.5 x ULN (patients that have an isolated indirect bilirubin that causes total bilirubin to be elevated beyond 1.5 x ULN due to documented Gilbert's syndrome or hemolysis may be included). No detectable PNH (paroxysmal nocturnal hemoglobinuria) clone where tested

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PEGASYS<br>The subject will begin receiving the PEGASYS at a dose level of 45 micrograms weekly and gradually get increased to the maximum dose of 180 micrograms per week. The dose will be administered by prefilled syringes that will be injected subcutaneously. Subjects will receive therapy for up to 12 months. | Drug: PEGASYS<br>* The subject will begin receiving the PEGASYS at a dose level of 45 micrograms weekly and gradually get increased to the maximum dose of 180 micrograms per week. The dose will be administered by prefilled syringes that will be injected subcutaneously. Subjects will receive therapy for up to 12 months.<br>* Other names: Pegylated Interferon Alfa-2a;Drug: Aspirin<br>* Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.<br>* Other names: acetylsalicylic acid;|
| Active Comparator: Hydroxyurea<br>Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment. | Drug: Hydroxyurea<br>* Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment.<br>* Other names: Hydroxycarbamide;Drug: Aspirin<br>* Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.<br>* Other names: acetylsalicylic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Remission (CR) | Number of participants with Complete Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Complete remission means no evidence of disease. | 12 months | 
| Number of Participants With Partial Remission (PR) | Number of participants with Partial Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Partial Remission means decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 and Grade 4 Hematological and Non-hematological Events | Number of Participants with Grade 3 and Grade 4 Hematological and Non-hematological Events using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 to assess the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea). | 4 years | 
| Change in the Total Symptom Score (TSS) | Change in the Total Symptom Score which assessed improvement in disease symptoms measured by the change in TSS from the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study from baseline to 12 months. This 19 item instrument includes the previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. Each item is scored from 0-10 with full scale from 0-190, with higher scores mean worse symptoms. | baseline and 12 months | 
| JAK2 Allele Burden | To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on key biomarkers of the disease(s) by measuring the JAK2 allele burden. | 4 years | 
| Allele Burden | 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.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities. | 4 years | 
| Number of Participants With Progression of Disease or Death | Survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) by capturing the rate of progression to a more advanced myeloid malignancy. | 4 years | 
| Number of Participants With Major Cardiovascular Events After Therapy |  | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PEGASYS, Polycythemia vera, Essential thrombocythemia, Hydroxyurea, Pegylated Interferon Alfa-2a