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

Condition(s) targeted: High Risk Polycythemia Vera; High Risk Essential Thrombocythemia

Intervention: PEGASYS (Drug); Hydroxyurea (Drug); Aspirin (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Myeloproliferative Disorders-Research Consortium

Official(s) and/or principal investigator(s):
Ronald Hoffman, MD, Principal Investigator, Affiliation: Myeloproliferative Disorders-Research Consortium
Richard Silver, MD, Principal Investigator, Affiliation: Myeloproliferative Disorders-Research Consortium
Claire Harrison, MD, Principal Investigator, Affiliation: Myeloproliferative Disorders-Research Consortium
Alessandro Rambaldi, MD, Principal Investigator, Affiliation: m

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.

Official title: 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)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To compare hematologic response rates in patients randomized to treatment with Pegylated Interferon Alfa-2a vs Hydroxyurea in two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET).

Secondary outcome:

To compare the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) in the study populations by recording the adverse events that occur during the study using the CTC 4.0 as the guide.

To compare the hematologic partial response rates on therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

To compare specific pre-defined toxicity and tolerance of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) and validate the utility of sequential structured symptom assessment package of patient reported outcome instruments.

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.

To compare the impact of therapy on JAK2-V617F (JAK2), hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

To estimate incidence of major cardiovascular events after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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. Values below are at the time of diagnosis, not study entry.

- Diagnosis < 3 years prior to 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 4 major 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

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

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

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

(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

Other Inclusion criteria (Both Strata)

- Diagnosed less than 3 years prior to entry on trial

- Never treated with cytoreductive drugs except hydroxyurea for up to 3

months maximum (phlebotomy, aspirin 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

- Total Bilirubin within normal limits

- No known PNH (paroxysmal nocturnal hemoglobinuria) clone

- No concurrent hormonal oral contraceptive use

Exclusion Criteria:

(ANY of the following, both strata)

- 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)

- History of autoimmune disorder (e. g. hepatitis)

- 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

- Splanchnic vein thrombosis (includes Budd-Chiari, portal vein, splenic and

mesenteric thrombosis)

- 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

- Neutrophil count <1. 5 x 10 to 9/L

- JAK2 exon 12 mutation

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

B)

- 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.

- No 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

- Serum creatinine < 1. 5 x upper limit of normal

- AST and ALT < 2 x upper limit of normal

- Total Bilirubin within normal limits

Unicersite Catholique de Louvain, Brussels, Belgium; Not yet recruiting
Laurent Knoops, MD, Phone: 32-2-7641800, Email: laurent.knoops@uclouvain.be
Laurent Knoops, MD, Principal Investigator

Hopitaux de Paris, Paris 75010, France; Not yet recruiting
Jean-Jacques Kiladjian, MD, Email: jean-jacques.kiladjian@sls.aphp.fr
Jean-Jacques Kiladjian, m, Principal Investigator

Belfast City Hospital, Belfast BT9 7AB, Ireland; Not yet recruiting
Mary Frances McMullin, MD, Phone: 02890263733, Email: m.mcmullin@qub.ac.uk
Mary Frances McMullin, MD, Principal Investigator

Ospedale Riuniti de Bergamo, Bergamo, Italy; Not yet recruiting
Alessandro Rambaldi, MD, Phone: 39-03-5269490, Email: arambaldi@ospedaliriuniti.bergamo.it
Alessandro Rambaldi, MD, Principal Investigator

University Of Florence, Florence, Italy; Not yet recruiting
Alessandro Vannucchi, MD, Phone: 39-055-7947688, Email: a.vannucchi@unifi.it
Alessandro Vannucchi, MD, Principal Investigator

Ospedale San Maartino Genova, Genova 11632, Italy; Not yet recruiting
Francesco Frassoni, MD, Phone: 39-010-555469, Email: francesco.frassoni@hsanmartino.it
Francesco Frassoni, MD, Principal Investigator

San Matteo Hospital, Pavia 27100, Italy; Not yet recruiting
Gianni Barosi, MD, Phone: 39-038-2503636, Email: barosig@smateo.pv.it
Gianni Barosi, MD, Principal Investigator

Universita Cattolica del Sacro Cuore, Rome 00168, Italy; Not yet recruiting
Raffaele Landolfi, MD, Phone: 39-06-30154438, Email: rlandolfi@rm.unicatt.it
Raffaele Landolfi, MD, Principal Investigator

VU University Medical Centre, Amsterdam, Amsterdam, Netherlands; Not yet recruiting
Sonja Zweegman, MD, PhD, Phone: 31-20-4442604, Email: S.Zweegman@vumc.nl
Sonja Zweegman, MD, PhD, Principal Investigator

Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands; Not yet recruiting
Peter AW te Boekhorst, MD, PhD, Phone: 31 10 7033740, Email: p.teboekhorst@erasmusmusmc.nl
Peter AW te Boekhorst, MD, PhD, Principal Investigator

Sahlgrenska University Hospital, Goteborg, Sweden; Not yet recruiting
Bjorn Andreasson, MD, Phone: 46-31-3421000, Email: bjorn.andreasson@vgregion.se
Bjorn Andreasson, MD, Principal Investigator

Stockholm South Hospita, Sweden, Stockholm, Sweden; Not yet recruiting
Jan Samuelsson, MD, PhD, Phone: 46-8-6163225, Email: jan.samuelsson@sodersjukhuset.se
Jan Samuelsson, MD, PhD, Principal Investigator

University of Cambridge, Cambridge, United Kingdom; Not yet recruiting
Anthony Green, MD, Phone: 01-223 762668, Email: arg1000@cam.ac.uk
Anthony Green, MD, Principal Investigator

Guy's and St. Thomas' NHS Foundation Trust, London SE1 7EH, United Kingdom; Not yet recruiting
Claire Harrison, MD, Phone: 02 71882739, Email: claire.harrison@gstt.sthames.nhs.uk
Claire Harrison, MD, Principal Investigator

Mayo Clinic, Scottsdale, Arizona 85259, United States; Recruiting
Ruben Mesa, MD, Phone: 480-301-8335, Email: mesa.ruben@mayo.edu
Ruben Mesa, MD, Principal Investigator

The Palo Alto Clinic, Palo Alto, California 94301, United States; Recruiting
David Liebowitz, MD, Phone: 650-853-2905, Email: liebowd@pamf.org
David Liebowitz, MD, Principal Investigator

Georgetown University Medical Center, Washington, District of Columbia 20007, United States; Recruiting
Craig Kessler, MD, Phone: 202-444-8676, Email: kesslerc@gunet.georgetown.edu
Craig Kessler, MD, Principal Investigator

Emory Hospital, Atlanta, Georgia 30322, United States; Recruiting
Elliot Winston, MD, Phone: 404-778-5871, Email: ewinston@emory.edu
Elliot Winston, MD, Principal Investigator

John H. Stroger Hospital of Cook County, Chicago, Illinois 60612, United States; Not yet recruiting
Rose Catchatorian, MD, Phone: 312-864-7257, Email: rcatchator@ccbhs.org
Rose Catchatorian, MD, Principal Investigator

University of Illinois at Chicago, Chicago, Illinois 60612, United States; Not yet recruiting
Damiano Rondelli, MD, Phone: 312-996-6179, Email: drond@uic.edu
Damiano Rondelli, MD, Principal Investigator

University of Maryland, Baltimore, Maryland 21201, United States; Not yet recruiting
Maria Baer, MD, Phone: 410-328-8708, Email: mbaer@umm.edu
Maria Baer, MD, Principal Investigator

Mount Sinai School of Medicine, New York, New York 10029, United States; Recruiting
Ronald Hoffman, MD, Phone: 212-241-2296, Email: ronald.hoffman@mssm.edu
Ronald Hoffman, MD, Principal Investigator

Weill Cornell Medical College, New York, New York 10065, United States; Not yet recruiting
Richard Silver, MD, Phone: 212-746-2856, Email: rtsilver@med.cornell.edu
Richard Silver, MD, Principal Investigator

Ohio State University, Columbus, Ohio 43210, United States; Not yet recruiting
Rebecca Klisovic, MD, Phone: 614-293-4696, Email: rebecca.klisovic@osumc.edu
Rebecca Klisovic, MD, Principal Investigator

Geisinger Cancer Center, Hazelton, Pennsylvania 18201, United States; Recruiting
Paul Roda, MD, Phone: 570-459-2901, Email: Proda@geisinger.edu
Paul Roda, MD, Principal Investigator

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting
Elizabeth Hexner, MD, Phone: 215-662-4137, Email: elizabeth.hexner@uphs.upenn.edu
Elizabeth Hexner, MD, Principal Investigator

University of Utah, Salt Lake City, Utah 84132, United States; Recruiting
Josef Prchal, MD, Phone: 801-581-4220, Email: josef.prchal@hsc.utah.edu
Josef Prchal, MD, Principal Investigator

Starting date: September 2011
Last updated: September 10, 2012