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A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms

Information source: Odense University Hospital
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Polycythemia Vera; Essential Thrombocythemia; Primary Myelofibrosis

Intervention: PegIntron (Drug); Pegasys (Drug); PegIntron (Drug); Pegasys (Drug); Hydrea (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Thomas Stauffer Larsen

Official(s) and/or principal investigator(s):
Thomas S Larsen, MD PhD, Principal Investigator, Affiliation: Dept. of Hematology, Odense University Hospital

Overall contact:
Thomas S Larsen, MD PhD, Phone: 0045 6541 2942, Email: thomas.stauffer.larsen@ouh.regionsyddanmark.dk

Summary

The purpose of the study is to compare the efficacy and toxicity including quality of life of two types of low-dose interferon alpha compounds (PegIntron and Pegasys) with hydroxyurea (Hydrea), and to investigate the occurence of neutralizing antibodies against recombinant interferon.

Clinical Details

Official title: Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms.

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

Primary outcome: molecular response (changes from baseline)

Secondary outcome:

toxicity (discontinuation of therapy due to intolerability)

Quality of life (changes from baseline)

Histopathological response (changes from baseline)

Sustained molecular response (changes from level at time of discontinuation of therapy)

Neutralizing antibodies against PegIntron and Pegasys

hematological response

Detailed description: Chronic myeloid neoplasms (CMPN) consists of three main entities, polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). These three disorders have many overlapping clinical features. The diseases are clonal stem cell disorders characterized by a chronic excess production of mainly mature myeloid cells. The excess production of clonal red cells (in PV), platelets (in PV, ET and PMF) and leukocytes (mainly PV and PMF)leads to a highly increased risk of thrombosis. Patients may also suffer from constitutional symptoms, pruritus and splenomegaly. An inherent feature of these diseases are the risk of ET and PV of transformation to myelofibrosis and a risk of both ET, PV and PMF of leukemic transformation. In 2005 major breakthrough in our understanding of the molecular pathophysiology was achieved with the identification of the JAK2 V617F mutation which is present in almost all patients with PV (98%) and about half of patients with ET and PMF. This somatic gain-of-function point mutation in the JAK2 tyrosine kinase leads to constitutive activation of the kinase. By this mechanism a clonal non-growth factor dependent myeloproliferation is established. Traditionally the excess platelet and white cell production in ET, PV and PMF has been treated with cytoreductive agents such as hydroxyurea and busulfan in order to normalize the blood counts and thereby reducing the risk of thrombosis. However, in younger patients there is a concern of the leukemogenic potential of these agents. In younger patients an alternative treatment option is recombinant pegylated interferon alpha (IFN-alpha), which has demonstrated high clinical efficacy and has no leukemogenic potential. Within recent years IFN-alpha has demonstrated a capacity of inducing deep molecular remission (evaluated by JAK2 V617F qPCR) and normalisation of bone marrow morphology. These remissions have been sustained for up to 3 years after discontinuation of IFN-alpha therapy. Accordingly a perspective of changing the natural history of these disorders towards myelofibrosis and ultimately acute leukemia has emerged. However toxicity has been a major issue and drop-of rates have been reported consistently around 25 %. It is well known from other diseases (e. g multiple sclerosis and hepatitis) that some patients develop neutralizing antibodies against IFN-alpha. This issue is however only scarcely investigated in CMPN and has never been tested in a prospective design. The purpose of this study is to compare the efficacy (hematological and molecular) and toxicity profile of two different recombinant interferon alpha products, IFN-alpha2a and IFN-alpha2b in a prospective randomized design. In patients over the age of 60 there will be a third study arm with hydroxyurea. In order to decrease drop out rates and thereby increasing response rates patients will be started of at a low-dose of IFN-alpha. If patients fail to respond or looses their response and develops neutralizing antibodies against IFN-alpha therapy will be stopped. If patients have a sustained deep molecular response (below 1 % JAK2 V617F mutated alleles for 12 months) therapy will be stopped to asses the sustainability of the remission off therapy. Patients over the age of 75 and intolerant or resistant to hydroxyurea will be offered rescue treatment with orally busulfan (Myleran). As an important part of the study quality of life will be investigated.

Eligibility

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

Criteria:

Inclusion Criteria:

- Male or female > 18 years of age

- Newly diagnosed, or previously diagnosed untreated patients with ET, PV or PMF

including prefibrotic myelofibrosis according to the WHO classification

- Active disease defined by one of the following criteria:

- need for phlebotomy

- leukocytosis > 10 mia/l

- thrombocytosis > 400 mia/l

- constitutional symptoms (fatigue, weight loss, night sweats or fewer > 38 degrees

celsius)

- Pruritus

- splenomegaly causing symptoms

- previous thrombosis

Exclusion Criteria:

- Fertile women without a negative pregnancy test

- Other malignant disease within last 5 years

- ECOG performance score >/= 3

- Creatinine > 2x ULN

- Bilirubin > 1. 5x ULN

- ALAT > 3x ULN

- Previous psychiatric disorder (depression)

- active autoimmune disease

- Uncontrolled thyroid disease

Locations and Contacts

Thomas S Larsen, MD PhD, Phone: 0045 6541 2942, Email: thomas.stauffer.larsen@ouh.regionsyddanmark.dk

Dept of Hematology, Aalborg hospital, Aalborg 9000, Denmark; Recruiting
Morten S Steffensen, MD, Phone: 0045 9932 6301, Email: moss@rn.dk

Dept. of Hematology, Aarhus University Hospital, Aarhus 8000, Denmark; Recruiting
Jesper Stentoft, MD PhD, Phone: 0045 8949 4444, Email: jepsten@rm.dk

Dept of Hematology, Esbjerg Hospital, Esbjerg 6700, Denmark; Recruiting
Olav Bergmann, MD DMSC, Phone: 0045 7918 2247, Email: olav.bergmann@svs.regionsyddanmark.dk

Dept of Hematology, Herlev Hospital, Herlev 2730, Denmark; Recruiting
Daniel E Fassi, MD PhD, Phone: 0045 3868 9153, Email: daniel.el.fassi.01@regionh.dk

Dept of Hematology, Holstebro Hospital, Holstebro 7500, Denmark; Recruiting
Jørgen Starklint, MD PhD, Phone: 0045 9912 5000, Email: jørgen.starklint@rm.dk

Dept of Hematology, Rigshospitalet, København 2100, Denmark; Recruiting
Ole W Bjerrum, DMSC, Phone: 0045 3585 4387, Email: ole.weis.bjerrum@rh.regionh.dk

Dept of hematology, Odense University Hospital, Odense 5000, Denmark; Recruiting
Thomas S Larsen, MD PhD, Phone: 0045 6541 2942, Email: thomas.stauffer.larsen@rsyd.dk
Sally Grant, Phone: 0045 6541 1637, Email: sally.grant@rsyd.dk
Hanne Vestergaard, MD PhD, Sub-Investigator

Dept. of Hematology, Roskilde Hospital, Roskilde 4000, Denmark; Recruiting
Hans C Hasselbalch, MD DMSC, Phone: 0045 4732 4800, Email: hans.hasselbalch@dadlnet.dk

Additional Information

Starting date: January 2012
Last updated: April 20, 2015

Page last updated: August 23, 2015

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