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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Odense University Hospital
Sponsor:
Information provided by (Responsible Party):
Thomas Stauffer Larsen, Odense University Hospital
ClinicalTrials.gov Identifier:
NCT01387763
First received: June 23, 2011
Last updated: March 26, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention Phase
Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Drug: PegIntron
Drug: Pegasys
Drug: Hydrea
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Danish Study of Low-dose Interferon Alpha Versus Hydroxyurea in the Treatment of Philadelphia Chromosome Negative (Ph-)Chronic Myeloid Neoplasms - A National Randomized Prospective Study With Focus on Efficacy, Toxicity and Quality of Life

Resource links provided by NLM:


Further study details as provided by Odense University Hospital:

Primary Outcome Measures:
  • molecular response (changes from baseline) [ Time Frame: 18, 36 and 60 months ] [ Designated as safety issue: No ]
    Molecular responses (JAK V617F allele burden) are assessed by qPCR according to the ELN guidelines.


Secondary Outcome Measures:
  • toxicity (discontinuation of therapy due to intolerability) [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
    The proportion of patients treated with PegIntron, Pegasys and Hydrea who need to discontinue therapy due to intolerability

  • Quality of life (changes from baseline) [ Time Frame: 4, 12, 24, 36, 48 and 60 months ] [ Designated as safety issue: No ]
    Quality of life will be evaluated according to EORTC QLQ C-30 and MPN-SAF

  • Histopathological response (changes from baseline) [ Time Frame: 36 and 60 months ] [ Designated as safety issue: No ]
    A bone marrow sample will be evaluated in order to detect and grade changes in bone marrow morphology.

  • Sustained molecular response (changes from level at time of discontinuation of therapy) [ Time Frame: 12, 24 and 36 months ] [ Designated as safety issue: No ]

    investigation of the sustainability of an obtained molecular remission (<

    1% JAK2V617F mutated alleles) after discontinuation of interferon- alpha( Pegasys, PegIntron, Multiferon) or Hydrea.


  • Neutralizing antibodies against PegIntron and Pegasys [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    Proprotion of patients treated with Peintron and Pegasys who have developed neutralizing antibodies.

  • hematological response [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Hematological response will be evaluated according to the ELN guidelines.


Estimated Enrollment: 200
Study Start Date: January 2012
Estimated Study Completion Date: January 2020
Estimated Primary Completion Date: January 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: PegIntron <= 60 years
In patients <= 60 years PegIntron is started at low-dose 30 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 90 micrograms weekly.
Drug: PegIntron
PegIntron, prefilled syringe 50 micrograms/0.5 ml. 30 micrograms subcutaneously once weekly.
Other Name: Pegylated interferon alpha 2b
Active Comparator: Pegasys <= 60 years
In patients <= 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.
Drug: Pegasys
Pegasys, prefilled syringe 180 micrograms/0.5 ml 45 micrograms subcutaneously once weekly
Other Name: Pegylated interferon alpha 2a
Active Comparator: PegIntron > 60 years
In patients < 60 years PegIntron is started at low-dose 30 micrograms once weekly. Dose escalation to 50 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 50 micrograms weekly at 12 months and 18 months respectively, dose escalation to 90 micrograms weekly.
Drug: PegIntron
PegIntron, prefilled syringe 50 micrograms/0.5 ml. 30 micrograms subcutaneously once weekly.
Other Name: Pegylated interferon alpha 2b
Active Comparator: Pegasys > 60 years
In patients > 60 years Pegasys is started at low-dose 45 micrograms once weekly. Dose escalation to 90 micrograms weekly if lack of complete hematological response at 4 months or lack of at least partial molecular response at 8 months. If complete hematological response or lack of at least partial molecular response is not achieved at 90 micrograms weekly at 12 months and 18 months respectively, dose escalation to 135 micrograms weekly.
Drug: Pegasys
Pegasys, prefilled syringe 180 micrograms/0.5 ml 45 micrograms subcutaneously once weekly
Other Name: Pegylated interferon alpha 2a
Active Comparator: Hydroxyurea > 60 years
Capsule Hydrea 500-2000 mg orally QD or BID
Drug: Hydrea
Capsule Hydrea 500-2000 mg orally QD or BID
Other Names:
  • hydroxyurea
  • hydroxycarbamide

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT01387763

Contacts
Contact: Thomas S Larsen, MD PhD 0045 6541 2942 thomas.stauffer.larsen@ouh.regionsyddanmark.dk
Contact: Sally Grant 0045 6541 1637 sally.grant@ouh.regionsyddanmark.dk

Locations
Denmark
Dept of Hematology, Aalborg hospital Recruiting
Aalborg, Denmark, 9000
Contact: Inge Helleberg, MD DMSC    0045 9932 6301    ihr@rn.dk   
Dept. of Hematology, Aarhus University Hospital Recruiting
Aarhus, Denmark, 8000
Contact: Jesper Stentoft, MD PhD    0045 8949 4444    jepsten@rm.dk   
Dept of Hematology, Esbjerg Hospital Recruiting
Esbjerg, Denmark, 6700
Contact: Olav Bergmann, MD DMSC    0045 7918 2247    olav.bergmann@svs.regionsyddanmark.dk   
Dept of Hematology, Herlev Hospital Recruiting
Herlev, Denmark, 2730
Contact: Morten K Jensen, MD DMSc    0045 3868 9153    mokrje@heh.regionh.dk   
Dept of Hematology, Holstebro Hospital Recruiting
Holstebro, Denmark, 7500
Contact: Jørgen Starklint, MD PhD    0045 9912 5000    jørgen.starklint@rm.dk   
Dept of Hematology, Rigshospitalet Recruiting
København, Denmark, 2100
Contact: Ole W Bjerrum, DMSC    0045 3585 4387    ole.weis.bjerrum@rh.regionh.dk   
Dept of hematology, Odense University Hospital Recruiting
Odense, Denmark, 5000
Contact: Thomas S Larsen, MD PhD    0045 6541 2942    thomas.stauffer.larsen@ouh.regionsyddanmark.dk   
Contact: Sally Grant    0045 6541 1637    sally.grant@ouh.regionsyddanmark.dk   
Sub-Investigator: Hanne Vestergaard, MD PhD         
Dept. of Hematology, Roskilde Hospital Recruiting
Roskilde, Denmark, 4000
Contact: Hans C Hasselbalch, MD DMSC    0045 4732 4800    hans.hasselbalch@dadlnet.dk   
Dept of Hematology, Vejle Hospital Not yet recruiting
Vejle, Denmark, 7100
Contact: Dorthe R Jessen, MD DMSC    0045 7940 6335    adrj@dadlnet.dk   
Sponsors and Collaborators
Thomas Stauffer Larsen
Investigators
Principal Investigator: Thomas S Larsen, MD PhD Dept. of Hematology, Odense University Hospital
  More Information

No publications provided

Responsible Party: Thomas Stauffer Larsen, MD PhD, Odense University Hospital
ClinicalTrials.gov Identifier: NCT01387763     History of Changes
Other Study ID Numbers: daliah2011
Study First Received: June 23, 2011
Last Updated: March 26, 2013
Health Authority: Denmark: Danish Medicines Agency

Additional relevant MeSH terms:
Primary Myelofibrosis
Philadelphia Chromosome
Polycythemia
Polycythemia Vera
Thrombocythemia, Essential
Thrombocytosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Interferon-alpha
Interferon Alfa-2a
Interferon Alfa-2b
Interferons
Peginterferon alfa-2a
Peginterferon alfa-2b
Reaferon
Hydroxyurea
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014