Safety and Efficacy of Pegylated IFN-alpha 2B Added to Dasatinib in Newly Diagnosed Chronic Phase Myeloid Leukemia (NordCML007)

This study is currently recruiting participants.
Verified April 2014 by Norwegian University of Science and Technology
Sponsor:
Information provided by (Responsible Party):
Norwegian University of Science and Technology
ClinicalTrials.gov Identifier:
NCT01725204
First received: November 8, 2012
Last updated: April 16, 2014
Last verified: April 2014
  Purpose

Patients with newly diagnosed CML have excellent outcomes with tyrosine kinase inhibitors (TKI). However, a few patients will be cured with TKIs alone, and thus need continued life-long treatment. Some patients achieve complete molecular remission (CMR), and this rate is higher with second generation TKIs compared with imatinib. Some experience with drug discontinuation in CMR has been derived from a few small studies, most notably the French STIM study. Approximately 40 % of patients with a minimum of two years in MR4.5 (4.5 log reduction in molecular response) can stop imatinib without relapse, indicating possible cure. To increase the non-relapse rate is of major importance. To achieve a permanent "cure" without stem cell transplantation is presently the most relevant goal of clinical studies in CML.

The investigators hypothesize that to significantly increase cure rates in CML, therapy should eradicate leukemic stem cells and/or induce or restore anti-CML immunity. Second generation TKIs may have a more profound effect on the stem cell pool as compared to imatinib. This is assessed in our current randomized study with a reduction in leukemic stem cell burden as the primary endpoint (NordCML006). Interferon-alpha (IFN) has a prominent immunomodulatory and antiproliferative mode of action, and has also activity in stem cells. Pegylated IFN in combination with imatinib results in improved therapy responses as compared to imatinib monotherapy. This advantage may translate into higher cure rates.

Dasatinib has a unique dual mechanism of action: it is the most potent of available TKIs and induces immunological effects that are different from those of IFN. Both of these drugs may have immunological adverse-effects when used as a monotherapy. However, immunological adverse-effects may also be markers of anti-leukemia efficacy. A combination of dasatinib and pegylated IFN (PegIFN) may have additive or synergistic effects and should be tested in a clinical study.


Condition Intervention Phase
Leukemia, Myeloid, Chronic-Phase
Drug: Dasatinib + PegIFN
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Safety and Efficacy Study of Adding Low Dose Pegylated IFN-alpha 2B to Standard Dose Dasatinib in Patients With Newly Diagnosed Chronic Phase Myeloid Leukemia

Resource links provided by NLM:


Further study details as provided by Norwegian University of Science and Technology:

Primary Outcome Measures:
  • major molecular response rates [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    defined as ≤0.1% BCR-ABL1 on the MMR International Scale


Secondary Outcome Measures:
  • overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • quality of life [ Time Frame: up to 18 months (after 3, 6, 12, 18 months) ] [ Designated as safety issue: No ]
  • Rate of CCgR [ Time Frame: up to 18 months (after 3, 6, 12 and 18 months) ] [ Designated as safety issue: No ]
  • Rate of MR4.0 and MR4.5 [ Time Frame: up to 24 months (after 3, 6, 12, 15, 18, and 24 months) ] [ Designated as safety issue: No ]

Estimated Enrollment: 35
Study Start Date: September 2012
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dasatinib + PegIFN
Dasatinib 100mg OD for three months single drug, with subsequent addition of PegIFN 15 μg/ week for 3 months. If well tolerated (less than grade 2 non-hematological or grade 3 hematological AE) the dose should be increased to 25μg weekly for the remaining 9 months on combination treatment. Thereafter dasatinib will be given as monotherapy. Patients will be followed for 24 months totally.
Drug: Dasatinib + PegIFN

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of chronic myeloid leukemia in chronic phase (CML-CP) associated with BCR-ABL1 quantifiable by RQ-PCR (IS)
  • No other current or planned anti-leukemia therapies excluding hydroxyurea treatment for up to two months.
  • ECOG Performance status 0,1, or 2
  • Adequate organ function as defined by: Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab) in absence of Gilbert genotype; ASAT and ALAT < 2.5 x ULN. Creatinine < 2x ULN. Potassium, magnesium and phosphate not below LLN (LLN= lower level of normal)
  • Life expectancy of more than 12 months in the absence of any intervention
  • Patient has given written informed consent to participate in the study

Exclusion Criteria:

  • Prior accelerated phase or blast crisis
  • Uncontrolled or significant cardiovascular disease, including any of the following:

    • A myocardial infarction within 6 months
    • Uncontrolled angina within 3 months
    • Congestive heart failure within 3 months
    • Diagnosed or suspected congenital long QT syndrome
    • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe)
    • Prolonged QTcF interval > 450 msec on pre-entry ECG
  • Atypical BCR-ABL1 transcript not quantifiable by RQ-PCR.
  • Another primary malignant disease, which requires systemic treatment (chemotherapy or radiation) Severe and/or life-threatening medical disease including acute liver disease
  • History of significant congenital or acquired bleeding disorder unrelated to cancer
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dasatinib
  • Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
  • Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
  • Female patients who are: pregnant, breast feeding or potentially fertile without a negative pregnancy test prior to baseline or unwilling to use contraception on trial
  • Previous history of pericarditis or pleuritis
  • History of non-compliance, abuse of alcohol, illicit drugs, severe psychiatric disorders or other inability to grant informed consent.
  • Current treatment for depression.
  • Hypersensitivity to any interferon preparation;
  • Autoimmune hepatitis or a history of autoimmune disease;
  • Pre-existing thyroid disease unless it can be controlled with conventional treatment;
  • Epilepsy and/or compromised central nervous system (CNS) function;
  • HCV/HIV patients
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01725204

Contacts
Contact: Henrik Hjorth-Hansen, MD PhD +47 72825100 henrik.hjorth-hansen@ntnu.no
Contact: Satu Mustjoki +358 947171898 satu.mustjoki@helsinki.fi

Locations
Finland
Helsinki University Central Hospital Recruiting
Helsinki, Finland
Contact: Satu Mustjoki    +358947171898    satu.mustjoki@helsinki.fi   
Contact: Kimmo Porkka    +358947171890    kimmo.porkka@helsinki.fi   
Sub-Investigator: Perttu Koskenvesa         
Norway
Bergen University Central Hospital Recruiting
Bergen, Norway
Contact: Bjorn Gjertsen, MD PhD         
Rikshospitalet Recruiting
Oslo, Norway
Contact: Tobias Gedde-Dahl, MD PhD         
Stavanger University Hospital Recruiting
Stavanger, Norway
Contact: Waleed Majeed         
University Hospital of Northern Norway Recruiting
Tromsø, Norway
Contact: Franz Gruber         
St Olavs Hospital - Trondheim University Hospital Recruiting
Trondheim, Norway
Contact: Henrik Hjorth-Hansen, MD PhD    +47 72825100    henrik.hjorth-hansen@ntnu.no   
Sweden
Linköping University Hospital Recruiting
Linköping, Sweden
Contact: Claes Malm         
Sunderby Sjukhus Recruiting
Luleå, Sweden
Contact: Kristina M Eriksson         
Lund University Hospital Recruiting
Lund, Sweden
Contact: Johan Richter, MD PhD         
Karolinska University Hospital Recruiting
Stockholm, Sweden
Contact: Leif Stenke, MD PhD         
Contact: Sören Lehmann, MD PhD         
Sub-Investigator: Lotta Ohm         
Sundsvall County Hospital Recruiting
Sundsvall, Sweden
Contact: Anders Själander         
Umeå University Hospital Recruiting
Umeå, Sweden
Contact: Berit Markevärn         
Uppsala University Hospital Recruiting
Uppsala, Sweden
Contact: Ulla Olsson-Strömberg, MD PhD         
Örebro University Hospital Recruiting
Örebro, Sweden
Contact: Mats Björeman         
Sponsors and Collaborators
Norwegian University of Science and Technology
Investigators
Study Chair: Henrik Hjorth-Hansen, MD PhD Norwegian University of Science and Technology
  More Information

No publications provided

Responsible Party: Norwegian University of Science and Technology
ClinicalTrials.gov Identifier: NCT01725204     History of Changes
Other Study ID Numbers: NordCML007, 2011-005989-38
Study First Received: November 8, 2012
Last Updated: April 16, 2014
Health Authority: Norway:National Committee for Medical and Health Research Ethics

Keywords provided by Norwegian University of Science and Technology:
dasatinib
Protein Kinase Inhibitors
pegylated IFN-alpha 2B
Interferon-alpha

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Interferon Alfa-2a
Interferon-alpha
Interferon Alfa-2b
Reaferon
Dasatinib
Protein Kinase Inhibitors
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors
Adjuvants, Immunologic
Alcohol Deterrents
Central Nervous System Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 22, 2014