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

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

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.

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