Safety and Efficacy of Pegylated IFN-alpha 2B Added to Dasatinib in Newly Diagnosed Chronic Phase Myeloid Leukemia (NordCML007)
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.
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (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|
- major molecular response rates [ Time Frame: 1 year ]defined as ≤0.1% BCR-ABL1 on the MMR International Scale
- overall survival [ Time Frame: 2 years ]
- quality of life [ Time Frame: up to 18 months (after 3, 6, 12, 18 months) ]
- Rate of CCgR [ Time Frame: up to 18 months (after 3, 6, 12 and 18 months) ]
- Rate of MR4.0 and MR4.5 [ Time Frame: up to 24 months (after 3, 6, 12, 15, 18, and 24 months) ]
|Study Start Date:||September 2012|
|Study Completion Date:||May 2016|
|Primary Completion Date:||May 2016 (Final data collection date for primary outcome measure)|
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|
Please refer to this study by its ClinicalTrials.gov identifier: NCT01725204
|Helsinki University Central Hospital|
|Bergen University Central Hospital|
|Stavanger University Hospital|
|University Hospital of Northern Norway|
|St Olavs Hospital - Trondheim University Hospital|
|Linköping University Hospital|
|Lund University Hospital|
|Karolinska University Hospital|
|Sundsvall County Hospital|
|Umeå University Hospital|
|Uppsala University Hospital|
|Örebro University Hospital|
|Study Chair:||Henrik Hjorth-Hansen, MD PhD||Norwegian University of Science and Technology|