Chronic Myeloid Leukemia CML
Conditions
Interventions
Patients will be treated with nilotinib 300 mg BID at the beginning of the
study to establish the tolerability before adding PegIFN. Combination treatment
will be continued until Month 12, which is
Sponsors
Vrije Universiteit Medisch Centrum
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Patients *18 years of age. 2. At diagnosis CML in chronic phase. 3. Persistent disease demonstrated by two PCR positive tests (i.e. BCR ABL level above 0.01% IS) which have been performed during the past 9 months and more than 10 weeks apart. One of these should be performed within 1 month of registration. 4. Treatment with imatinib * 600 mg for at least 2 years.The dose must have been stable in the previous 6 months and, before that, may not have exceeded 600 mg because of pre-existent hematologic, cytogenetic or molecular resistance . 5. No other current or planned anti leukemia therapies. 6.ECOG Performance status 0,1, or 2. 7. Adequate organ function as defined by: a)Total bilirubin
Exclusion criteria
Exclusion criteria: 1.Prior accelerated phase or blast crisis. 2.Patient has received another investigational agent within last 6 months. 3.Previous treatment with nilotinib or dasatinib. 4.Prior stem cell transplantation. 5.Impaired cardiac function including any one of the following: a) Inability to monitor the QT/QTc interval on ECG. b) Long QT syndrome or a known family history of long QT syndrome. c) Clinically significant resting brachycardia (450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re screened for QTc. e) Myocardial infarction within 12 months prior to starting study. f) Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension). g) History of or presence of clinically significant ventricular or atrial tachyarrhythmias. 6.Known atypical BCR ABL transcript not quantifiable by standard RQ PCR 7.Presence of uncontrolled cardiovascular risk factors: history of cardiovascular events, like myocardial infarction, symptomaticvascular disease, stroke or transient ischemic attacks; untreated hypertension; untreated hypercholesterolemia, smoking, when patient refuses to quit; poorly controlled diabetes mellitus(i.e. HbA1c >9.0% (>75 mmol/mol)) or clinically relevant diabetic complications such as neuropathy, retinopathy, nephropathy, coronary or peripheral vascular disease. 8.History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or carcinoma in situ of cervix uteri or breast. 9.Acute liver disease or cirrhosis. 10. Previous or active acute or chronic pancreatic disease. 11.Another severe and/or life threatening medical disease. 12.History of significant congenital or acquired bleeding disorder unrelated to cancer. 13.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug. 14.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. 15.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. 16.Patients who are: a)pregnant. b)breast feeding. c)of childbearing potential without a negative pregnancy test prior to baseline. d)male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post menopausal women must be amenorrheic for at least 12 months to be considered of non childbearing potential). 17. Interruption of imatinib therapy for a cumulative period in excess of 21 days in the preceding 3 months. 18. Major toxicity on imatinib in past 3 months. 19. History of non compliance, or other inability to grant informed consent. 20. Past or present history of alcohol abuse, use of illicit drugs, or severe psychiatric disorders, including depression. 21. Known hypersensitivity to any interferon preparation 22. Autoimmune hepatitis or a history of autoimmune disease 23. Pre existing thyroid disease unless it can be controlled w
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| * The proportion of patients with confirmed MR4.0 IS at Month 12. For the substudies: The predictive value for response of * relative and absolute numbers of CD4+ and CD8+ T cells, NK cells, NKT cells, B cells and regulatory T cells (CD4+, CD25+, FoxP3+), as measured by flow cytometry assay pre- and post-treatment. * the presence and frequency of BCR-ABL-, WT1, Prame- or PR1-specific cytotoxic T-cells as measured by flow cytometry using tetramer technique. * the cytotoxic capacity of lymphocytes, as measured by killing activity of NK cells, IFN * production by and granzyme B staining of T cells after stimulation, all performed pre- and post treatment. * plasma cytokine profiles, as measured by the Luminex multiplex array system pre- and post-treatment. * phosphoproteomic profiles pre- and post-treatment. * the frequency of residual leukemic stem cells, as detected by flow cytometry using phospho-CRKL activity as a read-out of BCR-ABL activity. | — |
Secondary
| Measure | Time frame |
|---|---|
| * Safety and tolerability, including frequency and type of AEs/serious AEs. * The proportion of patients with MR4.0 and with MR4.5 IS at or by Month 3, 6, 12, 18 and 24. * The proportion of patients who complete the planned 9 months of combination therapy with PegIFN (i.e. to Month 12 assessment). * The rate of loss of CCyR, MMR and MR4.0 at Month 12, 18. * The proportion of patients progressing to advanced disease phase. * Overall survival. * Quality of Life as assessed by standard questionaires * ECOG performance rating at baseline, month 3, 6, 12 and 18. | — |
Countries
Netherlands
Outcome results
None listed