A Phase II, Single Arm, Multicenter Study of Nilotinib in Combination With Pegylated Interferon-α2b in Patients With Suboptimal Molecular Response or Stable Detectable Molecular Residual Disease After at Least Two Years of Imatinib Treatment (NordDutchCML009)
1. Patients ≥ 18 years
2. At diagnosis CML in chronic phase
3. Documented complete cytogenetic response by bone marrow (standard cytogenetics) or
peripheral blood BCR ABL <1% IS
4. Persistent disease demonstrated by two PCR positive tests (i.e. BCR ABL level between
0.01% and 1% 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
5. Treatment with imatinib for at least 2 years with 400 mg and at a stable dose (i.e.
the dose has not changed in the previous 6 months)
6. No other current or planned anti leukemia therapies
7. ECOG Performance status 0,1, or 2
8. Adequate organ function as defined by:
1. Total bilirubin <1.5 x ULN. Does not apply to patients with isolated
hyperbilirubinemia (e.g. Gilbert's disease) grade <3.
2. ASAT and ALAT <2.5 x ULN.
3. Serum amylase and lipase ≤1.5 x ULN.
4. Alkaline phosphatase ≤2.5 x ULN.
5. Creatinine clearance >30 ml/min.
6. Mg++, K+ ≥LLN.
9. Life expectancy > 12 months in the absence of any intervention
10. Patient has given written informed consent
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:
1. Inability to monitor the QT/QTc interval on ECG.
2. Long QT syndrome or a known family history of long QT syndrome.
3. Clinically significant resting brachycardia (<50 bpm).
4. QTc >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.
5. Myocardial infarction within 12 months prior to starting study.
6. Other clinically significant uncontrolled heart disease (e.g. unstable angina,
congestive heart failure or uncontrolled hypertension).
7. History of or presence of clinically significant ventricular or atrial
6. Known atypical BCR ABL transcript not quantifiable by standard RQ PCR
7. 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.
8. Acute liver disease or cirrhosis.
9. Previous or active acute or chronic pancreatic disease.
10. Another severe and/or life threatening medical disease.
11. History of significant congenital or acquired bleeding disorder unrelated to cancer.
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of study drug.
13. Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment
cannot be either discontinued or switched to a different medication prior to starting
14. 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.
15. Patients who are pregnant, breast feeding, of childbearing potential without a
negative pregnancy test prior to baseline; 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
16. Interruption of imatinib therapy for a cumulative period in excess of 21 days in the
preceding 3 months.
17. Major toxicity on imatinib in past 3 months.
18. History of non compliance, or other inability to grant informed consent.
19. Past or present history of alcohol abuse, use of illicit drugs, or severe psychiatric
disorders, including depression.
20. Known hypersensitivity to any interferon preparation.
21. Autoimmune hepatitis or a history of autoimmune disease.
22. Pre existing thyroid disease unless it can be controlled with conventional treatment.
23. Epilepsy and/or compromised central nervous system (CNS)function.
24. HCV/HIV patients.
25. Poorly controlled diabetes mellitus(i.e. HbA1c >9.0) or clinically relevant diabetic
complications such as neuropathy, retinopathy, nephropathy, coronary or peripheral