Phase II study of nilotinib plus pegylated interferon alfa-2b as first-line therapy in chronic phase chronic myeloid leukaemia aiming to maximize complete molecular response and major molecular response (CML11)

Funding

Other Collaborative groups,Australasian Leukaemia and Lymphoma Group

Scientific enquiries

Prof Timothy Hughes

Brief Summary

This study aims to determine the safety and efficacy of treatment with a tyrosine kinase inhibitor (TKI) and pegylated interferon in patients with previously untreated chronic myeloid leukaemia (CML). Who is it for? You may be eligible to join this study if you are aged at least 18 years and have been diagnosed with CML. You must have received no previous treatment for CML. Trial details All participants in this trial will commence treatment with the TKI oral nilotinib alone for 3 months. Provid .... This study aims to determine the safety and efficacy of treatment with a tyrosine kinase inhibitor (TKI) and pegylated interferon in patients with previously untreated chronic myeloid leukaemia (CML). Who is it for? You may be eligible to join this study if you are aged at least 18 years and have been diagnosed with CML. You must have received no previous treatment for CML. Trial details All participants in this trial will commence treatment with the TKI oral nilotinib alone for 3 months. Provided the drug is tolerated, participants will commence injections of pegylated interferon at a dose of 30 micrograms per week. After a month of pegylated interferon and nilotinib treatment, and provided the pegylated interferon is tolerated, patients will escalate pegylated interferon treatment to a dose of 50 micrograms per week in combination with nilotinib. Participants will be assessed at regular timepoints until the end of the trial to determine the safety and clinical benefit of the treatments. Treatment duration will be a minimum of 24 months. This Phase II study will: Investigate the survival benefit, the rate of remission and safety of the patients allocated to each group and compare the groups to eachother.
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Key Inclusion Criteria

1. Post-pubertal male or female patients aged 18 years or above. 2. Newly diagnosed (within six months of study entry) Ph+ CML-chronic phase with a quantifiable BCR-ABL transcript 3. No prior therapy for CML and no other current anti-leukaemic therapies (other than prior or current treatment with hydroxyurea or anagrelide). 4. No signs of extramedullary leukaemia, except for hepatosplenomegaly. 5. Documented chronic-phase CML as defined by: i. <15% blasts in both the peripheral blood and bone ma .... 1. Post-pubertal male or female patients aged 18 years or above. 2. Newly diagnosed (within six months of study entry) Ph+ CML-chronic phase with a quantifiable BCR-ABL transcript 3. No prior therapy for CML and no other current anti-leukaemic therapies (other than prior or current treatment with hydroxyurea or anagrelide). 4. No signs of extramedullary leukaemia, except for hepatosplenomegaly. 5. Documented chronic-phase CML as defined by: i. <15% blasts in both the peripheral blood and bone marrow ii. <30% blasts and promyelocytes in both the peripheral blood and bone marrow iii. <20% basophils in the peripheral blood iv. Platelet count >100 × 10^9/L 6. Eastern cooperative oncology group Performance Status score less than or equal to 2 7. Patients must have the following laboratory values: a) Potassium level > lower limit of normal (LLN) b) Calcium (corrected for serum albumin) > LLN c) Magnesium level > LLN d) Phosphorus > LLN e) Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) < 2.5 × upper limit of normal (ULN) or < 5.0 × ULN if considered due to tumour f) Alkaline phosphatase (ALP) < 2.5 × ULN unless considered due to tumour g) Bilirubin < 1.5 × ULN unless due to Gilbert’s syndrome h) Creatinine < 1.5 × ULN i) Amylase and lipase < 1.5 × ULN 8. a) Female patients of childbearing potential must have a negative serum pregnancy test within one week prior to study entry OR have been amenorrhoeic for at least 12 months. b) All patients of reproductive potential must agree to use birth control for the duration of the study. This is only required for as long as the patient has reproductive potential. The type of birth control is a decision which should be made between the treating clinician and the patient. 9. Life expectancy of more than 12 months. 10. Patient has given written, informed consent to participate in the study
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Key Exclusion Criteria

1. Patients who have previously received radiotherapy to >25% of their bone marrow. 2. Patients who have undergone major surgery within the 4 weeks prior to study entry or have not recovered from earlier surgery. 3. Impaired cardiac function, including any of the following: a. Inability to monitor the QT/QTcorrected interval on electrocardiogram (ECG) b. Long QT syndrome or a known family history of long QT syndrome. c. Resting bradycardia (<50 beats per minute) suspected to be secondary to card .... 1. Patients who have previously received radiotherapy to >25% of their bone marrow. 2. Patients who have undergone major surgery within the 4 weeks prior to study entry or have not recovered from earlier surgery. 3. Impaired cardiac function, including any of the following: a. Inability to monitor the QT/QTcorrected interval on electrocardiogram (ECG) b. Long QT syndrome or a known family history of long QT syndrome. c. Resting bradycardia (<50 beats per minute) suspected to be secondary to cardiac pathology d. Qt interval corrected (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 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 4. Treatment with agents (other than warfarin) that prolong QT interval or inhibit CYP3A4, unless judged to be clinically essential. 5. Another primary malignant disease, except for such conditions that do not currently require treatment, lesions that can be or had been completely excised (eg Skin Cancers) and neoplasms that does not significantly affect long term survival of the patient 6. Significantly impaired gastrointestinal (GI) function or GI disease that may alter nilotinib absorption. 7. Other concurrent uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol. 8. History of confirmed acute or chronic pancreatitis. 9. Cytopathologically confirmed central nervous system (CNS) infiltration. [In the absence of suspicion of CNS involvement, lumbar puncture is not required.] 10. Patients unwilling or unable to comply with protocol and patients with a history of noncompliance or inability to grant informed consent. 11. Known diagnosis of human immunodeficiency virus (HIV) infection. 12. Prior allogeneic stem cell transplantation 13. Patients who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Male and female patients of childbearing potential must agree to employ an effective method of birth control throughout the study and for up to 3 months following discontinuation of study drug; The type of birth control is a decision which should be made between the treating clinician and the patient 14. Known history of uncontrolled depression or any other psychiatric disease likely to be exacerbated by study treatment. A formal psychiatric assessment at baseline is not required. 15. Current participation in another therapeutic clinical trial (participation in clinical trials that do not involve active interventions is not an exclusion for the study.) 16. Previous adverse reaction to the trial drug/s
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