A Phase II study in adult patients with newly diagnosed chronic-phase chronic myeloid leukaemia of initial intensified imatinib therapy and sequential dose-escalation followed by treatment with nilotinib in suboptimal responders to determine the rate and duration of major molecular response (CML09)

Funding

Commercial sector/Industry,Novartis Australia

Scientific enquiries

Prof Timothy Hughes

Brief Summary

This trial tests the hypothesis that molecular response can be maximised by a combined approach of higher dose imatinib for all de-novo CML patients plus a rapid switch to nilotinib in patients who are intolerant or have suboptimal response to imatinib.

Key Inclusion Criteria

1. Post-pubertal patients who weigh 40kg or over. 2. Newly diagnosed (within six months of study entry) chronic phase, Philadelphia chromosome-positive Chronic Myeloid Leukaemia (Ph+ CML-CP) involving a BCR-ABL transcript known to be quantifiable.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 de .... 1. Post-pubertal patients who weigh 40kg or over. 2. Newly diagnosed (within six months of study entry) chronic phase, Philadelphia chromosome-positive Chronic Myeloid Leukaemia (Ph+ CML-CP) involving a BCR-ABL transcript known to be quantifiable.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:6. Eastern Cooperative Oncology Group Performance Status score <2 7. Patients must have the following laboratory values:a) Potassium level > lower limit of normalb) Calcium (corrected for serum albumin) > lower limit of normalc) Magnesium level > lower limit of normald) Phosphorus > lower limit of normale) ALT and AST < 2.5 × upper limit of normal or < 5.0 × upper limit of normal if considered due to tumourf) ALP < 2.5 × upper limit of normal unless considered due to tumourg) Bilirubin < 1.5 × upper limit of normalh) Creatinine < 1.5 × upper limit of normali) Amylase and lipase < 1.5 × upper limit of normal8. a) Female patients of childbearing potential must have a negative pregnancy test within one week prior to study entry OR have been amenorrhoeic for at least two years. b) All patients of reproductive potential must agree to use birth control for the duration of the study.9. Life expectancy of more than 12 months in the absence of any intervention10. 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.4 Impaired cardiac function5 Treatment with agents (other than warfarin) that prolong QT interval or inhibit CYP3A4, unless judged to be clinically essential. 6 Patients with international normalized ratio (INR) or activated partial thromboplastin time (APTT) >1.5 x upper limit of normal, .... 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.4 Impaired cardiac function5 Treatment with agents (other than warfarin) that prolong QT interval or inhibit CYP3A4, unless judged to be clinically essential. 6 Patients with international normalized ratio (INR) or activated partial thromboplastin time (APTT) >1.5 x upper limit of normal, except for patients requiring anticoagulants. 7 Cytokine therapy within 4 weeks prior to study entry.8 Another primary malignant disease, except for such conditions that do not currently require treatment9 Impaired gastro-intestinal function or gastro-intestinal disease that may alter imatinib/nilotinib absorption.10 Acute or chronic hepatic or renal disease considered unrelated to cancer.11 Occurrence of pancreatitis within six months of study entry. 12 Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol.13 Cytopathologically confirmed central nervous system infiltration 14 Patients unwilling or unable to comply with protocol and patients with a history of non-compliance or inability to grant informed consent.15 Known diagnosis of human immunodeficiency virus (HIV) infection.16 Prior allogeneic stem cell transplantation. 17 Current participation in another therapeutic clinical trial.
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