Nilotinib-Chemotherapy in CML Myeloid BP or Bcr-abl(+) AML

Study Overview
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Brief Summary
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The current standard therapy in previously untreated adults with chronic phase (CP) of CML is imatinib and the result of long-term follow-up of IRIS study proves that imatinib for CML CP is reasonable therapy.(1, 2) However, some patients were initially diagnosed as advanced CML, accelerated phase (AP) or blastic phase (BP). Various chemotherapies were tried and were found that there were no highly effective chemotherapies for CML BP.(3-11) Imatinib in patients with these advanced CML is also disappointing because of low response rates as well as short response duration, and sudden transformation to BC is found even in initial CML CP patients. (12-17). Recent studies showed that nilotinib or dasatinib is better than imatinib in terms of rapid response and higher molecular response in newly diagnosed CML patients.(18-21) More potent bcr-abl suppression of nilotinib is supposed to be more active than imatinib even in patients with advanced CML. However, nilotinib in patients with imatinib-resistant or -intolerant CML BP showed low hematologic response and major cytogenetic response.(22, 23)

Detailed Description
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IMATINIB COMBINED WITH CHEMOTHERAPY FOR PHYLADELPHIA POSITIVE ACUTE LYMPHOBLASTIC LYMPHOMA (PH+ ALL) The trials combining imatinib with high-dose chemotherapy were successfully resulting in high response rate and longer survival and a role for bridging therapy to allogeneic hematopoietic stem cell transplantation (alloHSCT) by means of concurrent or alternating regimen in patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL).(24-29) Current combination therapy of imatinib and chemotherapy became standard therapy of Ph+ ALL and new 2nd generation TKIs are investigating. These experiences may be translated into the treatment of CML BP. HIGH-DOSE DAUNORUBICIN IN ACUTE MYELOID LEUKEMIA (AML) INDUCTION CHEMOTHERAPY Two recently published papers of randomized trials comparing standard dose daunorubicin (45 mg/m2 for 3 days) and high dose daunorubicin (90 mg/m2 for 3 days) demonstrated improved CR rate and survival with high dose daunorubicin in younger (60 years or younger) and older (over 60 years) patients, respectively.(30, 31) Therefore high-dose daunorubicin can be applied safely and effectively to the treatment of CML BP. NILOTINIB COMBINED WITH CHEMOTHERAPY FOR PHYLADELPHIA POSITIVE CML MYELOID BLASTIC PHASE (MBP) OR PHYLADELPHIA POSITIVE AML We will try 2nd generation TKI, nilotinib and high-dose daunorubicin induction chemotherapy combination to find out the combination therapy can improve response rate and survival in patients with CML MBP.

Official Title
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Nilotinib Combined by Chemotherapy for Myeloid Blastic Phase of Chronic Myeloid Leukemia or Bcr-abl Positive Acute Myeloid Leukemia

Conditions
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Chronic Myeloid Leukemia in Myeloid Blast Crisis, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Nilotinib+AD induction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with previously-untreated patients having bcr-abl gene rearrangement (or t(9;22)) and 20% or more of myeloid blasts in bone marrow and/or blood, or converted CML CP/AP to MBP after initial imatinib treatment. 15 years old or older, but 65 years or younger Adequate performance status (Karnofsky score of 50 or more) Adequate hepatic and renal function (AST, ALT, bilirubin and creatinine < 2.5 x upper normal limit). Elevation of AST or ALT due to hepatic infiltration of leukemic cells will be permitted. Adequate cardiac function (left ventricular ejection fraction of 45% or more on heart scan or echocardiogram) Signed and dated informed consent must be obtained. Exclusion Criteria: Patients without bcr-abl gene rearrangement Acute lymphoblastic leukemia with bcr-abl gene rearrangement or t(9;22) Any previous history of TKIs except for imatinib in CML CP. Therapy-related leukemia or leukemia after myelodysplastic syndrome. Patients with CNS leukemia Patients with primary granulocytic sarcoma without bone marrow involvement Prior chemotherapy for leukemia or anthracycline treatment for any malignancy. Hydroxyurea for reduction of leukemic cell burden before induction chemotherapy will be permitted. Presence of significant active infection Presence of uncontrolled bleeding Significant cardiovascular disease including myocardial infarction within previous 6 months Cardiac dysfunction: LVEF < 45% or institutional lower normal range (any higher value of them) by echocardiogram or MUGA scan; Long QT syndrome or its family history; Clinically significant resting bradycardia (<50 beats/minute); QTc > 450 msec (by QTcF formula) on baseline ECG . If QTcF > 450 msec and electrolytes are abnormal, retest QTc after the correction of electrolytes; Myocardial infarction within 12 months; Other clinically significant cardiac diseases (for example, unstable angina, congestive heart failure, uncontrolled hypertension or uncontrolled arrhythmia) Chronic or acute hepatic disease, pancreatic disease or severe renal disease Severe or life-threatening other medical conditions Any coexisting major illness or organ failure Patients with psychiatric disorder or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible History of congenital or acquired coagulopathy unrelated to malignancy Pregnancy issues: (a) pregnant woman, (b) lactating woman, (c) reproductive woman who does not confirm negative baseline pregnancy test (d) man or reproductive woman who cannot continue an appropriate contraceptive method (postmenopausal woman who has no menstruation for last 12 months is considered as non-reproductive) Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years following therapy with curative intent (except curatively treated nonmelanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia) History of non-compliance or patient who cannot sign informed consent Hypersensitivity to nilotinib or any of the experience Concurrent medications (Gastrointestinal dysfunction that can significantly change the absorption of test drug; - Strong CYP3A4 inhibitor and cannot stop or change the medication before starting study; Medication to prolong QT interval and cannot stop or change the medication before starting study) • The capsules contain lactose, and nilotinib is therefore not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib+AD induction<br>Nilotinib plus AD induction chemotherapy AD regimen : Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 7 days (D 1-7) plus Daunorubicin 90 mg/m2/day iv daily for 3 days (D 1-3) Nilotinib 400mg bid PO (continuous without interruption from D8 of induction chemotherapy) Re-induction chemotherapy AD regimen : Cytarabine 200 mg/m2/day by continuous iv infusion over 24 hours daily for 5 days (D 1-5) plus Daunorubicin 45 mg/m2/day iv daily for 2 days (D 1-2) | Drug: Nilotinib+AD induction<br>* • Post-remission consolidation chemotherapy 4 courses of high-dose cytarabine will be given as post-remission therapy. Cytarabine 3 g/m2 will be administered in a 3-hour iv infusion every 12 hours on days 1, 3, and 5 (a total of six doses per course). Nilotinib 400mg bid PO will be administered continuously during consolidation chemotherapy and for 2 years after the consolidation therapy or until allogeneic hematopoietic stem cell transplantation<br>* Other names: Tasigna;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate | Primary purpose of this study is to define the efficacy of combined chemotherapy and nilotinib in chronic myeloid leukemia (CML) myeloid blastic phase (MBP) and bcr-abl positive acute myeloid leukemia (AML). The efficacy will be evaluated by complete remission (CR) rate. | Within 8 weeks after induction therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | This study will also evaluate the safety of nilotinib and chemotherapy combination therapy. CTCAE ver. 4.03 will be used for safety measurement. | Within 8 weeks after induction therapy | 
| Time-dependent variables | • This study will evaluate the impacts of nilotinib combined with chemotherapy on duration of CR, relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS). | at least 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bcr-abl(+) acute myeloid leukemia, nilotinib, chronic myeloid leukemia, myeloid blastic phase