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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01690065
Recruitment Status : Recruiting
First Posted : September 21, 2012
Last Update Posted : May 11, 2016
The Korean Society of Hematology CML working party
Information provided by (Responsible Party):
Hawk Kim, Ulsan University Hospital

Brief Summary:
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)

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia in Myeloid Blast Crisis Untreated Adult Acute Myeloid Leukemia Drug: Nilotinib+AD induction Phase 2

Detailed Description:
  1. 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.
  2. 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.
  3. 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nilotinib Combined by Chemotherapy for Myeloid Blastic Phase of Chronic Myeloid Leukemia or Bcr-abl Positive Acute Myeloid Leukemia
Study Start Date : September 2012
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2019

Arm Intervention/treatment
Experimental: Nilotinib+AD induction

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

• 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
Other Name: Tasigna

Primary Outcome Measures :
  1. Complete remission rate [ Time Frame: Within 8 weeks after induction therapy ]
    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.

Secondary Outcome Measures :
  1. Safety [ Time Frame: Within 8 weeks after induction therapy ]
    • This study will also evaluate the safety of nilotinib and chemotherapy combination therapy.
    • CTCAE ver. 4.03 will be used for safety measurement.

  2. Time-dependent variables [ Time Frame: at least 2 years ]
    • 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).

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01690065

Contact: Hawk Kim, M.D., Ph.D. +82-52-250-8892
Contact: Min Jung Kim, R.N. +82-52-250-8515

Korea, Republic of
Seoul St Mary's Hospital Recruiting
Seoul, Korea, Republic of
Contact: Dong-Wook Kim, M.D., Ph.D.   
Principal Investigator: Dong-Wook Kim, M.D., Ph.D.         
Ulsan University Hospital Recruiting
Ulsan, Korea, Republic of, 682714
Principal Investigator: Hawk Kim, M.D., Ph.D.         
Sub-Investigator: Jae-Hoo Park, M.D., Ph.D.         
Sub-Investigator: Jae-Cheol Jo, M.D., Ph.D.         
Sponsors and Collaborators
Ulsan University Hospital
The Korean Society of Hematology CML working party
Principal Investigator: Hawk Kim, M.D., Ph.D. Ulsan University Hospital, University of Ulsan College of Medicine


Responsible Party: Hawk Kim, Associate Professor, Ulsan University Hospital Identifier: NCT01690065     History of Changes
Other Study ID Numbers: CAMN107AKR07T
First Posted: September 21, 2012    Key Record Dates
Last Update Posted: May 11, 2016
Last Verified: May 2016

Keywords provided by Hawk Kim, Ulsan University Hospital:
chronic myeloid leukemia
myeloid blastic phase
bcr-abl(+) acute myeloid leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Neoplasms by Histologic Type
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Cell Transformation, Neoplastic
Neoplastic Processes
Pathologic Processes
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs