Clinical Trials /

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

NCT01690065

Description:

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)

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nilotinib-Chemotherapy in CML Myeloid BP or Bcr-abl(+) AML
  • Official Title: Nilotinib Combined by Chemotherapy for Myeloid Blastic Phase of Chronic Myeloid Leukemia or Bcr-abl Positive Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: CAMN107AKR07T
  • NCT ID: NCT01690065

Conditions

  • Chronic Myeloid Leukemia in Myeloid Blast Crisis
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Nilotinib+AD inductionTasignaNilotinib+AD induction

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Nilotinib+AD inductionExperimentalNilotinib 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)
  • Nilotinib+AD induction

Eligibility Criteria

        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
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete remission rate
Time Frame:Within 8 weeks after induction therapy
Safety Issue:
Description: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

Measure:Safety
Time Frame:Within 8 weeks after induction therapy
Safety Issue:
Description:This study will also evaluate the safety of nilotinib and chemotherapy combination therapy. CTCAE ver. 4.03 will be used for safety measurement.
Measure:Time-dependent variables
Time Frame:at least 2 years
Safety Issue:
Description:• 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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ulsan University Hospital

Trial Keywords

  • chronic myeloid leukemia
  • myeloid blastic phase
  • bcr-abl(+) acute myeloid leukemia
  • nilotinib

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