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Safety and Efficacy Study of Nilotinib Combined With Mitoxantrone, Etoposide, and High-dose Cytarabine Induction Chemotherapy Followed by Consolidation for Patients With C-kit Positive Acute Myeloid Leukemia

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. Read our disclaimer for details. Identifier: NCT01222143
Recruitment Status : Terminated
First Posted : October 18, 2010
Last Update Posted : June 22, 2015
Novartis Pharmaceuticals
Information provided by (Responsible Party):
University Health Network, Toronto

Brief Summary:

This is a phase I/II open-label study that is evaluating the toxicity and efficacy of nilotinib combined with mitoxantrone, etoposide, and high-dose cytarabine (NOVE-HiDAC) chemotherapy for patients with poor-risk acute myeloid leukemia (AML). There are two parts to the study. The first part (Phase I) will determine the maximum dose of nilotinib that can safely be given when combined with NOVE-HiDAC. This dose will then be used in combination with the NOVE-HiDAC regimen in the second part of the study (Phase II), which will evaluate the antileukemic activity of the treatment. The patients who achieve complete remission from the induction therapy (1 cycle) will then receive consolidation therapy combined with nilotinib (maximum of 2 cycles).

The patient population for this study will have AML and will fall into a poor risk category. This means they have persistent leukemia after induction therapy, they relapse within two years of achieving complete remission with induction therapy, or they have certain poor risk features at diagnosis. The AML cells will also be positive for c-kit (a stem cell factor receptor), which is involved in cancer cell growth. Nilotinib is a drug that blocks the effects of c-kit. Using this drug in combination with chemotherapy may improve ability of the chemotherapy drugs to kill leukemia cells. This may then increase the chances of the leukemia going into complete remission.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: NOVE-HiDAC Drug: Nilotinib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study Evaluating the Safety and Efficacy of Nilotinib Combined With Mitoxantrone, Etoposide, and High-Dose Cytarabine (NOVE-HiDAC) Induction Chemotherapy Followed by Consolidation Therapy for Poor-Risk Patients With C-kit Positive Acute Myeloid Leukemia (AML) up to Age 65
Study Start Date : October 2010
Actual Primary Completion Date : April 2015
Actual Study Completion Date : April 2015

Arm Intervention/treatment
Experimental: NOVE-HiDAC and Nilotinib
All patients will be receiving nilotinib combined with mitoxantrone, etoposide and high-dose cytarabine reinduction therapy. Patients achieving complete remission will receive consolidation therapy with nilotinib combined with high-dose cytarabine and mitoxantrone.

NOVE-HiDAC consists of mitoxantrone, etoposide, and modified high-dose cytarabine. During induction patients will receive mitoxantrone by IV on Days 6-10, etoposide by IV on Days 6-10 and cytarabine by IV on Days 11-12.

During consolidation patients will be receiving mitoxantrone by IV on Days 1-10 and cytarabine by IV on Days 6, 8 and 10.

Drug: Nilotinib

The dose of nilotinib will be determined according to a dose escalation design. There will be three dose levels used in the study.

During induction, nilotinib will be given orally on Days 1-12.

During consolidation, nilotinib will be given orally on Days 1-10.

Primary Outcome Measures :
  1. To determine the maximum tolerated dose (MTD) of nilotinib when combined with the NOVE-HiDAC regimen (mitoxantrone, etoposide, and modified high-dose cytarabine). [ Time Frame: 2 years ]
    To determine the maximum tolerated dose (MTD) of nilotinib combined with mitoxantrone, etoposide, and modified high-dose cytarabine (NOVE-HiDAC) induction chemotherapy followed by consolidation chemotherapy for patients with poor risk c-kit positive AML.

  2. To evaluate the toxicity of the treatment regimen. [ Time Frame: 2 years ]
  3. To determine the complete response (CR) rate of this combination at the maximum tolerate dose (MTD) of nilotinib. [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. To determine the disease-free survival of this combination. [ Time Frame: 2 years ]
  2. To evaluate the pharmacodynamic effects of nilotinib on pERK and pAKT (phosphorylated ERK and AKT) in AML cells in vivo. [ Time Frame: 2 years ]
  3. To correlate clinical responses with the degree of pAKT and pERK inhibition achieved in vivo. [ Time Frame: 2 years ]
  4. To correlate the degree of pAKT and pERK inhibition with nilotinib pharmacokinetics. [ Time Frame: 2 years ]
  5. To correlate pAKT and pERK inhibition with c-kit mutations. [ Time Frame: 2 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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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:

  • AML as defined by WHO (World Health Organization) criteria, all subtypes except APL (acute promyelocytic leukemia).
  • One of the following poor risk features:

    1. Persistent leukemia (at least 10% bone marrow blasts) after induction therapy, consisting of cytarabine 100-200 mg/m2 plus an anthracycline.
    2. Relapse within two years of achieving complete remission with such induction therapy. Any consolidation therapy is acceptable, including stem cell transplantation.
    3. No prior inductions, but antecedent myeloproliferative disorder or CMML (chronic myelomonocytic leukemia) (These patients are given NOVE-HiDAC as frontline therapy at Princess Margaret Hospital).
  • Positivity for c-kit (CD117) in at least 30% of blasts as measured by flow cytometry. For relapsed patients, this will be assessed at the time of relapse. For primary induction failures the initial diagnostic sample may be used.
  • Age 18-65.
  • ECOG performance status < 3 (see Appendix I).
  • Patients must have the following laboratory values within normal limits (WNL) at the local institution lab or corrected to WNL with supplements prior to first dose of study medication.

    1. Potassium (WNL)
    2. Magnesium (WNL)
  • No chemotherapy within the previous four weeks, other than hydroxyurea to control counts. Hydroxyurea may be continued up to Day 4 of treatment with nilotinib. If hydroxyurea is used, it must be stopped at least 48 hours prior to starting chemotherapy.
  • Able to give informed consent.

Exclusion Criteria:

  • Active uncontrolled infection.
  • Active CNS (central nervous system) leukemia
  • Serum creatinine > 200 umol/L.
  • Serum bilirubin > 1.5 x ULN, AST (aspartate aminotransferase) or ALT (alanine aminotransferase) > 2x ULN (upper limit of normal).
  • Serum amylase and lipase > 1.5x ULN
  • Left ventricular ejection fraction < 50%
  • Impaired cardiac function including any of the following:

    1. Long QT syndrome or a known family history of long QT syndrome
    2. History or presence of clinically significant ventricular or atrial tachyarrhythmias
    3. Clinically significant resting bradycardia (< 50 beats per minute)
    4. Inability to monitor the QT interval by ECG
    5. QTc > 450 msec on baseline ECG (electrocardiogram). If QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
    6. Myocardial infarction within 1 year of starting study drug
    7. Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
  • Patients currently receiving treatment with strong CYP3A4 inhibitors as listed in Section 5.8 and treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
  • Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
  • History of acute or chronic pancreatic disease.
  • Women who are pregnant, breast feeding, or of childbearing potential without a negative serum test at baseline. Male or female patients of childbearing potential unwilling to use contraceptive precautions throughout the trial and 3 months following discontinuation of study drug. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women of childbearing potential must have a negative serum pregnancy test prior to the first dose of nilotinib.
  • Known hypersensitivity to study drugs or other components.

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): NCT01222143

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Canada, Ontario
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
University Health Network, Toronto
Novartis Pharmaceuticals
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Principal Investigator: Joseph M Brandwein, MD, FRCPC Princess Margaret Hospital, Canada
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Responsible Party: University Health Network, Toronto Identifier: NCT01222143    
Other Study ID Numbers: CAMN107YCA03T
First Posted: October 18, 2010    Key Record Dates
Last Update Posted: June 22, 2015
Last Verified: June 2015
Keywords provided by University Health Network, Toronto:
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type