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An Open-Label, Phase I/II Study of Nilotinib (Tasigna) and MEK-162 (ARRY-162) Used in Combination for Patients With Refractory or Advanced Chronic Myeloid Leukemia and Philadelphia Positive Acute Leukemia (Protocol CAMN107AUS41T)

NCT02225574

Description:

The goal of this clinical research study is to find the highest tolerated dose of the combination of nilotinib and MEK-162 that can be given to patients with CML or acute leukemia. Researchers also want to learn if the drug combination can help to control the disease. The safety of the drug combination will also be studied.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

An Open-Label, Phase I/II Study of <span class="go-doc-concept go-doc-intervention">Nilotinib</span> (<span class="go-doc-concept go-doc-intervention">Tasigna</span>) and <span class="go-doc-concept go-doc-intervention">MEK-162</span> (ARRY-162) Used in Combination for Patients With Refractory or Advanced <span class="go-doc-concept go-doc-disease">Chronic Myeloid Leukemia</span> and Philadelphia Positive Acute Leukemia (Protocol CAMN107AUS41T)

Title

  • Brief Title: An Open-Label, Phase I/II Study of Nilotinib (Tasigna) and MEK-162 (ARRY-162) Used in Combination for Patients With Refractory or Advanced Chronic Myeloid Leukemia and Philadelphia Positive Acute Leukemia (Protocol CAMN107AUS41T)
  • Official Title: An Open-Label, Phase I/II Study of Nilotinib (Tasigna) and MEK-162 (ARRY-162) Used in Combination for Patients With Refractory or Advanced Chronic Myeloid Leukemia and Philadelphia Positive Acute Leukemia (Protocol CAMN107AUS41T)
  • Clinical Trial IDs

    NCT ID: NCT02225574

    ORG ID: 2014-0128

    NCI ID: NCI-2015-00044

    Trial Conditions

    Leukemia

    Trial Interventions

    Drug Synonyms Arms
    MEK-162 Advanced CML + Philadelphia positive Acute Leukemia-Group 1, Chronic Phase CML - Group 2
    Nilotinib AMN107, Tasigna Advanced CML + Philadelphia positive Acute Leukemia-Group 1, Chronic Phase CML - Group 2

    Trial Purpose

    The goal of this clinical research study is to find the highest tolerated dose of the
    combination of nilotinib and MEK-162 that can be given to patients with CML or acute
    leukemia. Researchers also want to learn if the drug combination can help to control the
    disease. The safety of the drug combination will also be studied.

    Detailed Description

    Study Groups:

    If you are found to be eligible to take part in this study, you will be assigned to a study
    group based on when you join this study. Up to 5 groups of up to 6 participants will be
    enrolled in Phase 1 of the study, and up to 60 participants will be enrolled in Phase 2.

    If you are enrolled in Phase 1, the dose of nilotinib and MEK-162 you receive will depend on
    when you joined this study. The first group of participants will receive the starting dose
    combination level. The next group will receive a higher dose of MEK-162 than Group 1, if no
    intolerable side effects were seen. If intolerable side effects are seen, the next group
    may receive a lower dose level of nilotinib and/or MEK-162. This will continue until the
    highest tolerable combination dose is found.

    If you are enrolled in Phase 2, you will receive nilotinib and MEK-162 at the highest dose
    that was tolerated in Phase 1.

    Study Treatment:

    You will take nilotinib and MEK-162 two times every day by mouth.

    Participants enrolled in Phase 1 of the study will start taking MEK-162 on Day 1 and
    nilotinib on Day 2.

    Participants in Phase 2 of the study will be divided in 2 groups: one group will start
    MEK-162 on Day 1 and nilotinib on Day 2, while the other group will start MEK-162 on Day 1
    and nilotinib on Day 8. You will be placed in a Phase 2 treatment group based on the
    characteristics of your disease type.

    You will be given a drug diary and asked to write down what time you take the study drugs
    every day. Bring in any unused study drugs and bottles to each study visit.

    Each cycle is 28 days.

    If the disease does not appear to get better after 1 or 3 cycles, you may be able to receive
    a higher dose of the study drug as long as you are not already receiving the highest dose
    planned for this study. The study doctor will tell you if you can receive a higher dose.

    Study Visits:

    On Days 1 and 8 of Cycle 1:

    - You will have a physical exam.

    - Blood (about 2-3 tablespoons) will be drawn for routine tests.

    - You will have an EKG.

    At the end of Cycle 1:

    - You will have a physical exam.

    - Blood (about 2-3 tablespoons) will be drawn for routine tests.

    - You will have an EKG and either a MUGA scan or an ECHO.

    - You will complete a questionnaire about how you are feeling.

    - If the doctor thinks it is needed, you will have a bone marrow aspirate to check the
    status of the disease.

    At the end of Cycles 2, 3, and every 3 cycles after that (6, 9, 12, and so on):

    - You will have a physical exam.

    - Blood (about 2-3 tablespoons) will be drawn for routine tests.

    - You will have an EKG.

    - You will complete a questionnaire about how you are feeling.

    At the end of Cycles 2, 3, 6, 9, and 12, blood (about 3-4 tablespoons each time) will be
    drawn for tests to check how the disease is responding to therapy. If the doctor thinks it
    is needed, these tests may be performed more often.

    Every 8-12 weeks, you will have a MUGA scan or an ECHO.

    You will have an eye exam by an eye doctor at the end of Cycles 2, 3, 6, 9, and 12, and then
    every 3 months after that until the End of Study Visit.

    You will have blood draws and/or bone marrow aspirations at any time that the doctor thinks
    it is needed while you are on study.

    Length of Study:

    You can take up to 12 cycles of nilotinib and MEK-162 on study. If the disease responds a
    certain way (called a hematological response) while you are on study, you may be able to
    continue taking the study drugs longer than 12 months, as long as the doctor thinks you are
    benefiting from the treatment. Even if the disease has not responded in this way, you may
    be able to continue taking the study drugs if the doctor thinks it is in your best interest.
    You will no longer be able to take the study drug if the disease gets worse, if intolerable
    side effects occur, or if you are unable to follow study directions.

    Your participation on the study will be over after the follow-up visits.

    End-of-Study Visit:

    If you come off study before the end of Cycle 12, the following tests and procedures will be
    performed:

    - You will have a physical exam.

    - Blood (about 2-3 tablespoons) will be drawn for routine tests.

    - You will have an EKG and either an ECHO or a MUGA scan.

    - You will have an eye exam by an eye doctor.

    - You will complete a questionnaire about how you are feeling.

    - If the doctor thinks it is needed, you will have a bone marrow aspirate to check the
    status of the disease.

    If you come off study at the end of Cycle 12, you will not have the End of Study visit.

    Follow-Up:

    You will be called about 30 days after you go off study and asked if you have had any side
    effects and/or any new treatment(s). This call will last about 5 minutes.

    This is an investigational study. Nilotinib is FDA approved and commercially available to
    treat CML and philadelphia-positive acute leukemia. MEK-162 is not FDA approved or
    commercially available. It is currently being used for research purposes only. The
    combination of nilotinib and MEK-162 to treat CML and Philadelphia-positive acute leukemia
    is investigational. The study doctor can explain how the study drugs are designed to work.

    Up to 90 patients will take part in this study. All will be enrolled at MD Anderson Cancer
    Center.

    Trial Arms

    Name Type Description Interventions
    Advanced CML + Philadelphia positive Acute Leukemia-Group 1 Experimental Phase 1 Starting dose of MEK-162: 30 mg by mouth twice a day of a 28 day cycle. Phase 1 Starting dose of Nilotinib: 400 mg by mouth twice a day of a 28 day cycle. Questionnaires completed and the end of cycle 1, 2, 3, 6, 9, and 12. Phase 2 Starting dose of MEK-162: MTD from Phase 1 to be taken by mouth twice a day starting on Day 1 of a 28 day cycle. Phase 2 Starting dose of Nilotinib: MTD from Phase 1 to be taken by mouth twice a day starting on Day 2 of a 28 day cycle. MEK-162, Nilotinib
    Chronic Phase CML - Group 2 Experimental Phase 1 Starting dose of MEK-162: 30 mg by mouth twice a day of a 28 day cycle. Phase 1 Starting dose of Nilotinib: 400 mg by mouth twice a day of a 28 day cycle. Questionnaires completed and the end of cycle 1, 2, 3, 6, 9, and 12. Phase 2 Starting Dose of Nilotinib: MTD from Phase 1 by mouth twice a day starting on Day 1 of a 28 day cycle. Phase 2 Starting Dose of MEK-162: MTD from Phase 1 by mouth twice a day starting on Day 8 of a 28 day cycle. MEK-162, Nilotinib

    Eligibility Criteria

    Inclusion Criteria:

    1. Patients 18 years of age or older with advanced CML (CML-AP, CML-BP and Philadelphia
    chromosome-positive acute leukemia) or refractory chronic phase CML are eligible, as
    defined as follows: The phase I portion of the study will be conducted first in
    advanced phase (accelerated phase CML, blast phase CML or Philadelphia-positive acute
    leukemia) patients. Once MTD is identified, a cohort of 6 patients with CML chronic
    phase who have failed prior therapy with at least two tyrosine kinase inhibitor will
    be treated at the MTD to determine if this dose is also acceptable for chronic phase
    patients. The phase II will be conducted in two treatment arms as follows: Treatment
    Arm A (Advanced phase disease) and treatment Arm B (Therapy for CP-CML
    refractory/resistant/suboptimally responding to at least two prior TKI's)

    2. (Cont - Inclusion Criteria #1) CML-AP is defined by the presence of one of the
    following: a. 15-29% blasts in peripheral blood (PB) or bone marrow (BM), b.>20%
    basophils in PB or BM, c.>30% blasts plus promyelocytes (with blasts <30%) in PB or
    BM, d.<100 x109/L platelets unrelated to therapy, or Clonal cytogenetics evolution
    (i.e., the presence of cytogenetic abnormalities other than the Philadelphia
    chromosome) except if only present at the time of diagnosis and not associated with
    other features of accelerated phase. CML-BP is defined by the presence of >/=30%
    blasts in the bone marrow and/or peripheral blood or the presence of extramedullary
    disease, with myeloid or lymphoid blast morphology. Philadelphia-chromosome acute
    leukemias are eligible and defined by >/=20% blasts in the peripheral blood or bone
    marrow at the time of diagnosis.

    3. Patients with advanced phase CML or acute leukemia must have failed at least one
    prior TKI. Patients with chronic phase CML must have failed, have resistance or
    suboptimal response to at least two tyrosine kinase inhibitors, or have intolerance
    to two prior tyrosine kinase inhibitors. For patient with prior intolerance, they
    should have received at least 2 TKI and experienced intolerance to one TKI and
    resistance/suboptimal.

    4. (Cont - Inclusion Criteria #3) a. Failure to tyrosine kinase inhibitors will be
    defined per European-Leukemia-Net (ELN) recommendations b.Resistance or suboptimal
    response to at least two prior Abl-kinase inhibitor, specifically: i.Chronic-phase
    with resistance to imatinib, dasatinib, nilotinib, bosutinib or ponatinib defined as
    1. Loss of CCyR (see Section 5.4.4.1) at any time or failure to achieve CCyR after
    >/=18 months 2. Loss of MCyR at any time or failure to achieve PCyR after >/=12
    months 3. Failure to achieve any CyR (ie, >/= 65% Ph+) after >/= 6 months 4.
    Hematologic relapse or failure to achieve CHR after >/=3 months ii. Chronic-phase
    with suboptimal response to imatinib, defined as 1. Failure to achieve PCyR after >/=
    6 months 2. Failure to achieve CCyR after >/=12 months iii. Chronic-phase with
    suboptimal response to nilotinib, bosutinib, dasatinib or ponatinib, defined as 1.
    Failure to achieve PCyR after >/= 3 months 2. Failure to achieve CCyR after >/= 6
    months of therapy

    5. Patients with cytogenetic BCR-Abl variants and additional chromosomal abnormalities
    ('clonal evolution') will be eligible. Cytogenetics to be performed, but results are
    not required to start therapy in patients with hematologic progression

    6. Patients who have failed nilotinib, including those who are refractory to nilotinib
    at any dose or have relapsed on nilotinib at any dose will be eligible for the study.
    Patients currently on nilotinib will continue on their prescribed dose of nilotinib
    and MEK-162 will be added based on the current cohort level in phase I or at the
    established MTD in phase II. In the instance the nilotinib dose is greater than the
    current cohort (in phase 1) or the MTD (in phase 2) patients will be dose reduced to
    the dosage as prescribed by protocol and then dose escalated as allowed in protocol
    at the PIs discretion.

    7. For the phase I portion of the study, patients who had received prior therapy with
    nilotinib should have been able to tolerate the dose equivalent to the starting dose
    of nilotinib in the dose level at which the patient is being entered. Patients who
    previously received nilotinib but never at the dose being proposed are eligible
    provided they tolerated the maximum dose they were prescribed with no grade 3 or 4
    toxicity not responding to optimal management.

    8. Patients must have been off all prior therapy for CML for 2 weeks prior to start of
    study therapy and recovered from the toxic effects of that therapy. Exceptions to
    these are hydroxyurea and TKIs (including but not limited to imatinib, nilotinib,
    dasatinib, ponatinib and bosutinib), which should be discontinued 48 hrs prior to
    the start of therapy. Patients who are receiving nilotinib prior to enrollment do not
    have to discontinue this agent prior to start of study therapy

    9. ECOG performance status </=2

    10. Men and women of childbearing potential should practice effective methods of
    contraception. Men and women of childbearing potential are defined as: a male that
    has not been surgically sterilized or female that has not been amenorrheic for at
    least 12 consecutive months or that has not been surgically sterilized. Patients must
    use birth control during the study and for 3 months after the last dose of study drug
    if they are sexually active.

    11. Adequate organ function: Serum creatinine </=2.0 mg/dl or creatinine clearance >/=60
    mL/min, Direct bilirubin </=2.0xULN (unless considered due to leukemia involvement),
    Alanine aminotransferase (ALT) </=2.5xULN (</=5.0xULN if considered due to leukemic
    involvement.)

    12. Adequate cardiac function: left ventricular ejection fraction (LVEF) >/= 50% as
    determined by a multigated acquisition (MUGA) scan or echocardiogram, QTc interval
    </= 480 ms;

    13. Women of childbearing potential must have a pregnancy test at screening.

    14. Signed informed consent.

    Exclusion Criteria:

    1. Impaired cardiac function including any one of the following: a. Inability to monitor
    the QT interval on ECG b. Congenital long QT syndrome or a known family history of
    long QT syndrome. c. Clinically significant resting brachycardia (<45 beats per
    minute) d. QTc > 480 msec on baseline ECG. If QTc >450 msec and electrolytes are not
    within normal ranges, electrolytes should be corrected and then the patient
    re-screened for QTc e. Impaired cardiovascular function or clinically significant
    cardiovascular diseases, including any of the following: History of acute coronary
    syndromes (including myocardial infarction, unstable angina, coronary artery bypass
    grafting, coronary angioplasty, or stenting) <6 months prior to screening,
    Symptomatic chronic heart failure, history or current evidence of clinically
    significant cardiac arrhythmia and/or conduction abnormality <6 months prior to
    screening except atrial fibrillation and paroxysmal supraventricular tachycardia

    2. History of Gilbert's syndrome.

    3. Uncontrolled arterial hypertension despite medical treatment

    4. Prior therapy with a MEK- inhibitor

    5. History or current evidence of retinal vein occlusion (RVO) or current risk factors
    for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
    or hypercoagulability syndromes)

    6. History of retinal degenerative disease;

    7. Patients with washout period < 6 weeks from the last dose of ipilimumab or other
    immunotherapy

    8. Known positive serology for HIV, active hepatitis B, and/or active hepatitis C
    infection

    9. Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,
    inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
    muscular atrophy)

    10. Patients who are planning on embarking on a new strenuous exercise regimen after
    first dose of study treatment. Muscular activities, such as strenuous exercise, that
    can result in significant increases in plasma CK levels should be avoided while on
    MEK162 treatment

    11. Patients currently receiving treatment with strong CYP3A4 inhibitors who cannot
    discontinue such treatment or be switched to a different medication prior to starting
    study drug are excluded from study entry. Strong CYP3A4 inhibitors include the
    following medications: itraconazole, ketoconazole, miconazole, voriconazole;
    amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir;
    ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, isoniazid,
    ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin.

    12. Patients receiving treatment with any medications that have the potential to prolong
    the QT interval who cannot discontinue such treatment or be switched to a different
    medication prior to starting study drug are excluded from the study entry. A list of
    anti-arrhythmic drugs and other drugs that may prolong the QT interval is added in
    protocol section 8.5 (page 53).

    13. Impaired gastrointestinal (GI) function or active GI disease that may significantly
    alter the absorption of study drug in the opinion of the treating physician (e.g.,
    active ulcerative diseases, uncontrolled nausea, uncontrolled vomiting, uncontrolled
    diarrhea, active malabsorption syndrome, small bowel resection within last 1 year or
    gastric bypass surgery within last 1 year).

    14. Another active primary malignant disease, which requires systemic treatment
    (chemotherapy or radiation)

    15. History of significant congenital or acquired bleeding disorder unrelated to cancer

    16. Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered
    from prior surgery.

    17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
    female after conception and until the termination of gestation, confirmed by a
    positive hCG laboratory test

    18. Women of child-bearing potential, defined as all women physiologically capable of
    becoming pregnant, unless they are using highly effective methods of contraception
    throughout the study and for 3 months after study drug discontinuation. Highly
    effective methods of contraception are further defined.

    19. Patients who are eligible, willing and able to receive an allogeneic stem cell
    transplant within 6 weeks are not eligible.

    20. Sexually active males unless they use a condom during intercourse while taking the
    drug and for 3 months after stopping treatment and should not father a child in this
    period. A condom is required to be used also by vasectomized men in order to prevent
    delivery of the drug via seminal fluid;

    21. History of non-compliance to medical regimens or inability to grant consent.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD) of MEK-162 and Nilotinib

    Secondary Outcome Measures

    Response Rate for Advanced CML and Philadelphia-Positive Acute Leukemia

    Response Rate for Chronic Phase CML

    Trial Keywords

    Leukemia

    Advanced phase chronic myeloid leukemia

    refractory chronic phase chronic myeloid leukemia

    CML

    Accelerated phase

    (AP)

    Blast phase

    (BP)

    Philadelphia-positive acute leukemia

    MEK-162

    Nilotinib

    AMN107

    Tasigna

    Questionnaires

    Surveys