<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01670084</url>
  </required_header>
  <id_info>
    <org_study_id>MC1184</org_study_id>
    <secondary_id>NCI-2012-01061</secondary_id>
    <nct_id>NCT01670084</nct_id>
  </id_info>
  <brief_title>Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia</brief_title>
  <official_title>A Phase II Study of Combination Nilotinib and Hyper-CVAD in Patients Newly Diagnosed With Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia or Chronic Myeloid Leukemia Blast-Phase Lymphoid Lineage</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this study researchers want to find out more about the side effects of a new drug for&#xD;
      Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic&#xD;
      myelogenous leukemia (CML) blastic phase (BP) and if this disease will respond better to&#xD;
      nilotinib combined with standard hyper-CVAD therapy rather than hyper-CVAD alone. Hyper-CVAD&#xD;
      is a combination of cyclophosphamide, mesna, vincristine (vincristine sulfate), doxorubicin&#xD;
      (doxorubicin hydrochloride), dexamethasone, methotrexate, cytarabine, and rituximab (only for&#xD;
      patients with cluster of differentiation [CD]20 positive disease). Researchers don't know all&#xD;
      the ways that this drug may affect people&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and&#xD;
      combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome&#xD;
      positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the 2-year overall survival rate. II. Determine the complete response (CR) rates&#xD;
      (hematological, cytogenetic, and molecular) in patients treated with this regimen.&#xD;
&#xD;
      III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety&#xD;
      and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria&#xD;
      for Adverse Events (CTCAE) version 4.0.&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. Assess the prognostic and predictive factors for patients treated with this regimen.&#xD;
&#xD;
      II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in&#xD;
      humans.&#xD;
&#xD;
      III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during therapy,&#xD;
      and at relapse.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive&#xD;
      cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV&#xD;
      continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV&#xD;
      on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate&#xD;
      intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14.&#xD;
      Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.&#xD;
&#xD;
      INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate IV&#xD;
      continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin&#xD;
      calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and&#xD;
      nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV&#xD;
      on days 1 and 11.&#xD;
&#xD;
      MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for&#xD;
      minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and&#xD;
      prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if&#xD;
      CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive.&#xD;
&#xD;
      INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of&#xD;
      maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance&#xD;
      therapy.&#xD;
&#xD;
      DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84.&#xD;
      Treatment repeats every 84 days for up to 4 courses.&#xD;
&#xD;
      Treatment continues in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 6-12 months for 4 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    No Accrual&#xD;
  </why_stopped>
  <start_date>December 2012</start_date>
  <completion_date type="Anticipated">September 2017</completion_date>
  <primary_completion_date type="Anticipated">September 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease-free survival rate, defined as a patient who is alive and relapse-free, in patients who achieve a CR during the first 2 courses out to 2 years</measure>
    <time_frame>2 years</time_frame>
    <description>The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival time, defined as the time from registration to death due to any cause out to 2 years</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete response (CR) rate estimated by the number of patients achieving an objective status of CR during the first 2 courses of treatment divided by the total number of evaluable patients</measure>
    <time_frame>56 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete response (CR) as defined for all evaluable patients who have achieved a CR as the date at which the patient's objective status is first noted to be a CR to the earliest date relapse is documented out to 4 years</measure>
    <time_frame>Up to 4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum grade for each type of adverse event, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0</measure>
    <time_frame>Up to 30 days after last dose of study drug</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>B-cell Adult Acute Lymphoblastic Leukemia</condition>
  <condition>Blastic Phase Chronic Myelogenous Leukemia</condition>
  <condition>Chronic Myelogenous Leukemia, BCR-ABL1 Positive</condition>
  <condition>Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia</condition>
  <condition>Untreated Adult Acute Lymphoblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>See Detailed Description</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>nilotinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>AMN 107</other_name>
    <other_name>Tasigna</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>rituximab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>IDEC-C2B8</other_name>
    <other_name>IDEC-C2B8 monoclonal antibody</other_name>
    <other_name>Mabthera</other_name>
    <other_name>MOAB IDEC-C2B8</other_name>
    <other_name>Rituxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cyclophosphamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>CPM</other_name>
    <other_name>CTX</other_name>
    <other_name>Cytoxan</other_name>
    <other_name>Endoxan</other_name>
    <other_name>Endoxana</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>doxorubicin hydrochloride</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>ADM</other_name>
    <other_name>ADR</other_name>
    <other_name>Adria</other_name>
    <other_name>Adriamycin PFS</other_name>
    <other_name>Adriamycin RDF</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vincristine sulfate</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>leurocristine sulfate</other_name>
    <other_name>VCR</other_name>
    <other_name>Vincasar PFS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>methotrexate</intervention_name>
    <description>Given IV or IT</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>amethopterin</other_name>
    <other_name>Folex</other_name>
    <other_name>methylaminopterin</other_name>
    <other_name>Mexate</other_name>
    <other_name>MTX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cytarabine</intervention_name>
    <description>Given IV or IT</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>ARA-C</other_name>
    <other_name>arabinofuranosylcytosine</other_name>
    <other_name>arabinosylcytosine</other_name>
    <other_name>Cytosar-U</other_name>
    <other_name>cytosine arabinoside</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>prednisone</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>DeCortin</other_name>
    <other_name>Deltra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mesna</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>mercaptoethane sulfonate</other_name>
    <other_name>Mesnex</other_name>
    <other_name>MSA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>dexamethasone</intervention_name>
    <description>Given IV or PO</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>Aeroseb-Dex</other_name>
    <other_name>Decaderm</other_name>
    <other_name>Decadron</other_name>
    <other_name>DM</other_name>
    <other_name>DXM</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>leucovorin calcium</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (nilotinib, combination chemotherapy)</arm_group_label>
    <other_name>CF</other_name>
    <other_name>CFR</other_name>
    <other_name>LV</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Untreated, histological confirmed Philadelphia positive B-cell acute lymphoblastic&#xD;
             leukemia or chronic myeloid leukemia blast-phase lymphoid lineage (bilineal,&#xD;
             biphenotypic or undifferentiated) per World Health Organization (WHO) criteria; NOTE:&#xD;
             Dexamethasone (or corticosteroids) use is allowed if needed before starting&#xD;
             chemotherapy; prior imatinib or dasatinib therapy for CML chronic phase (CP) or&#xD;
             accelerated phase (AP) is allowed&#xD;
&#xD;
          -  Molecular or cytogenetic documentation of BCR-ABL fusion gene via any of the&#xD;
             following: reverse transcriptase-polymerase chain reaction (RT-PCR), G-banding, or&#xD;
             fluorescence in situ hybridization (FISH) testing from peripheral blood and/or bone&#xD;
             marrow sampling&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2&#xD;
&#xD;
          -  Magnesium/potassium/phosphorus within normal limits (WNL)&#xD;
&#xD;
          -  Serum amylase =&lt; 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Lipase =&lt; 1.5 x ULN&#xD;
&#xD;
          -  Total bilirubin &lt; 1.5 x ULN (does not apply to patients with isolated&#xD;
             hyperbilirubinemia [e.g., Gilbert's disease], in this situation the direct bilirubin&#xD;
             =&lt; 2 x ULN)&#xD;
&#xD;
          -  Alkaline phosphatase =&lt; 3 x ULN&#xD;
&#xD;
          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =&lt; 3&#xD;
             x ULN&#xD;
&#xD;
          -  Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =&lt; 3 x ULN&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x ULN&#xD;
&#xD;
          -  Negative serum pregnancy test done =&lt; 7 days prior to registration, for women of&#xD;
             childbearing potential only&#xD;
&#xD;
          -  Provide informed written consent&#xD;
&#xD;
          -  Willing to return to Mayo Clinic Rochester or Mayo Clinic Arizona for follow-up during&#xD;
             the active monitoring phase of the study&#xD;
&#xD;
          -  Willing to provide CSF and blood samples for correlative research purposes&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any of the following because this study involves investigational agent(s) whose&#xD;
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are&#xD;
             unknown:&#xD;
&#xD;
               -  Pregnant women&#xD;
&#xD;
               -  Nursing women&#xD;
&#xD;
               -  Men or women of childbearing potential who are unwilling to employ adequate&#xD;
                  contraception throughout the study and for 3 months after completion of study&#xD;
                  treatment&#xD;
&#xD;
          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment&#xD;
             of the investigator, would make the patient inappropriate for entry into this study or&#xD;
             interfere significantly with the proper assessment of safety and toxicity of the&#xD;
             prescribed regimens&#xD;
&#xD;
          -  Immunocompromised patients (other than that related to the use of corticosteroids)&#xD;
             including patients known to be human immunodeficiency virus (HIV) positive (even if on&#xD;
             highly active antiretroviral therapy [HAART])&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Receiving any other investigational agent which would be considered as a treatment for&#xD;
             the primary neoplasm&#xD;
&#xD;
          -  Other active malignancy =&lt; 3 years prior to registration; EXCEPTIONS: Non-melanotic&#xD;
             skin cancer or carcinoma-in-situ of the cervix&#xD;
&#xD;
          -  History of myocardial infarction =&lt; 12 months, or congestive heart failure requiring&#xD;
             use of ongoing maintenance therapy for life-threatening ventricular arrhythmias&#xD;
&#xD;
          -  Previous treatment with chemotherapy or any other tyrosine kinase inhibitor (prior&#xD;
             imatinib or dasatinib for CML-CP/-AP is allowed)&#xD;
&#xD;
          -  Impaired cardiac function including any one of the following:&#xD;
&#xD;
               -  Inability to monitor the QT interval on electrocardiogram (ECG)&#xD;
&#xD;
               -  Congenital long QT syndrome or a known family history of long QT syndrome&#xD;
&#xD;
               -  Cardiac ejection fraction (EF) &lt; 45%&#xD;
&#xD;
               -  Clinically significant resting brachycardia (&lt; 50 beats per minute)&#xD;
&#xD;
               -  Corrected QT interval (QTc) &gt; 450 msec on baseline ECG; if QTc &gt; 450 msec and&#xD;
                  electrolytes are not within normal ranges, electrolytes should be corrected and&#xD;
                  then the patient re-screened for QTc&#xD;
&#xD;
               -  Other clinically significant uncontrolled heart disease (e.g. unstable angina,&#xD;
                  congestive heart failure or uncontrolled hypertension)&#xD;
&#xD;
               -  History of or presence of clinically significant ventricular or atrial&#xD;
                  tachyarrhythmias&#xD;
&#xD;
          -  Patients receiving any medications or substances that are strong or moderate&#xD;
             inhibitors of cytochrome P450 3A4 (CYP3A4); use of the following strong or moderate&#xD;
             inhibitors are prohibited =&lt; 7 days prior to registration:&#xD;
&#xD;
               -  Strong Inhibitors of CYP3A4; &gt; 5-fold increase in the plasma area under the curve&#xD;
                  (AUC) values or more than 80% decrease in clearance&#xD;
&#xD;
                    -  Indinavir (Crixivan®)&#xD;
&#xD;
                    -  Nelfinavir (Viracept®)&#xD;
&#xD;
                    -  Atazanavir (Reyataz®)&#xD;
&#xD;
                    -  Ritonavir (Norvir®)&#xD;
&#xD;
                    -  Clarithromycin (Biaxin®, Biaxin XL®)&#xD;
&#xD;
                    -  Itraconazole (Sporanox®)&#xD;
&#xD;
                    -  Ketoconazole (Nizoral®)&#xD;
&#xD;
                    -  Nefazodone (Serzone®)&#xD;
&#xD;
                    -  Saquinavir (Fortovase®, Invirase®)&#xD;
&#xD;
                    -  Telithromycin (Ketek®)&#xD;
&#xD;
               -  Moderate Inhibitors of CYP3A4; &gt; 2-fold increase in the plasma AUC values or&#xD;
                  50-80% decrease in clearance&#xD;
&#xD;
                    -  Aprepitant (Emend®)&#xD;
&#xD;
                    -  Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE®)&#xD;
&#xD;
                    -  Fluconazole (Diflucan®)&#xD;
&#xD;
                    -  Grapefruit juice&#xD;
&#xD;
                    -  Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan&#xD;
                       PM®)&#xD;
&#xD;
                    -  Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™,&#xD;
                       Dilacor XR®, Diltia XT®, Taztia XT™, Tiazac®)&#xD;
&#xD;
          -  Patients receiving any medications or substances that are inducers of CYP3A4; use of&#xD;
             the following inducers are prohibited =&lt; 7 days prior to registration&#xD;
&#xD;
             * Inducers of CYP3A4&#xD;
&#xD;
               -  Efavirenz (Sustiva®)&#xD;
&#xD;
               -  Nevirapine (Viramune®)&#xD;
&#xD;
               -  Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®)&#xD;
&#xD;
               -  Modafinil (Provigil®)&#xD;
&#xD;
               -  Phenobarbital (Luminal®)&#xD;
&#xD;
               -  Phenytoin (Dilantin®, Phenytek®)&#xD;
&#xD;
               -  Pioglitazone (Actos®)&#xD;
&#xD;
               -  Rifabutin (Mycobutin®)&#xD;
&#xD;
               -  Rifampin (Rifadin®)&#xD;
&#xD;
               -  St. John's wort&#xD;
&#xD;
          -  Patients currently receiving treatment with any medications that have the potential to&#xD;
             prolong the QT interval and the treatment cannot be either discontinued or switched to&#xD;
             a different medication prior to starting study drug&#xD;
&#xD;
          -  Impaired gastrointestinal (GI) function or GI disease that may significantly alter the&#xD;
             absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting,&#xD;
             diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)&#xD;
&#xD;
          -  Acute or chronic pancreatic disease&#xD;
&#xD;
          -  Known cytopathologically confirmed central nervous system (CNS) infiltration&#xD;
&#xD;
          -  Acute or chronic liver disease or severe renal disease considered unrelated to the&#xD;
             cancer&#xD;
&#xD;
          -  History of significant congenital or acquired bleeding disorder unrelated to cancer&#xD;
&#xD;
          -  Major surgery =&lt; 4 weeks prior to registration or not recovered from prior surgery&#xD;
&#xD;
          -  Treatment with other investigational agents =&lt; 14 days of registration&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Aref Al-Kali, M.D.</last_name>
    <role>Study Chair</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Arizona</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>August 17, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 21, 2012</study_first_posted>
  <last_update_submitted>October 29, 2015</last_update_submitted>
  <last_update_submitted_qc>October 29, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 30, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</mesh_term>
    <mesh_term>Blast Crisis</mesh_term>
    <mesh_term>Philadelphia Chromosome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Liposomal doxorubicin</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Levoleucovorin</mesh_term>
    <mesh_term>Mesna</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01670084
org study id: MC1184
secondary id: NCI-2012-01061
nct id: NCT01670084
lead sponsor: 
has dmc: Yes
In this study researchers want to find out more about the side effects of a new drug for
      Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic
      myelogenous leukemia (CML) blastic phase (BP) and if this disease will respond better to
      nilotinib combined with standard hyper-CVAD therapy rather than hyper-CVAD alone. Hyper-CVAD
      is a combination of cyclophosphamide, mesna, vincristine (vincristine sulfate), doxorubicin
      (doxorubicin hydrochloride), dexamethasone, methotrexate, cytarabine, and rituximab (only for
      patients with cluster of differentiation [CD]20 positive disease). Researchers don't know all
      the ways that this drug may affect people
PRIMARY OBJECTIVES:

      I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and
      combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome
      positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia.

      SECONDARY OBJECTIVES:

      I. Determine the 2-year overall survival rate. II. Determine the complete response (CR) rates
      (hematological, cytogenetic, and molecular) in patients treated with this regimen.

      III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety
      and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria
      for Adverse Events (CTCAE) version 4.0.

      TERTIARY OBJECTIVES:

      I. Assess the prognostic and predictive factors for patients treated with this regimen.

      II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in
      humans.

      III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during therapy,
      and at relapse.

      OUTLINE:

      INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive
      cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV
      continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV
      on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate
      intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14.
      Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.

      INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate IV
      continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin
      calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and
      nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV
      on days 1 and 11.

      MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for
      minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and
      prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if
      CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive.

      INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of
      maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance
      therapy.

      DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84.
      Treatment repeats every 84 days for up to 4 courses.

      Treatment continues in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6-12 months for 4 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease-free survival rate, defined as a patient who is alive and relapse-free, in patients who achieve a CR during the first 2 courses out to 2 years
time frame: 2 years
description: The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.
measure: Overall survival time, defined as the time from registration to death due to any cause out to 2 years
time frame: 2 years
measure: Complete response (CR) rate estimated by the number of patients achieving an objective status of CR during the first 2 courses of treatment divided by the total number of evaluable patients
time frame: 56 days
measure: Complete response (CR) as defined for all evaluable patients who have achieved a CR as the date at which the patient's objective status is first noted to be a CR to the earliest date relapse is documented out to 4 years
time frame: Up to 4 years
measure: Maximum grade for each type of adverse event, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
time frame: Up to 30 days after last dose of study drug
arm group label: Treatment (nilotinib, combination chemotherapy)
arm group type: Experimental
description: See Detailed Description
intervention type: Drug
intervention name: nilotinib
description: Given PO
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: AMN 107
other name: Tasigna
intervention type: Biological
intervention name: rituximab
description: Given IV
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: IDEC-C2B8
other name: IDEC-C2B8 monoclonal antibody
other name: Mabthera
other name: MOAB IDEC-C2B8
other name: Rituxan
intervention type: Drug
intervention name: cyclophosphamide
description: Given IV
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: CPM
other name: CTX
other name: Cytoxan
other name: Endoxan
other name: Endoxana
intervention type: Drug
intervention name: doxorubicin hydrochloride
description: Given IV
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: ADM
other name: ADR
other name: Adria
other name: Adriamycin PFS
other name: Adriamycin RDF
intervention type: Drug
intervention name: vincristine sulfate
description: Given IV
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: leurocristine sulfate
other name: VCR
other name: Vincasar PFS
intervention type: Drug
intervention name: methotrexate
description: Given IV or IT
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: amethopterin
other name: Folex
other name: methylaminopterin
other name: Mexate
other name: MTX
intervention type: Drug
intervention name: cytarabine
description: Given IV or IT
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: ARA-C
other name: arabinofuranosylcytosine
other name: arabinosylcytosine
other name: Cytosar-U
other name: cytosine arabinoside
intervention type: Drug
intervention name: prednisone
description: Given PO
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: DeCortin
other name: Deltra
intervention type: Drug
intervention name: mesna
description: Given IV
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: mercaptoethane sulfonate
other name: Mesnex
other name: MSA
intervention type: Drug
intervention name: dexamethasone
description: Given IV or PO
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: Aeroseb-Dex
other name: Decaderm
other name: Decadron
other name: DM
other name: DXM
intervention type: Drug
intervention name: leucovorin calcium
description: Given IV
arm group label: Treatment (nilotinib, combination chemotherapy)
other name: CF
other name: CFR
other name: LV
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Aref Al-Kali, M.D.
role: Study Chair
affiliation: Mayo Clinic
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
mesh term: Blast Crisis
mesh term: Philadelphia Chromosome
mesh term: Leucovorin
mesh term: Cytarabine
mesh term: Dexamethasone
mesh term: Prednisone
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Doxorubicin
mesh term: Liposomal doxorubicin
mesh term: Methotrexate
mesh term: Vincristine
mesh term: Levoleucovorin
mesh term: Mesna