<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/NCT02228772</url>
  </required_header>
  <id_info>
    <org_study_id>14-200</org_study_id>
    <nct_id>NCT02228772</nct_id>
  </id_info>
  <brief_title>Phase I Study of MLN 9708 in Addition to Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia in Older Adults</brief_title>
  <official_title>Phase I Study of MLN 9708 in Addition to Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia in Older Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Millennium Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is evaluating a combination of drugs considered standard treatment for&#xD;
      children and young adults with acute lymphoblastic leukemia (ALL), in combination with a new&#xD;
      drug called MLN 9708. Additionally, the study is also evaluating if bone marrow or stem cell&#xD;
      transplantation, which will be given to some participants, helps to prevent ALL from&#xD;
      returning.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this research study, the investigators are studying the optimal dose of the drug MLN 9708&#xD;
      when given with a standard multi-drug regimen. In the first part of the study, up to 18&#xD;
      participants will be enrolled at different doses of MLN 9708. Once the maximally tolerated&#xD;
      (highest, safest dose) is established, an additional 10 participants will be enrolled.&#xD;
&#xD;
      Additionally, bone marrow (tissue found in the inside of bones) or stem cell transplantation&#xD;
      will be given to some participants to study whether it helps to prevent ALL from returning.&#xD;
&#xD;
      The study treatment consists of several different stages&#xD;
&#xD;
        -  Induction&#xD;
&#xD;
        -  Consolidation 1&#xD;
&#xD;
        -  Or Stem Cell or Bone Marrow Transplant (if you are eligible based on your medical&#xD;
           condition and the availability of a matched stem cell donor)&#xD;
&#xD;
        -  Or If you do not have a transplant:&#xD;
&#xD;
             -  CNS Therapy&#xD;
&#xD;
             -  Consolidation 2&#xD;
&#xD;
             -  Continuation Therapy&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2014</start_date>
  <completion_date type="Actual">November 2019</completion_date>
  <primary_completion_date type="Actual">October 2016</primary_completion_date>
  <phase>Phase 1</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>Maximum Dose Tolerated of MLN 9708</measure>
    <time_frame>2 Years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patient with Complete Remission (CR) rate at the end of induction therapy</measure>
    <time_frame>30 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants with Disease Free Survival</measure>
    <time_frame>2 Years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Overall survival (OS)</measure>
    <time_frame>1 Year, 2 Year, 3 Year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Remission Rate</measure>
    <time_frame>2 Years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Toxicity</measure>
    <time_frame>2 Years</time_frame>
    <description>Assess adverse events, serious adverse events, neurotoxicity grading</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Lymphoblastic Lymphoma</condition>
  <condition>B-cell Adult Acute Lymphoblastic Leukemia</condition>
  <condition>T-cell Adult Acute Lymphoblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>MLN 9708</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation.&#xD;
MLN 9708 will be given with standard multi-drug regimen for ALL . MLN 9708 will be administered on determined days during Induction therapy cycle and Consolidation cycle. If remission occurs and if eligible, the next stage with be either Stem Cell or Bone Marrow Transplant.&#xD;
If not eligible to receive a transplant, the participant will continue on this study for the next 3 stages.&#xD;
CNS Therapy&#xD;
Consolidation 2&#xD;
Continuation Therapy&#xD;
No further MLN9708, the investigational drug, will be given after Consolidation 1 Standard chemotherapy -Vincristine, Cytarabine, Doxorubicin, Mercaptopurine, Cyclophosphamide, Methotrexate</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MLN 9708</intervention_name>
    <description>Patients will received standard chemotherapy as well as MLN 9708 in escalating doses.</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>Ixazomib</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>Standard chemotherapy dosage and duration</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>Oncovin</other_name>
    <other_name>Vincasar PFS</other_name>
    <other_name>Vincrex</other_name>
    <other_name>Vincristine sulfate</other_name>
    <other_name>VCR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>Standard chemotherapy dosage and duration</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>Ara-C</other_name>
    <other_name>Cytosar-U</other_name>
    <other_name>Cytosine arabinoside</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Standard chemotherapy dosage and duration</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>Adriamycin, Rubex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mercaptopurine</intervention_name>
    <description>Standard chemotherapy dosage and duration</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>6-MP</other_name>
    <other_name>Purinethol</other_name>
    <other_name>Purixan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Standard chemotherapy dosage and duration</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>Cytoxan</other_name>
    <other_name>Neosar</other_name>
    <other_name>CTX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Standard chemotherapy dosage and duration</description>
    <arm_group_label>MLN 9708</arm_group_label>
    <other_name>Folex</other_name>
    <other_name>Mexate</other_name>
    <other_name>MTX</other_name>
    <other_name>Methotrex (formerly Amethopterin)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Acute lymphoblastic leukemia, excluding known mature B-cell ALL by the presence of any&#xD;
             of the following: surface immunoglobulin, L3 morphology, t(8;14)(q24;q32), t(8;22), or&#xD;
             t(2;8).&#xD;
&#xD;
          -  Patients with mature B-cell ALL will be removed from the protocol as soon as that&#xD;
             diagnosis is made and should be treated on a B-cell leukemia (Burkitt's) protocol.&#xD;
             NOTE: Patients with T-cell surface markers and a t(8;14)(q24;q11) remain eligible.&#xD;
&#xD;
          -  Patients with lymphoblastic lymphoma are also eligible&#xD;
&#xD;
          -  No prior anti-leukemic therapy except the following are allowed: &lt;1 week of&#xD;
             corticosteroids, or hydroxyurea or emergent leukopheresis. Longer steroid use for&#xD;
             diseases other than leukemia is permitted.&#xD;
&#xD;
          -  Age 51- 75 years&#xD;
&#xD;
          -  Voluntary written consent must be given before performance of any study-related&#xD;
             procedures not part of standard medical care, with the understanding that consent may&#xD;
             be withdrawn by the patient at any time without prejudice to future medical care.&#xD;
&#xD;
          -  If patient is known to be HIV positive, they will not be eligible for the protocol.&#xD;
             HIV testing is not mandatory prior to protocol enrollment.&#xD;
&#xD;
          -  Patients whose comorbid medical condition, in the investigator's opinion, would make&#xD;
             participation in this trial and adherence to the protocol guidelines difficult should&#xD;
             be excluded.&#xD;
&#xD;
          -  Patients with an active psychiatric or mental illness making informed consent or&#xD;
             careful clinical follow-up unlikely are excluded.&#xD;
&#xD;
          -  Ejection fraction ≥ 45%&#xD;
&#xD;
          -  Creatinine&lt;2.0 times upper limit of normal&#xD;
&#xD;
          -  Total bilirubin &lt; 1.5 times upper limit of normal except for known conjugation&#xD;
             diseases such as Gilbert's, ALT and AST &lt;3.0 times upper limit of normal. Direct&#xD;
             bilirubin is not an inclusion criteria.&#xD;
&#xD;
          -  ECOG performance status of 0, 1, 2&#xD;
&#xD;
          -  Non pregnant and non lactating Female patients who:&#xD;
&#xD;
               -  Are postmenopausal for at least 1 year before the screening visit, OR&#xD;
&#xD;
               -  Are surgically sterile, OR&#xD;
&#xD;
               -  If they are of childbearing potential, agree to practice 2 effective methods of&#xD;
                  contraception, at the same time, from the time of signing the informed consent&#xD;
                  form through 90 days after the last dose of study drug, AND&#xD;
&#xD;
               -  Must also adhere to the guidelines of any treatment-specific pregnancy prevention&#xD;
                  program, if applicable, OR&#xD;
&#xD;
               -  Agree to practice true abstinence when this is in line with the preferred and&#xD;
                  usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,&#xD;
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods&#xD;
                  of contraception.)&#xD;
&#xD;
          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree&#xD;
             to one of the following:&#xD;
&#xD;
               -  Agree to practice effective barrier contraception during the entire study&#xD;
                  treatment period and through 90 days after the last dose of study drug, OR&#xD;
&#xD;
               -  Must also adhere to the guidelines of any treatment-specific pregnancy prevention&#xD;
                  program, if applicable, OR&#xD;
&#xD;
               -  Agree to practice true abstinence when this is in line with the preferred and&#xD;
                  usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation,&#xD;
                  symptothermal, post-ovulation methods] and withdrawal are not acceptable methods&#xD;
                  of contraception.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients meeting any of the following exclusion criteria are not to be enrolled in the&#xD;
             study.&#xD;
&#xD;
          -  Female patients who are lactating or have a positive serum pregnancy test during the&#xD;
             screening period.&#xD;
&#xD;
          -  Major surgery within 14 days before enrollment. Biopsies and line placement procedures&#xD;
             are not exclusion criteria.&#xD;
&#xD;
          -  Radiotherapy within 14 days before enrollment. Radiotherapy is excluded during&#xD;
             induction and consolidation 1 while receiving MLN 9708.&#xD;
&#xD;
          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled&#xD;
             hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,&#xD;
             unstable angina, or myocardial infarction within the past 6 months.&#xD;
&#xD;
          -  Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV)&#xD;
             positive. Hepatitis and HIV testing are not required prior to the start of treatment.&#xD;
&#xD;
          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,&#xD;
             potentially interfere with the completion of treatment according to this protocol.&#xD;
&#xD;
          -  Known allergy to any of the study medications, their analogues, or excipients in the&#xD;
             various formulations of any agent.&#xD;
&#xD;
          -  Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical&#xD;
             examination during the screening period.&#xD;
&#xD;
          -  Known GI disease or GI procedure that could interfere with the oral absorption or&#xD;
             tolerance of MLN9708 including difficulty swallowing.&#xD;
&#xD;
          -  Diagnosed or treated for another malignancy within 2 years before study enrollment or&#xD;
             previously diagnosed with another malignancy and have any evidence of residual&#xD;
             disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are&#xD;
             not excluded if they have undergone complete resection.&#xD;
&#xD;
          -  Participation in other clinical trials, including those with other investigational&#xD;
             agents not included in this trial, within 21days of the start of this trial and&#xD;
             throughout induction and consolidation 1 portions of this trial (while on MLN 9708).&#xD;
             Patients may enroll in transplant and post transplant studies after consolidation 1&#xD;
             treatment (See Section 6.5).&#xD;
&#xD;
          -  Systemic treatment, within 14 days before the first dose of MLN9708, with strong&#xD;
             inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A&#xD;
             (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone,&#xD;
             posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin,&#xD;
             carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.&#xD;
             Ciprofloxocin should not be administered for at least 2 days before MLN 9708&#xD;
             administration. Extended release ciprofloxocin should not be administered for at least&#xD;
             3 days prior to MLN 9708 administration.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>51 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philip Amrein, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>August 23, 2014</study_first_submitted>
  <study_first_submitted_qc>August 27, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2014</study_first_posted>
  <last_update_submitted>November 25, 2019</last_update_submitted>
  <last_update_submitted_qc>November 25, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Philip C. Amrein, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Acute lymphoblastic Leukemia</keyword>
  <keyword>Lymphoblastic lymphoma</keyword>
  <keyword>B-cell Adult Acute Lymphoblastic Leukemia</keyword>
  <keyword>T-cell Adult Acute Lymphoblastic Leukemia</keyword>
  <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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Mercaptopurine</mesh_term>
    <mesh_term>Ixazomib</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/NCT02228772
org study id: 14-200
nct id: NCT02228772
lead sponsor: 
collaborator: 
has dmc: Yes
This research study is evaluating a combination of drugs considered standard treatment for
      children and young adults with acute lymphoblastic leukemia (ALL), in combination with a new
      drug called MLN 9708. Additionally, the study is also evaluating if bone marrow or stem cell
      transplantation, which will be given to some participants, helps to prevent ALL from
      returning.
In this research study, the investigators are studying the optimal dose of the drug MLN 9708
      when given with a standard multi-drug regimen. In the first part of the study, up to 18
      participants will be enrolled at different doses of MLN 9708. Once the maximally tolerated
      (highest, safest dose) is established, an additional 10 participants will be enrolled.

      Additionally, bone marrow (tissue found in the inside of bones) or stem cell transplantation
      will be given to some participants to study whether it helps to prevent ALL from returning.

      The study treatment consists of several different stages

        -  Induction

        -  Consolidation 1

        -  Or Stem Cell or Bone Marrow Transplant (if you are eligible based on your medical
           condition and the availability of a matched stem cell donor)

        -  Or If you do not have a transplant:

             -  CNS Therapy

             -  Consolidation 2

             -  Continuation Therapy
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Dose Tolerated of MLN 9708
time frame: 2 Years
measure: Percentage of Patient with Complete Remission (CR) rate at the end of induction therapy
time frame: 30 Days
measure: Percentage of Participants with Disease Free Survival
time frame: 2 Years
measure: Rate of Overall survival (OS)
time frame: 1 Year, 2 Year, 3 Year
measure: Complete Remission Rate
time frame: 2 Years
measure: Rate of Toxicity
time frame: 2 Years
description: Assess adverse events, serious adverse events, neurotoxicity grading
arm group label: MLN 9708
arm group type: Experimental
description: Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation.
MLN 9708 will be given with standard multi-drug regimen for ALL . MLN 9708 will be administered on determined days during Induction therapy cycle and Consolidation cycle. If remission occurs and if eligible, the next stage with be either Stem Cell or Bone Marrow Transplant.
If not eligible to receive a transplant, the participant will continue on this study for the next 3 stages.
CNS Therapy
Consolidation 2
Continuation Therapy
No further MLN9708, the investigational drug, will be given after Consolidation 1 Standard chemotherapy -Vincristine, Cytarabine, Doxorubicin, Mercaptopurine, Cyclophosphamide, Methotrexate
intervention type: Drug
intervention name: MLN 9708
description: Patients will received standard chemotherapy as well as MLN 9708 in escalating doses.
arm group label: MLN 9708
other name: Ixazomib
intervention type: Drug
intervention name: Vincristine
description: Standard chemotherapy dosage and duration
arm group label: MLN 9708
other name: Oncovin
other name: Vincasar PFS
other name: Vincrex
other name: Vincristine sulfate
other name: VCR
intervention type: Drug
intervention name: Cytarabine
description: Standard chemotherapy dosage and duration
arm group label: MLN 9708
other name: Ara-C
other name: Cytosar-U
other name: Cytosine arabinoside
intervention type: Drug
intervention name: Doxorubicin
description: Standard chemotherapy dosage and duration
arm group label: MLN 9708
other name: Adriamycin, Rubex
intervention type: Drug
intervention name: Mercaptopurine
description: Standard chemotherapy dosage and duration
arm group label: MLN 9708
other name: 6-MP
other name: Purinethol
other name: Purixan
intervention type: Drug
intervention name: Cyclophosphamide
description: Standard chemotherapy dosage and duration
arm group label: MLN 9708
other name: Cytoxan
other name: Neosar
other name: CTX
intervention type: Drug
intervention name: Methotrexate
description: Standard chemotherapy dosage and duration
arm group label: MLN 9708
other name: Folex
other name: Mexate
other name: MTX
other name: Methotrex (formerly Amethopterin)
criteria: 
gender: All
minimum age: 51 Years
maximum age: 75 Years
healthy volunteers: No
last name: Philip Amrein, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Philip C. Amrein, M.D.
investigator title: Principal Investigator
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Cytarabine
mesh term: Cyclophosphamide
mesh term: Doxorubicin
mesh term: Methotrexate
mesh term: Vincristine
mesh term: Mercaptopurine
mesh term: Ixazomib