<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/NCT03236792</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 16-1853</org_study_id>
    <nct_id>NCT03236792</nct_id>
  </id_info>
  <brief_title>Ixazomib In Combination With Cyclophosphamide And Dexamethasone for Newly Diagnosed AL Amyloidosis</brief_title>
  <official_title>Phase 1/2 Study Of Ixazomib In Combination With Cyclophosphamide And Dexamethasone In Patients With Newly Diagnosed Immunoglobulin Light Chain AL Amyloidosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Icahn School of Medicine at Mount Sinai</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Millennium Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Light chain (AL) amyloidosis is a bone marrow disorder that affects a wide range of organs&#xD;
      that can lead to organ dysfunction and death. Amyloid is an abnormal protein that is produced&#xD;
      in your bone marrow and cannot be broken down. It builds up in different organs preventing&#xD;
      them from working well. The most commonly affected organs are the kidneys, heart, liver,&#xD;
      spleen, nervous system, and digestive tract. Treatment with chemotherapy can stop the growth&#xD;
      of abnormal cells that produce this abnormal protein. Decrease in amyloid protein in the body&#xD;
      improves the function of the affected organs.&#xD;
&#xD;
      The primary purpose of this study is to determine the safest dose of the medications and how&#xD;
      well you tolerate them or the &quot;maximum tolerated dose&quot; (MTD). The study uses Ixazomib in&#xD;
      combination with cyclophosphamide and dexamethasone to treat people with newly diagnosed AL&#xD;
      amyloidosis. This combination of medications is an oral regimen that is taken over 6 cycles.&#xD;
      The first part of study will determine the safety of this regimen and the second part of the&#xD;
      study will determine how effective this combination of drugs is to treat your disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a phase 1/2 study to assess safety and hematologic response rate of Ixazomib&#xD;
      (MLN) in combination with Cyclophosphamide (CTX) and Dexamethasone (DEX). This is an open&#xD;
      label multi-center, dose escalation safety study for patients with newly diagnosed AL&#xD;
      Amyloidosis.&#xD;
&#xD;
      A 3+3 design will be utilized to determine the MTD for MLN + CTX + DEX in 28-day treatment&#xD;
      cycle. Treatment cycles will be repeated up to 6 cycles or until disease progression or until&#xD;
      development of significant treatment-related toxicities. A total of up to 30 patients are&#xD;
      planned to enroll into the study, with a maximum of 18 patients in the dose escalation arm&#xD;
      and 18 patients in the MTD expansion arm. The cohort of 6 patients treated at the MTD during&#xD;
      the dose expansion phase will also serve as the initial 6 patients for the expansion Phase II&#xD;
      cohort. These 6 patients will contribute data to both the phase I dose escalation study and&#xD;
      the phase II expansion study. To complete the Phase II cohort, an additional 12 new patients&#xD;
      will need to be enrolled.&#xD;
&#xD;
      MLN will be taken orally on days 1, 8, and 15 at doses of 3 mg or 4 mg. CTX will be taken&#xD;
      orally on the same days with dose escalation from 300 mg up to 500 mg. DEX will be taken&#xD;
      orally on days 1, 8, 15, 22 at 20 mg in the 28-day cycle.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 12, 2017</start_date>
  <completion_date type="Actual">September 20, 2022</completion_date>
  <primary_completion_date type="Actual">September 20, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Single Group Assignment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD)</measure>
    <time_frame>up to 3 years</time_frame>
    <description>The MTD of ixazomib given in combination with cyclophosphamide and dexamethasone, 3 + 3 design in Phase 1 of this study</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response Rate</measure>
    <time_frame>up to 3 years</time_frame>
    <description>The incidence of hematologic response rate as defined by complete response (CR), very good partial response (VGPR), partial response (PR), and stable disease (SD)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of organ response</measure>
    <time_frame>up to 3 years</time_frame>
    <description>The frequency of organ response as per the ISA criteria: Cardiac response and progression -NT-proBNP response (&gt;30% and &gt; 300 ng/L decrease if baseline NT-proBNP 650 ng/L). NT-proBNP progression (&gt;30% and &gt;300 ng/L increase). cTn progression (&gt;33% increase). NYHA class response (&gt; two-class decrease if baseline NYHA class 3 or 4). EF progression (&gt;10% decrease). Renal response and progression - Renal response: &gt;30% decrease in proteinuria or drop of proteinuria below 0.5 g/24 h in the absence of renal progression. Renal progression: &gt;25% decrease in eGFR. Liver response criteria- include a 50% decrease in abnormal alkaline phosphatase value and decrease in liver size of at least 2cm.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>AL Amyloidosis</condition>
  <arm_group>
    <arm_group_label>Newly Diagnosed AL Amyloidosis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ixazomib/Cyclophosphamide/Dexamethasone. Treatment cycles will be repeated up to 6 cycles or until disease progression or until development of significant treatment-related toxicities.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ixazomib</intervention_name>
    <description>3 mg or 4mg of Ixazomib will be taken orally on days 1, 8, and 15 of a 28-day cycle</description>
    <arm_group_label>Newly Diagnosed AL Amyloidosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>300, 400, or 500 mg of oral Cyclophosphamide on days 1, 8, and 15 of a 28-day cycle</description>
    <arm_group_label>Newly Diagnosed AL Amyloidosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>20 mg of oral Dexamethasone on days 1, 8, 15, 22 in a 28-day cycle</description>
    <arm_group_label>Newly Diagnosed AL Amyloidosis</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female patients 18 years or older.&#xD;
&#xD;
          -  Biopsy-proven diagnosis of AL amyloidosis according to the following standard&#xD;
             criteria:&#xD;
&#xD;
               -  Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo&#xD;
                  red staining with exhibition of an apple-green birefringence&#xD;
&#xD;
               -  If clinical and laboratory parameters insufficient to establish AL amyloidosis or&#xD;
                  in cases of doubt, amyloid typing may be necessary&#xD;
&#xD;
               -  Measurable disease defined by serum differential free light chain concentration&#xD;
                  (difference between amyloid forming [involved] and non amyloid forming&#xD;
                  [uninvolved] free light chain [FLC]) ≥ 50 mg/L).&#xD;
&#xD;
               -  Amyloid organ involvement including renal, cardiac, GI and/or nervous system&#xD;
                  involvement as well as soft tissue disease&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance&#xD;
             status 0, 1, or 2.&#xD;
&#xD;
          -  Patients must meet the following clinical laboratory criteria:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥1,000/mm3 and platelet count ≥75,000/mm3.&#xD;
&#xD;
               -  Hemoglobin ≥ 8.0 g/dL&#xD;
&#xD;
               -  Platelet transfusions to help patients meet eligibility criteria are not allowed&#xD;
                  within 3 days before study enrollment.&#xD;
&#xD;
               -  Total bilirubin ≤ 2 the upper limit of the normal range (ULN) (except patients&#xD;
                  with Gilbert's syndrome who must have a total bilirubin of &lt; 3 x ULN)&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 ULN.&#xD;
&#xD;
               -  Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault Formula).&#xD;
&#xD;
        Exclusion Criteria:&#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.&#xD;
&#xD;
          -  Infection requiring systemic antibiotic therapy or other serious infection within 14&#xD;
             days before study enrollment.&#xD;
&#xD;
          -  Evidence of current uncontrolled cardiovascular conditions:&#xD;
&#xD;
               -  uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic&#xD;
                  congestive heart failure, *unstable angina, or myocardial infarction within the&#xD;
                  past 6 months.&#xD;
&#xD;
        Recent history of myocardial infarction in the six months prior to registration&#xD;
&#xD;
          -  Systemic treatment, within 14 days before the first dose of ixazomib, with strong&#xD;
             inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of&#xD;
             CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole,&#xD;
             nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin,&#xD;
             carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.&#xD;
&#xD;
          -  Ongoing or active systemic infection, active hepatitis B or C virus infection, or&#xD;
             known human immunodeficiency virus (HIV) positive.&#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;
          -  Known GI disease or GI procedure that could interfere with the oral absorption or&#xD;
             tolerance of ixazomib 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 early stage prostate cancer, non melanoma skin cancer or&#xD;
             carcinoma in situ of any type are not excluded; patients with malignancies that have&#xD;
             undergone complete resection are not excluded.&#xD;
&#xD;
          -  Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical&#xD;
             examination during the screening period.&#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 the duration of this trial.&#xD;
&#xD;
          -  New York Heart Association Class III or IV Heart Failure&#xD;
&#xD;
          -  NT Pro-BNP &gt; 8500pcg/mL.&#xD;
&#xD;
          -  Dialysis dependent renal failure&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Keren Osman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weill Cornell Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>July 20, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>September 28, 2022</last_update_submitted>
  <last_update_submitted_qc>September 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>Keren Osman</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Newly Diagnosed</keyword>
  <keyword>AL Amyloidosis</keyword>
  <keyword>Amyloid</keyword>
  <keyword>Light chain Amyloidosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulin Light-chain Amyloidosis</mesh_term>
    <mesh_term>Amyloidosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Ixazomib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03236792
org study id: GCO 16-1853
nct id: NCT03236792
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Light chain (AL) amyloidosis is a bone marrow disorder that affects a wide range of organs
      that can lead to organ dysfunction and death. Amyloid is an abnormal protein that is produced
      in your bone marrow and cannot be broken down. It builds up in different organs preventing
      them from working well. The most commonly affected organs are the kidneys, heart, liver,
      spleen, nervous system, and digestive tract. Treatment with chemotherapy can stop the growth
      of abnormal cells that produce this abnormal protein. Decrease in amyloid protein in the body
      improves the function of the affected organs.

      The primary purpose of this study is to determine the safest dose of the medications and how
      well you tolerate them or the "maximum tolerated dose" (MTD). The study uses Ixazomib in
      combination with cyclophosphamide and dexamethasone to treat people with newly diagnosed AL
      amyloidosis. This combination of medications is an oral regimen that is taken over 6 cycles.
      The first part of study will determine the safety of this regimen and the second part of the
      study will determine how effective this combination of drugs is to treat your disease.
This study is a phase 1/2 study to assess safety and hematologic response rate of Ixazomib
      (MLN) in combination with Cyclophosphamide (CTX) and Dexamethasone (DEX). This is an open
      label multi-center, dose escalation safety study for patients with newly diagnosed AL
      Amyloidosis.

      A 3+3 design will be utilized to determine the MTD for MLN + CTX + DEX in 28-day treatment
      cycle. Treatment cycles will be repeated up to 6 cycles or until disease progression or until
      development of significant treatment-related toxicities. A total of up to 30 patients are
      planned to enroll into the study, with a maximum of 18 patients in the dose escalation arm
      and 18 patients in the MTD expansion arm. The cohort of 6 patients treated at the MTD during
      the dose expansion phase will also serve as the initial 6 patients for the expansion Phase II
      cohort. These 6 patients will contribute data to both the phase I dose escalation study and
      the phase II expansion study. To complete the Phase II cohort, an additional 12 new patients
      will need to be enrolled.

      MLN will be taken orally on days 1, 8, and 15 at doses of 3 mg or 4 mg. CTX will be taken
      orally on the same days with dose escalation from 300 mg up to 500 mg. DEX will be taken
      orally on days 1, 8, 15, 22 at 20 mg in the 28-day cycle.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD)
time frame: up to 3 years
description: The MTD of ixazomib given in combination with cyclophosphamide and dexamethasone, 3 + 3 design in Phase 1 of this study
measure: Response Rate
time frame: up to 3 years
description: The incidence of hematologic response rate as defined by complete response (CR), very good partial response (VGPR), partial response (PR), and stable disease (SD)
measure: Frequency of organ response
time frame: up to 3 years
description: The frequency of organ response as per the ISA criteria: Cardiac response and progression -NT-proBNP response (>30% and > 300 ng/L decrease if baseline NT-proBNP 650 ng/L). NT-proBNP progression (>30% and >300 ng/L increase). cTn progression (>33% increase). NYHA class response (> two-class decrease if baseline NYHA class 3 or 4). EF progression (>10% decrease). Renal response and progression - Renal response: >30% decrease in proteinuria or drop of proteinuria below 0.5 g/24 h in the absence of renal progression. Renal progression: >25% decrease in eGFR. Liver response criteria- include a 50% decrease in abnormal alkaline phosphatase value and decrease in liver size of at least 2cm.
arm group label: Newly Diagnosed AL Amyloidosis
arm group type: Experimental
description: Ixazomib/Cyclophosphamide/Dexamethasone. Treatment cycles will be repeated up to 6 cycles or until disease progression or until development of significant treatment-related toxicities.
intervention type: Drug
intervention name: Ixazomib
description: 3 mg or 4mg of Ixazomib will be taken orally on days 1, 8, and 15 of a 28-day cycle
arm group label: Newly Diagnosed AL Amyloidosis
intervention type: Drug
intervention name: Cyclophosphamide
description: 300, 400, or 500 mg of oral Cyclophosphamide on days 1, 8, and 15 of a 28-day cycle
arm group label: Newly Diagnosed AL Amyloidosis
intervention type: Drug
intervention name: Dexamethasone
description: 20 mg of oral Dexamethasone on days 1, 8, 15, 22 in a 28-day cycle
arm group label: Newly Diagnosed AL Amyloidosis
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Keren Osman, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: Keren Osman
investigator title: Associate Professor
mesh term: Immunoglobulin Light-chain Amyloidosis
mesh term: Amyloidosis
mesh term: Dexamethasone
mesh term: Cyclophosphamide
mesh term: Ixazomib
sharing ipd: Undecided