<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/NCT02199665</url>
  </required_header>
  <id_info>
    <org_study_id>IRB14-0033</org_study_id>
    <secondary_id>NCI-2014-01199</secondary_id>
    <secondary_id>IRB14-0033</secondary_id>
    <secondary_id>P30CA014599</secondary_id>
    <nct_id>NCT02199665</nct_id>
  </id_info>
  <brief_title>Selinexor, Carfilzomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma</brief_title>
  <acronym>SINE</acronym>
  <official_title>A Phase I Study of the Combination of a Selective Inhibitor of Nuclear Export (SINE), Selinexor With Carfilzomib and Dexamethasone in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Chicago</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of selinexor and carfilzomib when&#xD;
      given together with dexamethasone in treating patients with multiple myeloma that has&#xD;
      returned or does not respond to treatment. Drugs used in chemotherapy, such as selinexor and&#xD;
      dexamethasone, work in different ways to stop the growth of cancer cells, either by killing&#xD;
      the cells, by stopping them from dividing, or by stopping them from spreading. Carfilzomib&#xD;
      may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.&#xD;
      Giving selinexor, carfilzomib, and dexamethasone may be a better treatment for multiple&#xD;
      myeloma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the&#xD;
      combination of selinexor, carfilzomib, and dexamethasone in relapsed and relapsed/refractory&#xD;
      multiple myeloma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Determine safety and tolerability.&#xD;
&#xD;
      II. Determine the efficacy, as measured by the rates of stable disease or better (including&#xD;
      minimal response, partial response, very good partial response, complete response, and&#xD;
      stringent complete response).&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of selinexor and carfilzomib.&#xD;
&#xD;
      Patients receive selinexor orally (PO), carfilzomib intravenously (IV), and dexamethasone PO&#xD;
      QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable&#xD;
      toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days and then every 3&#xD;
      months for 2 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 12, 2014</start_date>
  <completion_date type="Anticipated">December 25, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2024</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 Tolerated Dose (MTD) of selinexor, carfilzomib, and dexamethasone</measure>
    <time_frame>28 days</time_frame>
    <description>Defined as the dose level below the dose in which greater than or equal to 2 out of 6 patients experience dose limiting toxicity. Will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicities related to the combination of selinexor and carfilzomib assessed using NCI CTCAE version 4.0</measure>
    <time_frame>Up to 28 days after completion of study treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy as measured by stable disease or better (including MR, partial response, very good partial response, complete response and stringent complete response) according to IMWG criteria</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The number of patients with stable disease or better will be summarized by dose level; 90% confidence intervals will be generated for the RP2D cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicities assessed using NCI CTCAE version 4.0</measure>
    <time_frame>Up to 28 days after completion of study treatment</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Refractory Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Selinexor, carfilzomib, dexamethasone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive selinexor PO, carfilzomib IV, and dexamethasone PO QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>selinexor</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Selinexor, carfilzomib, dexamethasone</arm_group_label>
    <other_name>CRM1 nuclear export inhibitor KPT-330</other_name>
    <other_name>KPT-330</other_name>
    <other_name>selective inhibitor of nuclear export KPT-330</other_name>
    <other_name>SINE KPT-330</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>carfilzomib</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Selinexor, carfilzomib, dexamethasone</arm_group_label>
    <other_name>Kyprolis</other_name>
    <other_name>PR-171</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>dexamethasone</intervention_name>
    <description>Given PO or IV</description>
    <arm_group_label>Selinexor, carfilzomib, dexamethasone</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>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent in accordance with federal, local, and institutional&#xD;
             guidelines&#xD;
&#xD;
          -  Aged 18 years or older&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2&#xD;
&#xD;
          -  Diagnosis of multiple myeloma as per International Myeloma Working Group (IMWG)&#xD;
             uniform criteria&#xD;
&#xD;
          -  Measurable disease by IMWG as defined by at least one of the following:&#xD;
&#xD;
               -  Serum M-protein &gt;= 0.5 g/dL&#xD;
&#xD;
               -  Urine M-protein &gt;= 200 mg in a 24-hour collection&#xD;
&#xD;
               -  Serum free light chain level &gt;= 10 mg/dL provided the free light chain ratio is&#xD;
                  abnormal&#xD;
&#xD;
               -  Measurable plasmacytoma; if plasmacytoma measurement is the only measurable&#xD;
                  disease, subject eligibility must be reviewed with lead principal investigator&#xD;
                  (PI) prior to signing consent&#xD;
&#xD;
          -  Relapsed/refractory multiple myeloma with progressive disease at study entry&#xD;
&#xD;
          -  Subjects must have been treated with at least 2 prior therapies including a proteasome&#xD;
             inhibitor and a cereblon-binding agent&#xD;
&#xD;
               -  Subjects who are refractory to carfilzomib may enroll throughout the trial;&#xD;
                  carfilzomib refractory status is defined by IMWG criteria: disease that is&#xD;
                  nonresponsive while on salvage therapy, or progresses within 60 days of last&#xD;
                  therapy in patients who have achieved minimal response (MR) or better at some&#xD;
                  point previously before then progressing in their disease course&#xD;
&#xD;
          -  Ability to adhere with the study visit schedule and other protocol procedures&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1.0 x 10^9/L; screening ANC should be independent&#xD;
             of growth factor support for over one week for all patients&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dL; subjects may receive red blood cell transfusions as clinically&#xD;
             indicated per institutional guidelines but screening hemoglobin should be independent&#xD;
             of red blood cell transfusion for at least 3 days prior to cycle 1 day 1&#xD;
&#xD;
          -  Platelet count &gt;= 50,000mm^3; platelet count should be independent of transfusions for&#xD;
             at least 14 days for eligibility&#xD;
&#xD;
          -  Total bilirubin =&lt; 2 times the upper limit of normal (ULN) (except patients with&#xD;
             Gilbert's syndrome who must have a total bilirubin of &lt; 3 times ULN)&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) =&lt; 2.5 times ULN; in the case of known (radiological&#xD;
             and/or biopsy documented) liver metastasis, ALT =&lt; 2.5 times ULN is acceptable&#xD;
&#xD;
          -  Estimated creatinine clearance of &gt;= 30 mL/min, calculated using the formula of&#xD;
             Cockroft and Gault&#xD;
&#xD;
          -  Female patients of child-bearing potential must agree practice abstinence or use dual&#xD;
             methods of contraception during treatment and for 90 days after last dose of study&#xD;
             drug.&#xD;
&#xD;
          -  Female patients of child-bearing potential must have negative pregnancy test at&#xD;
             screening&#xD;
&#xD;
          -  Male patients must agree practice abstinence or use effective barrier methods of&#xD;
             contraception during treatment and for 90 days after last dose of study drug&#xD;
&#xD;
          -  Male patients must agree not to donate semen or sperm treatment and for 90 days after&#xD;
             last dose of carfilzomib&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are pregnant or lactating&#xD;
&#xD;
          -  Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =&lt; 2 weeks&#xD;
             prior to cycle 1 day 1&#xD;
&#xD;
          -  Concurrent therapy with approved or investigational anticancer therapeutic other than&#xD;
             steroids&#xD;
&#xD;
          -  Major surgery within four weeks before cycle 1 day 1&#xD;
&#xD;
          -  Unstable angina or myocardial infarction within 4 months prior to randomization, New&#xD;
             York Heart Association (NYHA) class III or IV heart failure, left ventricular ejection&#xD;
             fraction (LVEF) &lt; 40%, uncontrolled angina, history of severe coronary artery disease,&#xD;
             severe uncontrolled ventricular arrhythmias including uncontrolled chronic atrial&#xD;
             fibrillation/atrial flutter, history of torsades de pointe, sick sinus syndrome, or&#xD;
             electrocardiographic evidence of acute ischemia or grade 3 conduction system&#xD;
             abnormalities unless subject has a pacemaker&#xD;
&#xD;
          -  Subject has plasma cell leukemia or Waldenstrom's macroglobuleinemia or POEMS syndrome&#xD;
             (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)&#xD;
             or amyloidosis&#xD;
&#xD;
          -  Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to&#xD;
             randomization&#xD;
&#xD;
          -  Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals&#xD;
             within 14 days prior to first dose; patients with controlled infection or on&#xD;
             prophylactic antibiotics are permitted in the study&#xD;
&#xD;
          -  Known to be human immunodeficiency virus (HIV) seropositive&#xD;
&#xD;
          -  Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C&#xD;
             virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus [HBV] surface antigen)&#xD;
&#xD;
          -  Non-hematologic malignancy within the past 3 years with the exception of a) adequately&#xD;
             treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b)&#xD;
             carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason grade 6 or&#xD;
             less with stable prostate-specific antigen levels; or d) cancer considered cured by&#xD;
             surgical resection or unlikely to impact survival during the duration of the study,&#xD;
             such as localized transitional cell carcinoma of the bladder or benign tumors of the&#xD;
             adrenal or pancreas&#xD;
&#xD;
          -  Patients with markedly decreased visual acuity in the opinion of the treating&#xD;
             investigator after completion of screening ophthalmologic exam&#xD;
&#xD;
          -  Significant neuropathy (grades 3-4, or grade 2 with pain) within 14 days prior to&#xD;
             randomization&#xD;
&#xD;
          -  Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize&#xD;
             carfilzomib)&#xD;
&#xD;
          -  Any underlying condition that would significantly interfere with the absorption of an&#xD;
             oral medication&#xD;
&#xD;
          -  Serious psychiatric or medical conditions that could interfere with treatment&#xD;
&#xD;
          -  Contraindication to any of the required concomitant drugs or supportive treatments,&#xD;
             including hypersensitivity to all anticoagulation and antiplatelet options, antiviral&#xD;
             drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment&#xD;
&#xD;
          -  Subjects with pleural effusions requiring thoracentesis or ascites requiring&#xD;
             paracentesis within 14 days prior to randomization&#xD;
&#xD;
          -  Patients with coagulation problems and active bleeding in the last month prior to&#xD;
             cycle 1 day 1 (peptic ulcer, epistaxis, spontaneous bleeding)&#xD;
&#xD;
          -  Previous Selinexor exposure&#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>Andrzej Jakubowiak</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Chicago</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cancer Clinical Trials Office</last_name>
    <phone>1-855-702-8222</phone>
    <email>cancerclinicaltrials@bsd.uchicago.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Mayo Clinic (AZ)</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85259</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andrzej J. Jakubowiak</last_name>
      <phone>773-702-1345</phone>
      <email>ajakubowiak@medicine.bsd.uchicago.edu</email>
    </contact>
    <investigator>
      <last_name>Andrzej J. Jakubowiak</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Michigan Comprehensive Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Wayne State University Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Marano</last_name>
      <email>maranom@karmanos.org</email>
    </contact>
    <contact_backup>
      <last_name>Carol Muzyk</last_name>
      <phone>313 576 9690</phone>
      <email>muzykc@karmanos.org</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ajai Chari, MD</last_name>
      <email>ajai.chari@mountsinai.org</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 22, 2014</study_first_submitted>
  <study_first_submitted_qc>July 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 24, 2014</study_first_posted>
  <last_update_submitted>March 2, 2023</last_update_submitted>
  <last_update_submitted_qc>March 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 6, 2023</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>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</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/NCT02199665
org study id: IRB14-0033
secondary id: NCI-2014-01199
secondary id: IRB14-0033
secondary id: P30CA014599
nct id: NCT02199665
lead sponsor: 
collaborator: 
has dmc: Yes
This phase I trial studies the side effects and best dose of selinexor and carfilzomib when
      given together with dexamethasone in treating patients with multiple myeloma that has
      returned or does not respond to treatment. Drugs used in chemotherapy, such as selinexor and
      dexamethasone, work in different ways to stop the growth of cancer cells, either by killing
      the cells, by stopping them from dividing, or by stopping them from spreading. Carfilzomib
      may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
      Giving selinexor, carfilzomib, and dexamethasone may be a better treatment for multiple
      myeloma.
PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the
      combination of selinexor, carfilzomib, and dexamethasone in relapsed and relapsed/refractory
      multiple myeloma.

      SECONDARY OBJECTIVES:

      I. Determine safety and tolerability.

      II. Determine the efficacy, as measured by the rates of stable disease or better (including
      minimal response, partial response, very good partial response, complete response, and
      stringent complete response).

      OUTLINE: This is a dose-escalation study of selinexor and carfilzomib.

      Patients receive selinexor orally (PO), carfilzomib intravenously (IV), and dexamethasone PO
      QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 3
      months for 2 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of selinexor, carfilzomib, and dexamethasone
time frame: 28 days
description: Defined as the dose level below the dose in which greater than or equal to 2 out of 6 patients experience dose limiting toxicity. Will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
measure: Incidence of toxicities related to the combination of selinexor and carfilzomib assessed using NCI CTCAE version 4.0
time frame: Up to 28 days after completion of study treatment
measure: Efficacy as measured by stable disease or better (including MR, partial response, very good partial response, complete response and stringent complete response) according to IMWG criteria
time frame: Up to 2 years
description: The number of patients with stable disease or better will be summarized by dose level; 90% confidence intervals will be generated for the RP2D cohort.
measure: Incidence of toxicities assessed using NCI CTCAE version 4.0
time frame: Up to 28 days after completion of study treatment
arm group label: Selinexor, carfilzomib, dexamethasone
arm group type: Experimental
description: Patients receive selinexor PO, carfilzomib IV, and dexamethasone PO QD or IV. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: selinexor
description: Given PO
arm group label: Selinexor, carfilzomib, dexamethasone
other name: CRM1 nuclear export inhibitor KPT-330
other name: KPT-330
other name: selective inhibitor of nuclear export KPT-330
other name: SINE KPT-330
intervention type: Drug
intervention name: carfilzomib
description: Given IV
arm group label: Selinexor, carfilzomib, dexamethasone
other name: Kyprolis
other name: PR-171
intervention type: Drug
intervention name: dexamethasone
description: Given PO or IV
arm group label: Selinexor, carfilzomib, dexamethasone
other name: Aeroseb-Dex
other name: Decaderm
other name: Decadron
other name: DM
other name: DXM
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrzej Jakubowiak
role: Principal Investigator
affiliation: University of Chicago
last name: Cancer Clinical Trials Office
phone: 1-855-702-8222
email: cancerclinicaltrials@bsd.uchicago.edu
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone