<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/NCT03773107</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00081612</org_study_id>
    <secondary_id>00031040</secondary_id>
    <secondary_id>LCI-HEM-MYE-CRD-004</secondary_id>
    <nct_id>NCT03773107</nct_id>
  </id_info>
  <brief_title>LCI-HEM-MYE-CRD-004 (MMRC-073 CARJAK): Study of CRD for Carfilzomib-Refractory Multiple Myeloma</brief_title>
  <official_title>LCI-HEM-MYE-CRD-004 (MMRC-073 CARJAK): Phase I/II Study of Carfilzomib, Ruxolitinib, and Low Dose Dexamethasone for Carfilzomib-Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Incyte Corporation</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Multiple Myeloma Research Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</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>
      The primary objective of Phase I is to establish the maximum tolerated dose (MTD) of&#xD;
      ruxolitinib in combination with carfilzomib and dexamethasone. The primary objective of phase&#xD;
      II is to evaluate progression-free survival (PFS) at 4 months in multiple myeloma subjects&#xD;
      who receive the combination treatment carfilzomib, dexamethasone, and ruxolitinib.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, Phase I/II study of carfilzomib, ruxolitinib, and low-dose&#xD;
      dexamethasone for carfilzomib-refractory multiple myeloma. Phase I is designed to evaluate&#xD;
      overall maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and&#xD;
      dexamethasone in the following cohorts: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg&#xD;
      ruxolitinib, Cohort 3) 15mg ruxolitinib. Phase II is designed to evaluate 4-month&#xD;
      progression-free survival (PFS) in the following cohorts: Cohort A) non-responders to Phase I&#xD;
      regimen, Cohort B) responders to Phase I regimen. Up to 18 evaluable subjects will be&#xD;
      enrolled in Phase I over approximately 12 months. An additional 30 evaluable subjects will be&#xD;
      enrolled in Phase II over 24 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 3, 2019</start_date>
  <completion_date type="Anticipated">September 26, 2025</completion_date>
  <primary_completion_date type="Actual">November 7, 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>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>4-Month Progression Free Survival</measure>
    <time_frame>4 months</time_frame>
    <description>Progression-free survival (PFS4) will be determined for each subject as a binary variable indicating whether or not the subject is alive and progression free at 4 months</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Dose Limiting Toxicity (DLT)</measure>
    <time_frame>28 days</time_frame>
    <description>DLTs will be determined for each subject as a binary variable indicating whether or not the subject experienced a DLT during Cycle 1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>approx. 30 days after treatment completion</time_frame>
    <description>Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of PR or better as per the IMWG criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate</measure>
    <time_frame>approx. 30 days after treatment completion</time_frame>
    <description>Clinical benefit will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of minimal response (MR) or better as determined by the IMWG criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate</measure>
    <time_frame>approx. 8 weeks after best disease response assessment</time_frame>
    <description>Disease control will be determined for each subject as a binary variable indicating whether or not the subject achieved a disease response or stable disease for greater than or equal to 8 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>approx. 5 years</time_frame>
    <description>PFS is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death without progressive disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Best Response</measure>
    <time_frame>approx. 30 days after treatment completion</time_frame>
    <description>Time to best response will be defined as the time from initiation of ruxolitinib treatment to the time of best objective status assessment of response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>approx. 5 years</time_frame>
    <description>Overall survival is defined as the duration from initiation of ruxolitinib treatment to the date of death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Progression</measure>
    <time_frame>approx. 5 years</time_frame>
    <description>Time to progression (TTP) is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>approx. 5 years</time_frame>
    <description>Duration of response will be defined as the time from first objective status assessment of response to the time of first documented disease progression or death.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <description>Irreversible proteasome inhibitor</description>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_label>Phase II</arm_group_label>
    <other_name>Kyprolis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ruxolitinib</intervention_name>
    <description>Oral JAK inhibitor</description>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_label>Phase II</arm_group_label>
    <other_name>Jakafi</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>glucocorticoid</description>
    <arm_group_label>Phase I</arm_group_label>
    <arm_group_label>Phase II</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        Subjects must meet all of the following criteria:&#xD;
&#xD;
          1. Documented history of relapsed and/or refractory multiple myeloma with &gt; 2 lines of&#xD;
             therapy. One of the prior lines of therapy must have been a carfilzomib containing&#xD;
             regimen with evidence of relapse or progression within the last 60 days of the&#xD;
             carfilzomib containing regimen with a carfilzomib dose of at least 27 mg/m2.&#xD;
             Carfilzomib containing regimen at the standard dose of 20/27 mg/m2 is acceptable.&#xD;
&#xD;
          2. Measurable disease, as defined by at least one of the following:&#xD;
&#xD;
               1. Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease&#xD;
&#xD;
               2. Urinary M-protein excretion of ≥200 mg over a 24-hour period&#xD;
&#xD;
               3. Involved free light chain level ≥10 mg/dL, along with an abnormal free light&#xD;
                  chain ratio&#xD;
&#xD;
          3. Adequate bone marrow reserves, as defined by the following:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥1000 cells/mm3 within 1 week of the initiation&#xD;
                  of treatment&#xD;
&#xD;
               2. Platelet count of ≥75 ,000 cells/mm3 for subjects who have bone marrow&#xD;
                  plasmacytosis of &lt;50%, or ≥50,000 cells/mm3 for subjects who have bone marrow&#xD;
                  plasmacytosis of &gt;50%&#xD;
&#xD;
          4. Adequate hepatic function, as defined by the following:&#xD;
&#xD;
               1. Total bilirubin ≤ 2 times the upper limit of the institutional normal values&#xD;
&#xD;
               2. Total AST and ALT ≤ 3 times the upper limit of the institutional normal values&#xD;
&#xD;
          5. Adequate renal function, as defined by the following: creatinine clearance (CrCl) ≥ 30&#xD;
             mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and&#xD;
             Gault formula.&#xD;
&#xD;
          6. Adequate cardiac function defined as LVEF ≥ 40% by MUGA, echocardiogram or cardiac&#xD;
             MRI.&#xD;
&#xD;
          7. Be 18-75 years of age&#xD;
&#xD;
          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.&#xD;
&#xD;
          9. FOCBP and male subjects who are sexually active with FOCBP must agree to use two&#xD;
             highly effective (as determined per the Investigator) methods of contraception during&#xD;
             the study and for 30 days (female subjects) or for 90 days (male subjects) following&#xD;
             the last dose of study treatment including a male condom.&#xD;
&#xD;
         10. Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
         11. Recovered from all reversible acute toxic effects of prior therapy (other than&#xD;
             alopecia) to ≤ Grade 1 or baseline.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        Subjects must not meet any of the following criteria:&#xD;
&#xD;
          1. Non-secretory multiple myeloma&#xD;
&#xD;
          2. Known amyloidosis&#xD;
&#xD;
          3. Known POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,&#xD;
             endocrinopathy, monoclonal protein, and skin changes)&#xD;
&#xD;
          4. Clinically significant illness including, but not limited to the following: active&#xD;
             systemic infection, uncontrolled hypertension (as defined by BP &gt; 160/90), New York&#xD;
             Heart Association Class III and IV heart failure, unstable angina pectoris, myocardial&#xD;
             infarction within the past 6 months of consent, uncontrolled cardiac arrhythmia, or&#xD;
             any other condition (including laboratory abnormalities) that, in the opinion of the&#xD;
             Investigator, places the subject at unacceptable risk for adverse outcome if he/she&#xD;
             were to participate in the study&#xD;
&#xD;
          5. Prior cerebrovascular accident with persistent neurologic deficit.&#xD;
&#xD;
          6. Psychiatric illness/social situations that would limit compliance with study treatment&#xD;
             and requirements&#xD;
&#xD;
          7. Pregnant or breast feeding. Females of childbearing potential (FOCBP) must have a&#xD;
             negative serum pregnancy test within the 7 days prior to study drug administration and&#xD;
             a negative urine pregnancy test within the 3 days prior to the first study drug&#xD;
             administration.&#xD;
&#xD;
          8. Known human immunodeficiency virus (HIV) infection&#xD;
&#xD;
          9. Active hepatitis B and/or hepatitis C infection&#xD;
&#xD;
         10. Currently active second malignancy, other than non-melanoma skin cancer and carcinoma&#xD;
             in situ of the cervix, should not be enrolled. Subjects are not considered to have a&#xD;
             currently active malignancy if they have completed therapy for a prior malignancy, are&#xD;
             disease free from prior malignancies for &gt;5 years, and are considered by their&#xD;
             physician to be at less than 30% risk of relapse. In addition, subjects with basal&#xD;
             cell carcinoma of the skin, superficial carcinoma of the bladder, carcinoma of the&#xD;
             prostate with a current PSA value of &lt;0.5 ng/mL, or cervical intraepithelial neoplasia&#xD;
             will be eligible. Finally, subjects who are on hormonal therapy for a history of&#xD;
             either prostate cancer or breast cancer may enroll, provided that there has been no&#xD;
             evidence of disease progression during the previous three years.&#xD;
&#xD;
         11. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize&#xD;
             carfilzomib).&#xD;
&#xD;
         12. Contraindication to any of the required concomitant drugs or supportive treatments or&#xD;
             intolerance to hydration due to preexisting pulmonary or cardiac impairment including&#xD;
             pleural effusion requiring thoracentesis or ascites requiring paracentesis.&#xD;
&#xD;
         13. Known intolerance to carfilzomib.&#xD;
&#xD;
         14. Co-administration with strong CYP3A4 inhibitors (such as, but not limited to,&#xD;
             boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole,&#xD;
             lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole,&#xD;
             saquinavir, telaprevir, telithromycin, voriconazole) as well as fluconazole (a dual&#xD;
             inhibitor of CYP3A4 and CYP2C9).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shebli Atrash, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Levine Cancer Institute</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>December 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 12, 2018</study_first_posted>
  <last_update_submitted>September 5, 2023</last_update_submitted>
  <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 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>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 22, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/07/NCT03773107/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03773107
org study id: IRB00081612
secondary id: 00031040
secondary id: LCI-HEM-MYE-CRD-004
nct id: NCT03773107
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The primary objective of Phase I is to establish the maximum tolerated dose (MTD) of
      ruxolitinib in combination with carfilzomib and dexamethasone. The primary objective of phase
      II is to evaluate progression-free survival (PFS) at 4 months in multiple myeloma subjects
      who receive the combination treatment carfilzomib, dexamethasone, and ruxolitinib.
This is an open-label, Phase I/II study of carfilzomib, ruxolitinib, and low-dose
      dexamethasone for carfilzomib-refractory multiple myeloma. Phase I is designed to evaluate
      overall maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and
      dexamethasone in the following cohorts: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg
      ruxolitinib, Cohort 3) 15mg ruxolitinib. Phase II is designed to evaluate 4-month
      progression-free survival (PFS) in the following cohorts: Cohort A) non-responders to Phase I
      regimen, Cohort B) responders to Phase I regimen. Up to 18 evaluable subjects will be
      enrolled in Phase I over approximately 12 months. An additional 30 evaluable subjects will be
      enrolled in Phase II over 24 months.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 4-Month Progression Free Survival
time frame: 4 months
description: Progression-free survival (PFS4) will be determined for each subject as a binary variable indicating whether or not the subject is alive and progression free at 4 months
measure: Dose Limiting Toxicity (DLT)
time frame: 28 days
description: DLTs will be determined for each subject as a binary variable indicating whether or not the subject experienced a DLT during Cycle 1
measure: Objective Response Rate (ORR)
time frame: approx. 30 days after treatment completion
description: Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of PR or better as per the IMWG criteria
measure: Clinical Benefit Rate
time frame: approx. 30 days after treatment completion
description: Clinical benefit will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of minimal response (MR) or better as determined by the IMWG criteria
measure: Disease Control Rate
time frame: approx. 8 weeks after best disease response assessment
description: Disease control will be determined for each subject as a binary variable indicating whether or not the subject achieved a disease response or stable disease for greater than or equal to 8 weeks
measure: Progression-free survival (PFS)
time frame: approx. 5 years
description: PFS is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death without progressive disease.
measure: Time to Best Response
time frame: approx. 30 days after treatment completion
description: Time to best response will be defined as the time from initiation of ruxolitinib treatment to the time of best objective status assessment of response.
measure: Overall Survival
time frame: approx. 5 years
description: Overall survival is defined as the duration from initiation of ruxolitinib treatment to the date of death from any cause.
measure: Time to Progression
time frame: approx. 5 years
description: Time to progression (TTP) is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death.
measure: Duration of Response
time frame: approx. 5 years
description: Duration of response will be defined as the time from first objective status assessment of response to the time of first documented disease progression or death.
arm group label: Phase I
arm group type: Experimental
description: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib
arm group label: Phase II
arm group type: Other
description: Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen
intervention type: Drug
intervention name: Carfilzomib
description: Irreversible proteasome inhibitor
arm group label: Phase I
arm group label: Phase II
other name: Kyprolis
intervention type: Drug
intervention name: Ruxolitinib
description: Oral JAK inhibitor
arm group label: Phase I
arm group label: Phase II
other name: Jakafi
intervention type: Drug
intervention name: Dexamethasone
description: glucocorticoid
arm group label: Phase I
arm group label: Phase II
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Shebli Atrash, MD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
provided document: 