<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/NCT03236428</url>
  </required_header>
  <id_info>
    <org_study_id>17-212</org_study_id>
    <nct_id>NCT03236428</nct_id>
  </id_info>
  <brief_title>Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma</brief_title>
  <official_title>A Phase II Study of the CD38 Antibody Daratumumab in Patients With High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Janssen Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Multiple Myeloma Research Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Blood Cancer Research Partnership</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leukemia and Lymphoma Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</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>
      This research study is studying a drug as a possible treatment for Monoclonal Gammopathy of&#xD;
      Unknown Significance (MGUS) or Smoldering Multiple Myeloma (SMM).&#xD;
&#xD;
      The drug involved in this study is:&#xD;
&#xD;
      -Daratumumab&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase II clinical trial, which tests the effectiveness of an&#xD;
      investigational drug. Preliminary experience suggests that daratumumab may prevent or&#xD;
      postpone SMM from becoming active multiple myeloma. The purpose of this research study is to&#xD;
      determine if the this drug may improve the rate of prevention of multiple myeloma.&#xD;
&#xD;
      Multiple myeloma is a cancer of the plasma cell, which is an important part of the immune&#xD;
      system. Patients with active multiple myeloma generally require treatment. There are&#xD;
      currently no approved therapies for smoldering multiple myeloma or Monoclonal Gammopathy of&#xD;
      Unknown Significance.&#xD;
&#xD;
      Daratumumab is a drug that may kill or stop cancer cells from growing through a variety of&#xD;
      mechanisms by attaching to the CD38 molecule, which is over-expressed in multiple myeloma&#xD;
      cells. This type of drug is called a monoclonal antibody. The FDA (the U.S. Food and Drug&#xD;
      Administration) has not approved Daratumumab for the participant specific disease but it has&#xD;
      been approved for use in active Multiple Myeloma.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 24, 2017</start_date>
  <completion_date type="Anticipated">October 4, 2026</completion_date>
  <primary_completion_date type="Anticipated">October 4, 2026</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The Proportion Of Patients In Deep Response</measure>
    <time_frame>2 years</time_frame>
    <description>To determine the proportion of patients who are in VGPR or better after twenty cycles of therapy with Daratumumab. This will be determined at the time of best overall response. The estimate and the two-sided 90% binomial confidence interval will be provided in the analysis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>2 years</time_frame>
    <description>The objective response rate (partial response or better according to the modified IMWG criteria) and the proportion of patients with a MRD, CR, PR or MR will be reported with 90% exact binominal confidence interval (CI). The exact two-sided 90% CI around response rate will be no wider than 28% with 40 eligible patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>2 years</time_frame>
    <description>To estimate the duration of response (time from objective response to disease progression or death, or date last known progression-free and alive for those who have not progressed or died) the Kaplan-Meier method will be used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response Rate</measure>
    <time_frame>2 years</time_frame>
    <description>The duration of overall CR is progression or death. Patients who have not progressed or died are censored at the date last known progression-free.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>2 years</time_frame>
    <description>The duration of overall response is measured as the time from initiation of first response to first documentation of disease progression or death. Patients who have not progressed or died are censored at the date last known progression-free.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>2 years</time_frame>
    <description>PFS is defined as the time from first-dose to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment Emergent Adverse Events (Safety and Tolerability)</measure>
    <time_frame>2 years</time_frame>
    <description>Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>Monoclonal Gammopathy</condition>
  <condition>Smoldering Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Daratumumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Daratumumab will be administered by IV infusion weekly during cycles 1 and 2 Daratumumab will be administered by IV infusion every other week during cycles 3 through 6 Daratumumab will be administered by IV infusion monthly during cycles 7 through 20</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Daratumumab</intervention_name>
    <description>Daratumumab is a drug that may kill or stop cancer cells from growing through a variety of mechanisms by attaching to the CD38 molecule</description>
    <arm_group_label>Daratumumab</arm_group_label>
    <other_name>Darzalex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Must meet criteria for high-risk MGUS or low-risk smoldering myeloma as described&#xD;
             below:&#xD;
&#xD;
        High-Risk MGUS&#xD;
&#xD;
        Must have &lt;10% plasma cells and &lt;3.0g/dL M-spike and at least 2 of the following 3&#xD;
        criteria:&#xD;
&#xD;
          -  Abnormal free light-chain (FLC) ratio (&lt;0.26 or &gt;1.65)&#xD;
&#xD;
          -  M-protein concentration (≥1.5 g/dL)&#xD;
&#xD;
          -  Non-IgG M protein (including IgA)&#xD;
&#xD;
        Low-Risk Smoldering Multiple Myeloma&#xD;
&#xD;
        Must only present with 1 of the following criterion:&#xD;
&#xD;
          -  Monoclonal Protein ≥ 3 g/dL&#xD;
&#xD;
             ---≥ 10% Bone Marrow Plasma Cells&#xD;
&#xD;
          -  FLC ratio &lt; 0.125 or &gt; 8&#xD;
&#xD;
             -No evidence of CRAB criteria† or new criteria of active MM which including the&#xD;
             following:&#xD;
&#xD;
               -  Increased calcium levels (corrected serum calcium &gt;0.25 mmol/dL above the upper&#xD;
                  limit of normal or &gt;0.275 mmol/dL)&#xD;
&#xD;
               -  Renal insufficiency (attributable to myeloma)&#xD;
&#xD;
               -  Anemia (Hb 2 g/dL below the lower limit of normal or &lt;10 g/dL)&#xD;
&#xD;
               -  Bone lesions (lytic lesions or generalized osteoporosis with compression&#xD;
                  fractures)&#xD;
&#xD;
               -  No evidence of the following new criteria for active MM including the following:&#xD;
                  Bone marrow plasma cells &gt;60%, Serum involved/uninvolved FLC ratio ≥100, and MRI&#xD;
                  with more than one focal lesion&#xD;
&#xD;
                    -  Participants with CRAB criteria that are attributable to conditions other&#xD;
                       than the disease under study may be eligible&#xD;
&#xD;
                    -  ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)&#xD;
&#xD;
                    -  The following laboratory values obtained ≤ 21 days prior to registration:&#xD;
&#xD;
               -  ANC ≥ 1000/uL&#xD;
&#xD;
               -  PLT ≥ 50,000/uL&#xD;
&#xD;
               -  Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal&#xD;
                  patient is eligible.)&#xD;
&#xD;
               -  AST ≤ 3 x institutional upper limit of normal (ULN)&#xD;
&#xD;
               -  ALT ≤ 3 x institutional upper limit of normal (ULN)&#xD;
&#xD;
               -  Creatinine ≤ 2 mg/dL or Creatinine Clearance ≥ 40 mL/min&#xD;
&#xD;
                    -  Ability to understand and the willingness to sign an informed consent before&#xD;
                       performance of any study-related procedure not part of normal medical care,&#xD;
                       with the understanding that consent may be withdrawn by the subject at any&#xD;
                       time without prejudice to future medical care.&#xD;
&#xD;
                    -  Female patients who are postmenopausal for at least 1 year before the&#xD;
                       screening visit or are surgically sterile are eligible. Females of&#xD;
                       childbearing potential (as defined below) may also be eligible but must have&#xD;
                       a negative serum or urine pregnancy test with a sensitivity of at least 25&#xD;
                       mIU/mL within 21 days of registration.&#xD;
&#xD;
               -  A female of childbearing potential is a sexually mature female who:&#xD;
&#xD;
          -  Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral&#xD;
             oophorectomy (the surgical removal of both ovaries)&#xD;
&#xD;
        OR&#xD;
&#xD;
        ---Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule&#xD;
        out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any&#xD;
        time during the preceding 24 consecutive months)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any prior therapy for symptomatic Multiple Myeloma or smoldering Multiple Myeloma&#xD;
             should also be excluded, including prior use of IMIDs, proteasome inhibitors, or CD138&#xD;
             inhibitors. Prior therapy for smoldering Multiple Myeloma with agents that are not&#xD;
             therapeutically active against MM is not an exclusion criterion.&#xD;
&#xD;
          -  Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy&#xD;
             considered investigational. Prior therapy with bisphosphonates is allowed. Prior&#xD;
             radiation therapy to a solitary plasmacytoma is allowed.&#xD;
&#xD;
          -  Concurrent exposure to any commercially available agents known to be active against&#xD;
             SMM and MM.&#xD;
&#xD;
          -  Serious medical or psychiatric illness likely to interfere with participation in this&#xD;
             clinical study.&#xD;
&#xD;
          -  Diagnosed or treated for another malignancy within 2 years of enrollment, with the&#xD;
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of&#xD;
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.&#xD;
&#xD;
          -  Subject has known chronic obstructive pulmonary disease (COPD) with a Forced&#xD;
             Expiratory Volume in 1 second (FEV1) &lt; 50% of predicted normal.&#xD;
&#xD;
          -  Note that FEV1 testing is required for patients suspected of having COPD and subjects&#xD;
             must be excluded if FEV1 &lt;50% of predicted normal.&#xD;
&#xD;
               -  Subject has known moderate or severe persistent asthma within the past 2 years or&#xD;
                  currently has uncontrolled asthma of any classification.&#xD;
&#xD;
               -  Subjects who currently have controlled intermittent asthma or controlled mild&#xD;
                  persistent asthma are allowed in the study&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             uncontrollable cardiac arrhythmia, or psychiatric illness/social situations that would&#xD;
             limit compliance with study requirements.&#xD;
&#xD;
          -  Pregnant or nursing women will be excluded from the study.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to Daratumumab.&#xD;
&#xD;
          -  Known seropositive for or active viral infection with human immunodeficiency virus&#xD;
             (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are&#xD;
             seropositive because of hepatitis B virus vaccine are eligible. Patients who are&#xD;
             positive for hepatitis B core antibody or hepatitis B surface antigen must have a&#xD;
             negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR&#xD;
             positive will be excluded.&#xD;
&#xD;
          -  Major surgery within 4 weeks before enrollment.&#xD;
&#xD;
          -  Subject is known or suspected of not being able to comply with the study protocol (eg,&#xD;
             because of alcoholism, drug dependency, or psychological disorder). Subject has any&#xD;
             condition for which, in the opinion of the investigator, participation would not be in&#xD;
             the best interest of the subject (eg, compromise the well-being) or that could&#xD;
             prevent, limit, or confound the protocol-specified assessments.&#xD;
&#xD;
          -  Vaccination with live attenuated vaccines within 4 weeks of first study agent&#xD;
             administration&#xD;
&#xD;
          -  Subject has clinically significant cardiac disease, including significant ischemic&#xD;
             coronary disease, congestive heart failure (New York Heart Association [NYHA] Class&#xD;
             III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 6&#xD;
             months before randomization, a history of additional risk factors for torsades de&#xD;
             pointes (eg, electrolyte abnormalities, family history of Long QT Syndrome), or a&#xD;
             family history of sudden cardiac death before age 40.&#xD;
&#xD;
          -  Participation in other therapeutic clinical trials, including those with other&#xD;
             investigational agents not included in this trial, within 30 days of the start of this&#xD;
             trial and throughout the duration of this trial&#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>Irene Ghobrial, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Pacific Cancer Care</name>
      <address>
        <city>Monterey</city>
        <state>California</state>
        <zip>93940</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Colorado Blood Cancer Institute</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80218</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02214</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>
    <facility>
      <name>Karmanos Cancer Insitute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 11, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>July 30, 2023</last_update_submitted>
  <last_update_submitted_qc>July 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Irene Ghobrial, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Smoldering Multiple Myeloma</keyword>
  <keyword>Monoclonal Gammopathy</keyword>
  <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>
    <mesh_term>Smoldering Multiple Myeloma</mesh_term>
    <mesh_term>Paraproteinemias</mesh_term>
    <mesh_term>Monoclonal Gammopathy of Undetermined Significance</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Daratumumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03236428
org study id: 17-212
nct id: NCT03236428
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a drug as a possible treatment for Monoclonal Gammopathy of
      Unknown Significance (MGUS) or Smoldering Multiple Myeloma (SMM).

      The drug involved in this study is:

      -Daratumumab
This research study is a Phase II clinical trial, which tests the effectiveness of an
      investigational drug. Preliminary experience suggests that daratumumab may prevent or
      postpone SMM from becoming active multiple myeloma. The purpose of this research study is to
      determine if the this drug may improve the rate of prevention of multiple myeloma.

      Multiple myeloma is a cancer of the plasma cell, which is an important part of the immune
      system. Patients with active multiple myeloma generally require treatment. There are
      currently no approved therapies for smoldering multiple myeloma or Monoclonal Gammopathy of
      Unknown Significance.

      Daratumumab is a drug that may kill or stop cancer cells from growing through a variety of
      mechanisms by attaching to the CD38 molecule, which is over-expressed in multiple myeloma
      cells. This type of drug is called a monoclonal antibody. The FDA (the U.S. Food and Drug
      Administration) has not approved Daratumumab for the participant specific disease but it has
      been approved for use in active Multiple Myeloma.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The Proportion Of Patients In Deep Response
time frame: 2 years
description: To determine the proportion of patients who are in VGPR or better after twenty cycles of therapy with Daratumumab. This will be determined at the time of best overall response. The estimate and the two-sided 90% binomial confidence interval will be provided in the analysis.
measure: Objective Response Rate
time frame: 2 years
description: The objective response rate (partial response or better according to the modified IMWG criteria) and the proportion of patients with a MRD, CR, PR or MR will be reported with 90% exact binominal confidence interval (CI). The exact two-sided 90% CI around response rate will be no wider than 28% with 40 eligible patients.
measure: Duration of Response
time frame: 2 years
description: To estimate the duration of response (time from objective response to disease progression or death, or date last known progression-free and alive for those who have not progressed or died) the Kaplan-Meier method will be used.
measure: Complete Response Rate
time frame: 2 years
description: The duration of overall CR is progression or death. Patients who have not progressed or died are censored at the date last known progression-free.
measure: Overall Response Rate
time frame: 2 years
description: The duration of overall response is measured as the time from initiation of first response to first documentation of disease progression or death. Patients who have not progressed or died are censored at the date last known progression-free.
measure: Progression Free Survival
time frame: 2 years
description: PFS is defined as the time from first-dose to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free.
measure: Incidence of Treatment Emergent Adverse Events (Safety and Tolerability)
time frame: 2 years
description: Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.
arm group label: Daratumumab
arm group type: Experimental
description: Daratumumab will be administered by IV infusion weekly during cycles 1 and 2 Daratumumab will be administered by IV infusion every other week during cycles 3 through 6 Daratumumab will be administered by IV infusion monthly during cycles 7 through 20
intervention type: Drug
intervention name: Daratumumab
description: Daratumumab is a drug that may kill or stop cancer cells from growing through a variety of mechanisms by attaching to the CD38 molecule
arm group label: Daratumumab
other name: Darzalex
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Irene Ghobrial, MD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Irene Ghobrial, MD
investigator title: Principal Investigator
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Smoldering Multiple Myeloma
mesh term: Paraproteinemias
mesh term: Monoclonal Gammopathy of Undetermined Significance
mesh term: Daratumumab
sharing ipd: No