<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/NCT02998047</url>
  </required_header>
  <id_info>
    <org_study_id>Lin-AC225-MM01</org_study_id>
    <nct_id>NCT02998047</nct_id>
  </id_info>
  <brief_title>A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma</brief_title>
  <official_title>A Phase I Study of Lintuzumab-Ac225 in Patients With Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Actinium Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Actinium Pharmaceuticals</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      1. Establish the MTD of Lintuzumab-Ac225 as monotherapy&#xD;
&#xD;
        2. Establish overall response rate (ORR) where ORR = CR + sCR+ VGPR+PR)&#xD;
&#xD;
        3. Confirm the safety profile of the treatment regimen&#xD;
&#xD;
        4. Estimate progression-free survival (PFS) and overall survival&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is a multicenter, open label Phase I trial. Phase 1, dose-escalation : This study&#xD;
      uses a 3+3 design to estimate the maximum tolerated dose (MTD).&#xD;
&#xD;
      There will be 3 escalating dose levels in the trial (0.5 μCi/kg, 1 μCi/kg, and 1.5 μCi/kg).&#xD;
      Each dose can be administered in up to 3-8 cycles providing that the total dose received per&#xD;
      patient does not exceed 4.5 μCi/kg.&#xD;
&#xD;
      De-escalation (decrease dose level to 0.25 μCi/kg) is planned if at the first dose level of&#xD;
      0.5 μCi/kg, after expanding the cohort to a maximum of 6 patients, ≥2 patient have DLTs. At&#xD;
      the dose level of 0.25 μCi/kg, if eligible to continue receiving additional doses of the&#xD;
      study drug, patients will receive up to 8 doses in total, with the total administered&#xD;
      activity being 2 μCi/kg.&#xD;
&#xD;
      The starting dose level will be 0.5 μCi/kg of 225Ac-Lintuzumab administered on day 1 of each&#xD;
      cycle. If this dose level is safe, the second dose level of 1 μCi/kg will be explored. If the&#xD;
      starting dose level results in DLTs in ≥2 patients, the dose level of 0.25 μCi/kg will be&#xD;
      explored.&#xD;
&#xD;
      Subjects will receive the investigational drug as a single infusion at the prescribed dose&#xD;
      level.&#xD;
&#xD;
      Intra cohort dose escalation/ decrease is not allowed.&#xD;
&#xD;
      Minimum three to maximum six patients will be treated at each dose level, and dose escalation&#xD;
      will proceed as follows:&#xD;
&#xD;
        1. Rules for dose escalation are:&#xD;
&#xD;
             1. If 0 of 3 patients have a DLT, escalate to the next dose level (Unless enrolling&#xD;
                patients at the 0.25 µCi/kg dose level)&#xD;
&#xD;
             2. If 1 of 3 patients has a DLT, expand the cohort to 6 patients&#xD;
&#xD;
             3. If ≤1 of 6 patients has a DLT, escalate to the next dose level (Unless enrolling&#xD;
                patients at the 0.25 µCi/kg dose level)&#xD;
&#xD;
             4. If ≥2 of 3 or ≥2 of 6 patients have a DLT, then the previous dose is the MTD&#xD;
                (Unless enrolling patients at the 0.25 µCi/kg level, in which case the trial is&#xD;
                terminated)&#xD;
&#xD;
             5. Three patients will start at the 0.50 uCi/kg dose. The next dose level will be 1.0&#xD;
                µCi/kg and the final dose level will be 1.5 µCi/kg. Dose de-escalation to 0.25&#xD;
                µCi/kg will occur if, at the 0.5 µCi/kg dose, there are ≥2 of 3 or ≥2 of 6 patients&#xD;
                with a DLT.&#xD;
&#xD;
        2. If a patient has not progressed nor had CR by the end of a cycle, the patient can&#xD;
           continue treatment for a maximum of three (1.5 µCi/kg), four (1.0 µCi/kg), or eight&#xD;
           cycles (0.25 µCi/kg and 0.50 µCi/kg).&#xD;
&#xD;
      All patients may receive GCSF support starting on Day 9 if clinically indicated and&#xD;
      continuing until ANC&gt;1,000.&#xD;
&#xD;
      After the dose escalation portion is completed, treat 3 additional patients at the highest&#xD;
      established dose level to confirm MTD and establish that dose level as MTD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Poor recruitment&#xD;
  </why_stopped>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">May 2020</completion_date>
  <primary_completion_date type="Actual">May 2020</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 of Lintuzumab-AC225</measure>
    <time_frame>Through study completion, an average of 2.5 year</time_frame>
    <description>establish the maximum tolerated dose as monotherapy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse events- Treatment Emergent</measure>
    <time_frame>Through study completion, an average of 2.5 year</time_frame>
    <description>safety of lintuzumab-Ac225</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rates (objective response rate, complete response rate, stringent complete response rate, very good partial response rate and partial response rate)</measure>
    <time_frame>Through study completion, an average of 2.5 year</time_frame>
    <description>response rate, including ORR, CR, sCR, VGPR, and PR, PFS, and OS. Efficacy assessments will include serum and urine analyses for paraprotein levels and bone marrow analyses.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Through study completion, an average of 2.5 year</time_frame>
    <description>Progression free survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Through study completion, an average of 2.5 year</time_frame>
    <description>Overall survival</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Refractory Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>IV infusion of Lintuzumab AC225</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Starting dose - 0.5 μCi/Kg IV infusion of Lintuzumab AC225 on Day 1 of each cycle with dose escalation 1 μCi/Kg and 1.5 μCi/Kg or de-escalation to 0.25 μCi/Kg.&#xD;
1 cycle = 28 days, up to 3 to 8 cycles (depending on the cohort).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lintuzumab AC 225</intervention_name>
    <description>Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of multiple myeloma.</description>
    <arm_group_label>IV infusion of Lintuzumab AC225</arm_group_label>
    <other_name>HuM195-Ac225</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria-&#xD;
&#xD;
          -  Confirmed diagnosis of multiple myeloma with measurable disease, as defined by the&#xD;
             presence of M immunoglobulin protein in serum electrophoresis of at least 0.5 g/dL for&#xD;
             IgG or 0.5 g/dL for IgA or urinary excretion of at least 200 mg monoclonal light chain&#xD;
             per 24 hours.&#xD;
&#xD;
          -  Clinical diagnosis of multiple myeloma requiring treatment that has relapsed after or&#xD;
             proven refractory to at least three prior treatment regimens, and in the opinion of&#xD;
             the investigator must not be candidates for any FDA approved drug known to provide&#xD;
             clinical benefit.&#xD;
&#xD;
          -  All acute toxicities from any prior therapy (radiotherapy, chemotherapy, or surgical&#xD;
             procedures) resolved to Grade ≤ 2, NCI CTCAE.&#xD;
&#xD;
          -  Serum potassium and magnesium levels within institutional normal limits. Total serum&#xD;
             calcium or ionized calcium level must be greater than or equal to the lower limit of&#xD;
             normal.&#xD;
&#xD;
          -  Greater than 25% of myeloma plasmocytes from bone marrow must be CD33 positive.&#xD;
&#xD;
          -  Required baseline laboratory data including: White blood cell count, Absolute&#xD;
             neutrophil count (ANC), Platelets, Hemoglobin, Serum creatinine, AST, Creatinine&#xD;
             clearance, Bilirubin , AST and ALT , FEV1/FVC&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2&#xD;
&#xD;
        Exclusion Criteria-&#xD;
&#xD;
          -  Sex and Reproductive Status&#xD;
&#xD;
               -  Women of child bearing potential (WOCBP) who are unwilling or unable to use an&#xD;
                  acceptable method to avoid pregnancy for the entire study period and for at least&#xD;
                  one month (4 weeks) before and for at least six months (6 months) after the last&#xD;
                  dose of study medication.&#xD;
&#xD;
               -  Women who are pregnant or breastfeeding&#xD;
&#xD;
               -  Women with a positive pregnancy test on enrollment or prior to investigational&#xD;
                  product administration.&#xD;
&#xD;
               -  Men whose sexual partners are WOCBP, who are unwilling or unable to use an&#xD;
                  acceptable method to avoid pregnancy for the entire study period and for at least&#xD;
                  six months (6 months) after completion of study medication.&#xD;
&#xD;
          -  Target Disease Exceptions&#xD;
&#xD;
               -  Concurrent therapy with any other investigational agent.&#xD;
&#xD;
               -  Concomitant therapy with bisphosphonates.&#xD;
&#xD;
               -  Pathological fracture within 3 months prior to treatment;&#xD;
&#xD;
               -  Symptomatic spinal cord compression; .&#xD;
&#xD;
          -  Medical History and Concurrent Diseases&#xD;
&#xD;
               -  Treatment with chemotherapy or biological therapy 3 weeks prior to enrollment;&#xD;
&#xD;
               -  Presence of HAHA on screening&#xD;
&#xD;
               -  No bone marrow transplant within 3 months prior to treatment initiation&#xD;
&#xD;
               -  Prior treatment with radiation to cumulative maximum tolerated dose&#xD;
&#xD;
               -  Clinically significant cardiac disease (NYHA Class III or IV) including&#xD;
                  preexisting arrhythmia (such as ventricular tachycardia, ventricular&#xD;
                  fibrillation, or &quot;Torsade de Pointes&quot;)&#xD;
&#xD;
               -  Myocardial infarction, uncontrolled angina within 6 months, congestive heart&#xD;
                  failure, or cardiomyopathy.&#xD;
&#xD;
               -  Abnormal QTc interval prolonged (&gt; 450 msec) after electrolytes have been&#xD;
                  corrected on baseline ECG.&#xD;
&#xD;
               -  Clinically significant pleural effusion in the previous 12 months or current&#xD;
                  ascites.&#xD;
&#xD;
               -  Clinically-significant coagulation or platelet function disorder (eg, known von&#xD;
                  Willebrand's disease).&#xD;
&#xD;
               -  Prior or concurrent malignancy, except for the following:&#xD;
&#xD;
                  i) Adequately treated basal cell or squamous cell skin cancer ii) Cervical&#xD;
                  carcinoma in situ iii) Adequately treated Stage I or II cancer from which the&#xD;
                  subject is currently in complete remission iv) Or any other cancer from which the&#xD;
                  subject has been disease-free for 3 years.&#xD;
&#xD;
          -  Physical and Laboratory Test Findings&#xD;
&#xD;
             o Other severe, acute, or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality, serious uncontrolled medical disorder or active infection that may&#xD;
             increase the risk associated with study participation or study drug administration or&#xD;
             may interfere with the interpretation of study results and, in the judgment of the&#xD;
             investigator, would make the subject inappropriate for this study.&#xD;
&#xD;
          -  Allergies and Adverse Drug Reactions&#xD;
&#xD;
             o Intolerance to humanized monoclonal antibodies&#xD;
&#xD;
          -  Other Exclusion Criteria&#xD;
&#xD;
               -  Prisoners or subjects who are involuntarily incarcerated.&#xD;
&#xD;
               -  Subjects who are compulsorily detained for treatment of either a psychiatric or&#xD;
                  physical (eg, infectious disease) illness.&#xD;
&#xD;
          -  Treatment with radiation within 6 weeks&#xD;
&#xD;
          -  Active serious infections uncontrolled by antibiotics&#xD;
&#xD;
          -  Clinically significant pulmonary disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Avinash Desai, MD</last_name>
    <role>Study Director</role>
    <affiliation>Actinium Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCLA</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Of Kansas Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66205</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>Baylor Scott and White Research Institute, Charles A. Sammons Cancer Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75246</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>December 12, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>February 22, 2022</last_update_submitted>
  <last_update_submitted_qc>February 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 8, 2022</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>Lintuzumab</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/NCT02998047
org study id: Lin-AC225-MM01
nct id: NCT02998047
lead sponsor: 
has dmc: Yes
1. Establish the MTD of Lintuzumab-Ac225 as monotherapy

        2. Establish overall response rate (ORR) where ORR = CR + sCR+ VGPR+PR)

        3. Confirm the safety profile of the treatment regimen

        4. Estimate progression-free survival (PFS) and overall survival
The study is a multicenter, open label Phase I trial. Phase 1, dose-escalation : This study
      uses a 3+3 design to estimate the maximum tolerated dose (MTD).

      There will be 3 escalating dose levels in the trial (0.5 μCi/kg, 1 μCi/kg, and 1.5 μCi/kg).
      Each dose can be administered in up to 3-8 cycles providing that the total dose received per
      patient does not exceed 4.5 μCi/kg.

      De-escalation (decrease dose level to 0.25 μCi/kg) is planned if at the first dose level of
      0.5 μCi/kg, after expanding the cohort to a maximum of 6 patients, ≥2 patient have DLTs. At
      the dose level of 0.25 μCi/kg, if eligible to continue receiving additional doses of the
      study drug, patients will receive up to 8 doses in total, with the total administered
      activity being 2 μCi/kg.

      The starting dose level will be 0.5 μCi/kg of 225Ac-Lintuzumab administered on day 1 of each
      cycle. If this dose level is safe, the second dose level of 1 μCi/kg will be explored. If the
      starting dose level results in DLTs in ≥2 patients, the dose level of 0.25 μCi/kg will be
      explored.

      Subjects will receive the investigational drug as a single infusion at the prescribed dose
      level.

      Intra cohort dose escalation/ decrease is not allowed.

      Minimum three to maximum six patients will be treated at each dose level, and dose escalation
      will proceed as follows:

        1. Rules for dose escalation are:

             1. If 0 of 3 patients have a DLT, escalate to the next dose level (Unless enrolling
                patients at the 0.25 µCi/kg dose level)

             2. If 1 of 3 patients has a DLT, expand the cohort to 6 patients

             3. If ≤1 of 6 patients has a DLT, escalate to the next dose level (Unless enrolling
                patients at the 0.25 µCi/kg dose level)

             4. If ≥2 of 3 or ≥2 of 6 patients have a DLT, then the previous dose is the MTD
                (Unless enrolling patients at the 0.25 µCi/kg level, in which case the trial is
                terminated)

             5. Three patients will start at the 0.50 uCi/kg dose. The next dose level will be 1.0
                µCi/kg and the final dose level will be 1.5 µCi/kg. Dose de-escalation to 0.25
                µCi/kg will occur if, at the 0.5 µCi/kg dose, there are ≥2 of 3 or ≥2 of 6 patients
                with a DLT.

        2. If a patient has not progressed nor had CR by the end of a cycle, the patient can
           continue treatment for a maximum of three (1.5 µCi/kg), four (1.0 µCi/kg), or eight
           cycles (0.25 µCi/kg and 0.50 µCi/kg).

      All patients may receive GCSF support starting on Day 9 if clinically indicated and
      continuing until ANC>1,000.

      After the dose escalation portion is completed, treat 3 additional patients at the highest
      established dose level to confirm MTD and establish that dose level as MTD.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated dose of Lintuzumab-AC225
time frame: Through study completion, an average of 2.5 year
description: establish the maximum tolerated dose as monotherapy
measure: Adverse events- Treatment Emergent
time frame: Through study completion, an average of 2.5 year
description: safety of lintuzumab-Ac225
measure: Response rates (objective response rate, complete response rate, stringent complete response rate, very good partial response rate and partial response rate)
time frame: Through study completion, an average of 2.5 year
description: response rate, including ORR, CR, sCR, VGPR, and PR, PFS, and OS. Efficacy assessments will include serum and urine analyses for paraprotein levels and bone marrow analyses.
measure: Progression free survival
time frame: Through study completion, an average of 2.5 year
description: Progression free survival
measure: Overall survival
time frame: Through study completion, an average of 2.5 year
description: Overall survival
arm group label: IV infusion of Lintuzumab AC225
arm group type: Experimental
description: Starting dose - 0.5 μCi/Kg IV infusion of Lintuzumab AC225 on Day 1 of each cycle with dose escalation 1 μCi/Kg and 1.5 μCi/Kg or de-escalation to 0.25 μCi/Kg.
1 cycle = 28 days, up to 3 to 8 cycles (depending on the cohort).
intervention type: Drug
intervention name: Lintuzumab AC 225
description: Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of multiple myeloma.
arm group label: IV infusion of Lintuzumab AC225
other name: HuM195-Ac225
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Avinash Desai, MD
role: Study Director
affiliation: Actinium Pharmaceuticals
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Lintuzumab
sharing ipd: No