<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/NCT03019666</url>
  </required_header>
  <id_info>
    <org_study_id>2015LS057</org_study_id>
    <secondary_id>MT2015-46</secondary_id>
    <nct_id>NCT03019666</nct_id>
  </id_info>
  <brief_title>Ph I Trial of NAM NK Cells and IL-2 for Adult Pts With MM and NHL</brief_title>
  <official_title>A Phase I Trial Testing NAM Expanded Haploidentical or Mismatched Related Donor Natural Killer (NK) Cells Followed by a Short Course of IL-2 for the Treatment of Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Masonic Cancer Center, University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Masonic Cancer Center, University of Minnesota</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 is a phase I trial with pilot expansion of HLA-haploidentical or HLA-mismatched related&#xD;
      donor nicotinamide expanded-natural killer (NAM-NK) cell based therapy for patients with&#xD;
      relapsed or refractory multiple myeloma (MM) or relapsed/refractory CD20-positive non-Hodgkin&#xD;
      lymphoma (NHL). The primary endpoint of the study is to determine the maximum tolerated dose&#xD;
      (MTD) of NAM-NK cells while maintaining safety.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 18, 2017</start_date>
  <completion_date type="Actual">August 15, 2022</completion_date>
  <primary_completion_date type="Actual">August 15, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of any grade 4 or greater suspected adverse reaction</measure>
    <time_frame>24 hours post infusion</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Occurrence of Grade III or IV acute graft-versus-host disease (aGVHD)</measure>
    <time_frame>28 days post infusion</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Occurrence of treatment related mortality (TRM)</measure>
    <time_frame>2 months post infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of disease response</measure>
    <time_frame>28 days post infusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients alive without progression</measure>
    <time_frame>1 year post infusion</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">39</enrollment>
  <condition>Multiple Myeloma</condition>
  <condition>Non-Hodgkin Lymphoma</condition>
  <condition>Diffuse Large B Cell Lymphoma</condition>
  <condition>Mantle-Cell Lymphoma</condition>
  <condition>Follicular Lymphoma</condition>
  <condition>Indolent B Cell Lymphoma</condition>
  <condition>Primary Mediastinal Lymphoma</condition>
  <condition>Lymphoplasmacytic Lymphoma</condition>
  <arm_group>
    <arm_group_label>Multiple Myeloma</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, patients receive expanded NAM-NK cells followed by a short course of interleukin-2 (IL-2) to facilitate natural killer cell survival and expansion in vivo. Monoclonal antibodies and elotuzumab for Multiple Myeloma patients, will be administered prior to and after the natural killer cell infusion(s) to facilitate tumor targeting and antibody dependent cellular cytotoxicity (ADCC).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-Hodgkin Lymphoma</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, patients receive expanded NAM-NK cells followed by a short course of interleukin-2 (IL-2) to facilitate natural killer cell survival and expansion in vivo. Monoclonal antibodies and rituximab for Non-Hodgkin Lymphoma patients, will be administered prior to and after the natural killer cell infusion(s) to facilitate tumor targeting and antibody dependent cellular cytotoxicity (ADCC).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nicotinamide Expanded Haploidentical or Mismatched Related Donor Natural Killer Cells</intervention_name>
    <description>Cyclophosphamide 40 mg/kg x 1 day on Day -5&#xD;
Fludarabine 25 mg/m^2 x 3 days (Day -5, Day -4, day-3)</description>
    <arm_group_label>Multiple Myeloma</arm_group_label>
    <arm_group_label>Non-Hodgkin Lymphoma</arm_group_label>
    <other_name>NAM-NK</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patient Inclusion Criteria:&#xD;
&#xD;
          -  ≥18 to ≤70 years of age&#xD;
&#xD;
          -  Meets one of the following disease criteria:&#xD;
&#xD;
               -  Multiple Myeloma (MM) meeting one of the following:&#xD;
&#xD;
                    -  relapsed/refractory disease after two lines of therapies, including a&#xD;
                       proteasome inhibitor (bortezomib, carfilzomib or ixazomib) and an&#xD;
                       immunomodulatory drug (thalidomide, lenalidomide or pomalidomide)&#xD;
&#xD;
                    -  relapsed disease between 2-18 months of 1st autologous stem cell&#xD;
                       transplantation,&#xD;
&#xD;
                    -  relapsed disease at least 4 months after allogeneic stem cell&#xD;
                       transplantation with no evidence of active graft versus host disease and no&#xD;
                       availability of donor lymphocyte infusion&#xD;
&#xD;
                    -  measurable disease defined as serum IgG, A, M M-protein ≥ 0.5g/dL or serum&#xD;
                       IgD M-protein ≥ 0.5 g/dL, or urine M-protein ≥ 200 mg/24 hours&#xD;
&#xD;
                    -  at least 4 weeks since plasmapheresis&#xD;
&#xD;
                    -  at least 3 days between last corticosteroids and study treatment start&#xD;
&#xD;
               -  CD20-positive B-cell Non-Hodgkin Lymphoma (NHL)&#xD;
&#xD;
                    -  CD20 expression confirmed by flow cytometry or immunohistochemistry and&#xD;
                       meeting one or more of the following:&#xD;
&#xD;
                         -  evidence of relapsed/refractory disease that has failed conventional&#xD;
                            therapy and failed/not eligible/refused studies of a higher priority,&#xD;
&#xD;
                         -  relapsed disease at least 60 days after autologous stem cell&#xD;
                            transplantation&#xD;
&#xD;
                         -  relapsed disease at least 4 months after allogeneic stem cell&#xD;
                            transplantation with no evidence of active graft versus host disease&#xD;
                            and no availability of donor lymphocyte infusion&#xD;
&#xD;
                         -  has measurable disease &gt;1.5 cm in diameter&#xD;
&#xD;
          -  HLA-haploidentical or mismatched related donor (aged 12 to 70 years) with&#xD;
             donor/recipient match based on a minimum of intermediate resolution DNA based Class I&#xD;
             typing of the A and B locus (at least 2/4 class I allele) and absence of recipient&#xD;
             anti HLA antibodies against selected donor&#xD;
&#xD;
          -  Karnofsky Performance Status ≥ 60% - appendix III&#xD;
&#xD;
          -  Adequate organ function within 14 days of study registration (30 days for pulmonary&#xD;
             and cardiac assessments) defined as:&#xD;
&#xD;
               -  Bone Marrow: Total white blood cell (WBC) count ≥ 3000/μL, absolute neutrophil&#xD;
                  count (ANC) ≥ 1000/μL, platelet count ≥ 75,000/μL and hemoglobin ≥ 8.0 g/dL - may&#xD;
                  be waived if abnormalities are due to disease related bone marrow involvement&#xD;
&#xD;
               -  Renal: creatinine ≤ 1.5 mg/dL or creatinine clearance ≥40mL/min using&#xD;
                  Cockcroft-Gault formula&#xD;
&#xD;
               -  Hepatic: ALT or AST ≤ 3 x upper limit of institutional normal (ULN), total&#xD;
                  bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
               -  Pulmonary Function: oxygen saturation ≥ 90% on room air. If symptomatic or prior&#xD;
                  known impairment, pulmonary function ≥ 50% corrected DLCO and FEV1 is required&#xD;
&#xD;
               -  Cardiac Function: LVEF ≥ 40%, no uncontrolled angina, severe uncontrolled&#xD;
                  ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or&#xD;
                  active conduction system abnormalities&#xD;
&#xD;
               -  Calcium (MM only): Corrected calcium &lt; 11.5 mg/dL within 2 weeks prior to&#xD;
                  enrollment&#xD;
&#xD;
          -  Able to be off prednisone or other immunosuppressive medications for at least 3 days&#xD;
             prior to NAM-NK cell infusion (excluding preparative regimen pre-medications)&#xD;
&#xD;
          -  Sexually active females of child bearing potential and males with partners of child&#xD;
             bearing potential must agree to use effective contraception during therapy and for 4&#xD;
             months after completion of therapy&#xD;
&#xD;
          -  Must have recovered from acute effects of prior therapy - at least 2 weeks should have&#xD;
             elapsed since the last dose of chemotherapy&#xD;
&#xD;
          -  Voluntary written consent&#xD;
&#xD;
        Patient Exclusion Criteria:&#xD;
&#xD;
          -  Active, untreated CNS involvement&#xD;
&#xD;
          -  Chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), or high-grade&#xD;
             lymphomas (Burkittt's lymphoma/Lymphoblastic lymphoma)&#xD;
&#xD;
          -  Pregnant or breastfeeding - The agents used in this study include those that fall&#xD;
             under Pregnancy Category D - have known teratogenic potential. For elotuzumab arm:&#xD;
             Women of child bearing potential must have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 days of study&#xD;
             treatment start (24 hours prior to the start of elotuzumab)&#xD;
&#xD;
          -  Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval&#xD;
             greater than 500 milliseconds)&#xD;
&#xD;
          -  Class II or greater New York Heart Association Functional Classification criteria&#xD;
             (appendix III) or serious cardiac arrhythmias likely to increase the risk of cardiac&#xD;
             complications of cytokine therapy (e.g. ventricular tachycardia, frequent ventricular&#xD;
             ectopy, or supraventricular tachyarrhythmia requiring chronic therapy)&#xD;
&#xD;
          -  Active autoimmune disease requiring immunosuppressive therapy&#xD;
&#xD;
          -  History of severe asthma, presently on chronic medications (a history of mild asthma&#xD;
             requiring inhaled steroids only is eligible)&#xD;
&#xD;
          -  New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan&#xD;
             unless cleared for study by Pulmonary. Infiltrates attributed to infection must be&#xD;
             stable/improving (with associated clinical improvement) after 1 week of appropriate&#xD;
             therapy (4 weeks for presumed or documented fungal infections).&#xD;
&#xD;
          -  Active uncontrolled bacterial, fungal, or viral infections - all prior infections must&#xD;
             have resolved following optimal therapy&#xD;
&#xD;
          -  Known hypersensitivity to any of the study agents used&#xD;
&#xD;
          -  For MM patients only:&#xD;
&#xD;
               -  Prior radiotherapy within 2 weeks prior to the administration of study drug&quot;&#xD;
&#xD;
               -  Surgery within 4 weeks&#xD;
&#xD;
               -  Chemo within 3 weeks (6 weeks for melphalan, or monoclonal antibodies)&#xD;
&#xD;
          -  Received investigational drugs within the 14 days before 1st dose of study drug&#xD;
&#xD;
          -  High titer of donor specific anti-HLA antibodies (MFI &gt;1000)&#xD;
&#xD;
        DONOR INCLUSION CRITERIA:&#xD;
&#xD;
          -  HLA-haploidentical or mismatched related donor/recipient match based on a minimum of&#xD;
             intermediate resolution DNA based Class I typing of the A and B locus (at least 2/4&#xD;
             class I allele) and absence of recipient anti HLA antibodies&#xD;
&#xD;
          -  12 to 70 years of age - Priority should be given to age (&lt;35 years), followed by HLA&#xD;
             matching (haploidentical and if not available then fully mismatched donor).&#xD;
&#xD;
          -  At least 40 kilogram body weight&#xD;
&#xD;
          -  In general good health as determined by the evaluating medical provider&#xD;
&#xD;
          -  Adequate organ function defined as:&#xD;
&#xD;
               -  Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit of&#xD;
                  normal range of test (gender based for hemoglobin),&#xD;
&#xD;
               -  Hepatic: ALT &lt; 2 x upper limit of normal,&#xD;
&#xD;
               -  Renal: serum creatinine &lt; 1.8 mg/dl&#xD;
&#xD;
          -  Performance of a donor infectious disease screen panel including CMV Antibody,&#xD;
             Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV PCR,&#xD;
             HIV ½ Antibody, HTLVA ½ Antibody, Rapid Plasma (RPR) Treponema , Trypanosoma Cruzi (T.&#xD;
             Cruzi), HCV by NAT, HIV by NAT and WNV (West Nile Virus) by NAT or per current panel -&#xD;
             must be negative for HIV and active hepatitis B&#xD;
&#xD;
          -  Not pregnant - females of childbearing potential must have a negative pregnancy test&#xD;
             within 7 days of apheresis&#xD;
&#xD;
          -  Able and willing to undergo apheresis&#xD;
&#xD;
          -  Voluntary written consent (using assent form if donor &lt; 18 years of age)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Veronika Bachanova, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Masonic Cancer Center, University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MM</keyword>
  <keyword>NHL</keyword>
  <keyword>NK Cell</keyword>
  <keyword>NK Cells</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
    <mesh_term>Waldenstrom Macroglobulinemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Niacinamide</mesh_term>
    <mesh_term>Niacin</mesh_term>
    <mesh_term>Nicotinic Acids</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/NCT03019666
org study id: 2015LS057
secondary id: MT2015-46
nct id: NCT03019666
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase I trial with pilot expansion of HLA-haploidentical or HLA-mismatched related
      donor nicotinamide expanded-natural killer (NAM-NK) cell based therapy for patients with
      relapsed or refractory multiple myeloma (MM) or relapsed/refractory CD20-positive non-Hodgkin
      lymphoma (NHL). The primary endpoint of the study is to determine the maximum tolerated dose
      (MTD) of NAM-NK cells while maintaining safety.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of any grade 4 or greater suspected adverse reaction
time frame: 24 hours post infusion
measure: Occurrence of Grade III or IV acute graft-versus-host disease (aGVHD)
time frame: 28 days post infusion
measure: Occurrence of treatment related mortality (TRM)
time frame: 2 months post infusion
measure: Occurrence of disease response
time frame: 28 days post infusion
measure: Number of patients alive without progression
time frame: 1 year post infusion
arm group label: Multiple Myeloma
arm group type: Experimental
description: After a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, patients receive expanded NAM-NK cells followed by a short course of interleukin-2 (IL-2) to facilitate natural killer cell survival and expansion in vivo. Monoclonal antibodies and elotuzumab for Multiple Myeloma patients, will be administered prior to and after the natural killer cell infusion(s) to facilitate tumor targeting and antibody dependent cellular cytotoxicity (ADCC).
arm group label: Non-Hodgkin Lymphoma
arm group type: Experimental
description: After a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, patients receive expanded NAM-NK cells followed by a short course of interleukin-2 (IL-2) to facilitate natural killer cell survival and expansion in vivo. Monoclonal antibodies and rituximab for Non-Hodgkin Lymphoma patients, will be administered prior to and after the natural killer cell infusion(s) to facilitate tumor targeting and antibody dependent cellular cytotoxicity (ADCC).
intervention type: Biological
intervention name: Nicotinamide Expanded Haploidentical or Mismatched Related Donor Natural Killer Cells
description: Cyclophosphamide 40 mg/kg x 1 day on Day -5
Fludarabine 25 mg/m^2 x 3 days (Day -5, Day -4, day-3)
arm group label: Multiple Myeloma
arm group label: Non-Hodgkin Lymphoma
other name: NAM-NK
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Veronika Bachanova, MD, PhD
role: Principal Investigator
affiliation: University of Minnesota
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Lymphoma, Non-Hodgkin
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Waldenstrom Macroglobulinemia
mesh term: Niacinamide
mesh term: Niacin
mesh term: Nicotinic Acids