<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/NCT01670994</url>
  </required_header>
  <id_info>
    <org_study_id>CA-ALT-801-01-11</org_study_id>
    <nct_id>NCT01670994</nct_id>
  </id_info>
  <brief_title>QUILT-3.020: A Study of ALT-801 in Patients With Relapsed or Refractory Multiple Myeloma</brief_title>
  <official_title>A Study of ALT-801 in Patients With Relapsed or Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Altor BioScience</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Altor BioScience</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase Ib/II, open-label, multi-center and competitive enrollment study of ALT-801&#xD;
      in patients who have relapsed or refractory multiple myeloma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multiple Myeloma (MM) is a plasma cell malignancy that makes up 1% of all cancers and 10% of&#xD;
      hematologic neoplasma, and is the second most commonly diagnosed hematologic malignancy.&#xD;
      There are an estimated 20,520 new cases of MM and 10,610 deaths due to MM in the United&#xD;
      States. Historically, standard first-line therapy for MM consisted of combination therapy&#xD;
      with an alkylating agent, such as melphalan and prednisone. Response rates with such&#xD;
      combination therapy are approximately 50%, but five-year survival rates remain low at 33%.&#xD;
      For younger patients, debulking chemotherapy followed by autologous stem cell transplant&#xD;
      (ASCT) with melphalan is the treatment of choice to increase the potential for a sustained&#xD;
      durable remission. However, a large percentage of patients diagnosed with MM are not suitable&#xD;
      candidates for ASCT because of age or comorbidities. The approach to MM treatment has&#xD;
      undergone a radical transformation over the past decade with the introduction of the&#xD;
      proteasome inhibitor, bortezomib, and immunomodulatory drugs (ImiDs), thalidomide or&#xD;
      lenalidomide. Despite some advances in the treatment of MM, the disease remains incurable due&#xD;
      to the persistence of minimal residual disease. Thus, novel modalities complementing or&#xD;
      improving current treatment options are needed.&#xD;
&#xD;
      There is ample evidence that immunomodulatory drugs are effective against myeloma.&#xD;
      Lenalidomide and thalidomide have been shown to stimulate T cells in the presence of antigen&#xD;
      presenting cells via costimulatory pathway. Also, modulation of NK cell function has been&#xD;
      associated with anti-tumor activity observed in MM patients treated with lenalidomide. It has&#xD;
      been demonstrated that NK cells exhibit potent anti-MM activity following IL-2&#xD;
      administration, and ex vivo IL-2-activated and intravenously administered NK cells prolong&#xD;
      survival in MM-bearing mice. Thus further demonstrating the role and importance of NK cells&#xD;
      in the treatment of MM. Taken together, these data suggest that the use of a potent&#xD;
      immunotherapeutic is an attractive approach to provide durable immune responses to or even&#xD;
      potentially curing patients with MM.&#xD;
&#xD;
      Additionally, immunotherapy is a well-established approach for treating other cancer types.&#xD;
      One strategy that has received attention is treatment with cytokines such as IL-2 to enhance&#xD;
      anti-tumor immunity. Unfortunately, the considerable toxicity associated with this treatment&#xD;
      makes it difficult to achieve an effective dose at the site of the tumor and limits the&#xD;
      population that can be treated. Thus, there is a critical need for innovative strategies that&#xD;
      enhance the effects of IL-2, reduce its toxicity without compromising clinical benefit,&#xD;
      provide a more convenient dosing regimen, and treat other diagnoses including MM.&#xD;
&#xD;
      Altor Bioscience Corp. has developed a tumor-targeted IL-2 fusion protein, ALT-801,&#xD;
      comprising human recombinant IL-2 genetically linked to a TCR domain capable of binding a&#xD;
      tumor associated human p53 peptide presented in the context of HLA-A2. Animal studies have&#xD;
      indicated that ALT-801 could be useful in a therapeutic approach for activating immune&#xD;
      effector cells, bringing together effector cells and tumor cells and stimulating immune&#xD;
      cell-mediated activity. In addition, in various mouse xenograft models, this molecule&#xD;
      increases the efficacy but lessens the side effects of high-dose rhIL-2.&#xD;
&#xD;
      Moreover, human studies indicate ALT-801 given daily for two 4-day cycles at the MTD (i.e.&#xD;
      0.04 mg/kg) is well tolerated, exhibits a favorable PK drug profile, exhibits immunological&#xD;
      potency in humans, provides evidence of clinical benefit in cancer patients and a higher&#xD;
      dosing level (0.08 mg/kg) of ALT-801 in a monotherapy treatment was associated with better&#xD;
      clinical benefit in patients with metastatic cancer.&#xD;
&#xD;
      Also, the results of pre-clinical studies in various tumors with diverse origins and relevant&#xD;
      MM models indicates ALT-801 is a potent immunostimulatory molecule capable increasing NK cell&#xD;
      and CD8+ T cell numbers and percentages in myeloma tumor-bearing mice, ALT-801 in single or&#xD;
      multidose treatment regimens exhibits potent anti-tumor activity and induced long-lasting&#xD;
      immunologic memory against well-established myeloma cells in the immunocompetent mouse model,&#xD;
      suggesting the potential of curative treatment for patients with MM.&#xD;
&#xD;
      Based on these findings, ALT-801 as a single-agent therapeutic may provide durable clinical&#xD;
      benefit to patients with relapsed or relapsed and refractory MM. In this study, we will&#xD;
      establish the tolerable dose level of ALT-801 in MM patients, and estimate the anti-tumor&#xD;
      activity and characterize the pharmacokinetic and immunogenicity profile of ALT-801 in such&#xD;
      patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Patient population did not benefit from single agent treatment.&#xD;
  </why_stopped>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">September 2015</completion_date>
  <primary_completion_date type="Actual">August 2013</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>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>Safety Profile</measure>
    <time_frame>7 weeks</time_frame>
    <description>For phase Ib &amp; II&#xD;
Number and severity of treatment related AEs that occur or worsen after the first dose of study treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tolerability and MTD designation</measure>
    <time_frame>7 weeks</time_frame>
    <description>For phase Ib only&#xD;
To evaluate the tolerability and to determine the maximum tolerated dose (MTD) level.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit</measure>
    <time_frame>12 weeks</time_frame>
    <description>For phase Ib and II&#xD;
Number of participants with an objective response, which includes, a complete response, a partial response or a stable disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunogenicity and Pharmacokinetics</measure>
    <time_frame>8 weeks</time_frame>
    <description>For phase Ib and II&#xD;
Measures the anti-ALT-801 and IL-2 neutralizing effects&#xD;
Area under the plasma concentration-time curve from time zero to infinity (AUC) and the half-life of ALT-801</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor Typing</measure>
    <time_frame>1 month</time_frame>
    <description>For phase Ib and II&#xD;
To assess the relationship between tumor presentation of HLA-A*0201/p53 aa 264-272 complex and the safety, immune response and clinical benefit of study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall and progression-free survival</measure>
    <time_frame>3 years</time_frame>
    <description>For phase Ib and II&#xD;
All enrolled patients will be assessed every 3 months during year 1 and then every 6 months during years 2 and 3 from the start of study treatment to determine their overall and progression-free survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>up to 3 years</time_frame>
    <description>All enrolled patients will be assessed every 3 months during year 1 and then every 6 months during years 2 and 3 from the start of study treatment to determine their duration of response</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Relapsed or Refractory Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>ALT-801</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ALT-801</intervention_name>
    <description>Intravenous infusion; 2 treatment cycles: on day 1, 3, 8, and 15 of each cycle</description>
    <arm_group_label>ALT-801</arm_group_label>
    <other_name>c264scTCR-IL2</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        ENTRY CRITERIA:&#xD;
&#xD;
        DISEASE CHARATERISTICS:&#xD;
&#xD;
          -  Confirmed diagnosis of relapsed/refractory multiple myeloma after treatment with at&#xD;
             least two different previous regimens.&#xD;
&#xD;
               -  Refractory disease is defined as progressive disease while on therapy or&#xD;
                  progression within 60 days of therapy.&#xD;
&#xD;
               -  Progressive disease is defined by a 25% increase from the lowest response value&#xD;
                  in specified tests.&#xD;
&#xD;
          -  Measurable disease as defined by at least one of the following:&#xD;
&#xD;
               -  Serum M-protein ≥ 1g/dL (for IgG, IgM) or 0.5 g/dL (for IgA)&#xD;
&#xD;
               -  Urine M-protein ≥ 200mg/24hours&#xD;
&#xD;
               -  Serum free light chains ≥ 10 mg/dL and abnormal kappa/lambda ratio&#xD;
&#xD;
        PRIOR/CONCURRENT THERAPY:&#xD;
&#xD;
          -  No anti-myeloma treatments within 28 days before the start of study treatment.&#xD;
&#xD;
          -  Must have recovered from side effects of prior treatments.&#xD;
&#xD;
        PATIENT CHARACTERISTICS:&#xD;
&#xD;
        Age&#xD;
&#xD;
        • ≥ 18 years&#xD;
&#xD;
        Performance Status&#xD;
&#xD;
        • ECOG 0, 1, or 2&#xD;
&#xD;
        Bone Marrow Reserve&#xD;
&#xD;
          -  Absolute neutrophil count (AGC/ANC) ≥ 1,000/uL&#xD;
&#xD;
          -  Platelets ≥ 30,000/uL&#xD;
&#xD;
          -  Hemoglobin ≥ 8g/dL&#xD;
&#xD;
        Renal Function&#xD;
&#xD;
        • Glomerular Filtration Rate (GFR) &gt; 45mL/min/1.73m^2&#xD;
&#xD;
        Hepatic Function&#xD;
&#xD;
          -  Total bilirubin ≤ 2.0 X ULN&#xD;
&#xD;
          -  AST, ALT, ALP ≤ 3.0 X ULN, or ≤ 5.0 X ULN (if liver metastases exist)&#xD;
&#xD;
        Cardiovascular&#xD;
&#xD;
          -  No congestive heart failure &lt; 6 months&#xD;
&#xD;
          -  No unstable angina pectoris &lt; 6 months&#xD;
&#xD;
          -  No myocardial infarction &lt; 6 months&#xD;
&#xD;
          -  No history of ventricular arrhythmias&#xD;
&#xD;
          -  No history of supraventricular arrhythmias&#xD;
&#xD;
          -  No NYHA Class &gt; II CHF&#xD;
&#xD;
          -  Normal Transthoracic Echocardiogram (TTE) is required for patients with history of EKG&#xD;
             abnormalities, CHF, coronary artery disease or other cardiac disease, or with a&#xD;
             history of having received adriamycin or doxorubicin&#xD;
&#xD;
          -  Patients with a left ventricular ejection fraction (LVEF) of less than 50% will be&#xD;
             excluded from study entry&#xD;
&#xD;
        Pulmonary&#xD;
&#xD;
        • Normal clinical assessment of pulmonary function&#xD;
&#xD;
        Other&#xD;
&#xD;
          -  Negative serum pregnancy test if female and of childbearing potential&#xD;
&#xD;
          -  Women who are not pregnant or nursing&#xD;
&#xD;
          -  Subjects, both females and males, with reproductive potential must agree to use&#xD;
             effective contraceptive measures for the duration of the study&#xD;
&#xD;
          -  No known autoimmune disease other than corrected hypothyroidism&#xD;
&#xD;
          -  No known prior organ allograft or allogeneic transplantation&#xD;
&#xD;
          -  Not HIV positive&#xD;
&#xD;
          -  No history or evidence of uncontrollable CNS disease&#xD;
&#xD;
          -  No psychiatric illness/social situation&#xD;
&#xD;
          -  No other illness that in the opinion of the investigator would exclude the subject&#xD;
             from participating in the study&#xD;
&#xD;
          -  Must provide informed consent and HIPPA authorization and agree to comply with all&#xD;
             protocol-specified procedures and follow-up evaluations&#xD;
&#xD;
          -  Active systemic infection requiring parenteral antibiotic therapy.&#xD;
&#xD;
          -  No ongoing chronic systemic steroid therapy required.&#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>Hing C Wong, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Altor BioScience</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Iowa Hospitals</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>August 20, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 23, 2012</study_first_posted>
  <last_update_submitted>October 26, 2016</last_update_submitted>
  <last_update_submitted_qc>October 26, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 28, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cancer</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>immunochemotherapy</keyword>
  <keyword>targeted</keyword>
  <keyword>metastatic</keyword>
  <keyword>interleukin-2</keyword>
  <keyword>antitumor</keyword>
  <keyword>TCR</keyword>
  <keyword>T-cell receptor</keyword>
  <keyword>p53</keyword>
  <keyword>p53 gene</keyword>
  <keyword>p53 tumor supressor protein</keyword>
  <keyword>HLA-A2 positive</keyword>
  <keyword>HLA-A*0201/p53 aa264-272</keyword>
  <keyword>HLA complex</keyword>
  <keyword>multiple myeloma</keyword>
  <keyword>IFN-γ and TNF-α</keyword>
  <keyword>refractory</keyword>
  <keyword>relapsed</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>
  </condition_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/NCT01670994
org study id: CA-ALT-801-01-11
nct id: NCT01670994
lead sponsor: 
collaborator: 
has dmc: Yes
This is a Phase Ib/II, open-label, multi-center and competitive enrollment study of ALT-801
      in patients who have relapsed or refractory multiple myeloma.
Multiple Myeloma (MM) is a plasma cell malignancy that makes up 1% of all cancers and 10% of
      hematologic neoplasma, and is the second most commonly diagnosed hematologic malignancy.
      There are an estimated 20,520 new cases of MM and 10,610 deaths due to MM in the United
      States. Historically, standard first-line therapy for MM consisted of combination therapy
      with an alkylating agent, such as melphalan and prednisone. Response rates with such
      combination therapy are approximately 50%, but five-year survival rates remain low at 33%.
      For younger patients, debulking chemotherapy followed by autologous stem cell transplant
      (ASCT) with melphalan is the treatment of choice to increase the potential for a sustained
      durable remission. However, a large percentage of patients diagnosed with MM are not suitable
      candidates for ASCT because of age or comorbidities. The approach to MM treatment has
      undergone a radical transformation over the past decade with the introduction of the
      proteasome inhibitor, bortezomib, and immunomodulatory drugs (ImiDs), thalidomide or
      lenalidomide. Despite some advances in the treatment of MM, the disease remains incurable due
      to the persistence of minimal residual disease. Thus, novel modalities complementing or
      improving current treatment options are needed.

      There is ample evidence that immunomodulatory drugs are effective against myeloma.
      Lenalidomide and thalidomide have been shown to stimulate T cells in the presence of antigen
      presenting cells via costimulatory pathway. Also, modulation of NK cell function has been
      associated with anti-tumor activity observed in MM patients treated with lenalidomide. It has
      been demonstrated that NK cells exhibit potent anti-MM activity following IL-2
      administration, and ex vivo IL-2-activated and intravenously administered NK cells prolong
      survival in MM-bearing mice. Thus further demonstrating the role and importance of NK cells
      in the treatment of MM. Taken together, these data suggest that the use of a potent
      immunotherapeutic is an attractive approach to provide durable immune responses to or even
      potentially curing patients with MM.

      Additionally, immunotherapy is a well-established approach for treating other cancer types.
      One strategy that has received attention is treatment with cytokines such as IL-2 to enhance
      anti-tumor immunity. Unfortunately, the considerable toxicity associated with this treatment
      makes it difficult to achieve an effective dose at the site of the tumor and limits the
      population that can be treated. Thus, there is a critical need for innovative strategies that
      enhance the effects of IL-2, reduce its toxicity without compromising clinical benefit,
      provide a more convenient dosing regimen, and treat other diagnoses including MM.

      Altor Bioscience Corp. has developed a tumor-targeted IL-2 fusion protein, ALT-801,
      comprising human recombinant IL-2 genetically linked to a TCR domain capable of binding a
      tumor associated human p53 peptide presented in the context of HLA-A2. Animal studies have
      indicated that ALT-801 could be useful in a therapeutic approach for activating immune
      effector cells, bringing together effector cells and tumor cells and stimulating immune
      cell-mediated activity. In addition, in various mouse xenograft models, this molecule
      increases the efficacy but lessens the side effects of high-dose rhIL-2.

      Moreover, human studies indicate ALT-801 given daily for two 4-day cycles at the MTD (i.e.
      0.04 mg/kg) is well tolerated, exhibits a favorable PK drug profile, exhibits immunological
      potency in humans, provides evidence of clinical benefit in cancer patients and a higher
      dosing level (0.08 mg/kg) of ALT-801 in a monotherapy treatment was associated with better
      clinical benefit in patients with metastatic cancer.

      Also, the results of pre-clinical studies in various tumors with diverse origins and relevant
      MM models indicates ALT-801 is a potent immunostimulatory molecule capable increasing NK cell
      and CD8+ T cell numbers and percentages in myeloma tumor-bearing mice, ALT-801 in single or
      multidose treatment regimens exhibits potent anti-tumor activity and induced long-lasting
      immunologic memory against well-established myeloma cells in the immunocompetent mouse model,
      suggesting the potential of curative treatment for patients with MM.

      Based on these findings, ALT-801 as a single-agent therapeutic may provide durable clinical
      benefit to patients with relapsed or relapsed and refractory MM. In this study, we will
      establish the tolerable dose level of ALT-801 in MM patients, and estimate the anti-tumor
      activity and characterize the pharmacokinetic and immunogenicity profile of ALT-801 in such
      patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety Profile
time frame: 7 weeks
description: For phase Ib & II
Number and severity of treatment related AEs that occur or worsen after the first dose of study treatment
measure: Tolerability and MTD designation
time frame: 7 weeks
description: For phase Ib only
To evaluate the tolerability and to determine the maximum tolerated dose (MTD) level.
measure: Clinical Benefit
time frame: 12 weeks
description: For phase Ib and II
Number of participants with an objective response, which includes, a complete response, a partial response or a stable disease
measure: Immunogenicity and Pharmacokinetics
time frame: 8 weeks
description: For phase Ib and II
Measures the anti-ALT-801 and IL-2 neutralizing effects
Area under the plasma concentration-time curve from time zero to infinity (AUC) and the half-life of ALT-801
measure: Tumor Typing
time frame: 1 month
description: For phase Ib and II
To assess the relationship between tumor presentation of HLA-A*0201/p53 aa 264-272 complex and the safety, immune response and clinical benefit of study treatment
measure: Overall and progression-free survival
time frame: 3 years
description: For phase Ib and II
All enrolled patients will be assessed every 3 months during year 1 and then every 6 months during years 2 and 3 from the start of study treatment to determine their overall and progression-free survival
measure: Duration of Response
time frame: up to 3 years
description: All enrolled patients will be assessed every 3 months during year 1 and then every 6 months during years 2 and 3 from the start of study treatment to determine their duration of response
arm group label: ALT-801
arm group type: Experimental
intervention type: Biological
intervention name: ALT-801
description: Intravenous infusion; 2 treatment cycles: on day 1, 3, 8, and 15 of each cycle
arm group label: ALT-801
other name: c264scTCR-IL2
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Hing C Wong, PhD
role: Study Chair
affiliation: Altor BioScience
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
sharing ipd: No