<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/NCT02992860</url>
  </required_header>
  <id_info>
    <org_study_id>SAMBA-trial</org_study_id>
    <secondary_id>11274</secondary_id>
    <nct_id>NCT02992860</nct_id>
  </id_info>
  <brief_title>Single Agent JNJ-56022473 in MDS and AML Patients FAILING HYPOMETHYLATING AGENT BASED THERAPY</brief_title>
  <acronym>SAMBA</acronym>
  <official_title>Single Agent JNJ-56022473 in MDS and AML Patients Failing Hypomethylating Agent Based Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GWT-TUD GmbH</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>GWT-TUD GmbH</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The outcome of HMA-refractory patients with MDS or AML is dismal with a median survival of 5&#xD;
      months after failure, representing a significant unmet medical need due to the very limited&#xD;
      treatment options. In this context, a specific targeting of the leukemic stem cell (LSC)&#xD;
      seems a promising option to selectively combat the leukemic progenitor cells. In fact, CD123&#xD;
      is overexpressed in AML and MDS progenitors making it an attractive target for&#xD;
      immunotherapy-based approaches. JNJ-56022473 is a promising compound that has been engineered&#xD;
      with regard to this strategy and the current phase II trial has the aim to evaluate the&#xD;
      overall hematological response rate at 3 months in HMA refractory/relapsed AML and MDS&#xD;
      patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies of&#xD;
      the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis and&#xD;
      progressive bone marrow failure. Clinically, patients suffer from fatigue and are at high&#xD;
      risk of infections or bleeding. Also, MDS patients are endangered by progression to secondary&#xD;
      acute myeloid leukemia (AML), a disorder of early hematopoietic progenitor cells&#xD;
      characterised by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow,&#xD;
      and/or other tissues.&#xD;
&#xD;
      Up to now, allogeneic transplantation is considered the only curative option for both MDS and&#xD;
      AML patients. However, as MDS and AML mainly manifest in the 7th and 8th decade of life, only&#xD;
      a limited number of patients tolerating bone marrow transplantation and are therefore&#xD;
      eligible for this procedure. In fact, comorbid conditions are common among the elderly such&#xD;
      as heart disease, renal insufficiency and vascular disease thus influencing the ability to&#xD;
      withstand exhausting transplantation procedures.&#xD;
&#xD;
      Hence in recent years, novel therapeutic strategies have been developed and hypomethylating&#xD;
      agents (HMAs) azacitidine and decitabine have emerged as new therapeutic options. In 2009,&#xD;
      azacitidine was the first HMA in use having received approval for treatment of MDS and AML&#xD;
      patients with 20-30% blasts. In 2012, also the sister compound decitabine got approval for&#xD;
      treatment of AML patients ≥ 65 years of age and in 2015, azacitidine's approval was extended&#xD;
      to AML patients ≥ 65 years of age that are considered unfit for allogeneic transplantation&#xD;
      with &gt; 30% blasts.&#xD;
&#xD;
      However, despite the efficacy and reported activity, only 50% of patients respond to the&#xD;
      treatment with HMAs and the majority of them do relapse. Also the outcome of HMA- refractory&#xD;
      patients is dismal with a median survival of 5 months after failure and hence MDS and AML&#xD;
      patients with HMA failure represent a significant unmet medical need due to the poor&#xD;
      prognosis and very limited treatment options.&#xD;
&#xD;
      In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising&#xD;
      option to selectively combat the leukemic cells. In fact, CD123 (also known as&#xD;
      interleukin-3-Rα) is expressed in different hematological malignancies, among others in MDS&#xD;
      and AML. Interestingly, CD123 is expressed by the majority of AML blasts and it is also&#xD;
      overexpressed by CD34+ CD38- LSCs compared with normal hematopoietic stem cells and other&#xD;
      normal tissues. These features make CD123 an attractive target for anti-leukemia therapy.&#xD;
      Recent data suggests that treatment with HMA can induce expression of CD123 on AML tumors&#xD;
      opening up the potential that HMA failure patients may have even higher expression levels of&#xD;
      CD123.&#xD;
&#xD;
      Indeed, JNJ-56022473 is a promising compound that has been engineered with regard to this&#xD;
      strategy. JNJ-56022473 is a humanized monoclonal antibody that targets the alpha chain of the&#xD;
      interleukin-3-receptor and is optimized at the Fcγ region for enhanced activation of&#xD;
      antibody- dependent cell-mediated cytotoxicity (ADCC) via natural killer cells.&#xD;
&#xD;
      Recently, JNJ-56022473 has been evaluated in a phase I study with AML patients at high risk&#xD;
      for early relapse. There was a clear dose dependency on depletion of peripheral CD123 cell&#xD;
      populations such as pDC and basophile with complete and sustained depletion seen in pts at&#xD;
      doses ≥3 mg/kg Given the encouraging results of this phase I trial we now propose a phase II&#xD;
      trial to evaluate JNJ-56022473 in AML patients as well as in MDS patients that have failed or&#xD;
      are refractory to HMA- treatment.&#xD;
&#xD;
      The clinical trial will be accompanied by a translational research program which aims at&#xD;
      elucidating specific immune responses mediated by JNJ-56022473, in particular by descriptive&#xD;
      and functional analyses. In this context bone marrow and peripheral blood will be collected&#xD;
      during the study as well as before and after therapy.&#xD;
&#xD;
      Constitutive overexpression of the α-subunit of the interleukin-3 receptor i.e. IL-3Rα, is a&#xD;
      hallmark of the early AML progenitor cell population (i.e. leukemic stem cells) as well as&#xD;
      leukemic blasts and IL-3Rα is also overexpressed in myelodysplastic syndromes. In fact, CD123&#xD;
      is unique to the IL-3 receptor and is responsible for the high specificity and low affinity&#xD;
      binding of IL-3. Upon ligand binding, the α-subunit CD123 associates with the βc-subunit&#xD;
      (CD131) to form a high-affinity receptor complex initiating an intracellular signaling&#xD;
      cascade through phosphorylation and activation of at least 3 distinct signal transduction&#xD;
      pathways: the JAK/STAT-kinase, MAP-kinase-, and PI3-kinase-pathways. Under physiological&#xD;
      conditions, activation of the IL-3 receptor induces proliferative, anti-apoptotic, and&#xD;
      differentiating signals.&#xD;
&#xD;
      JNJ-56022473 (CSL362) is a second generation antibody developed from the murine 7G3 anti-&#xD;
      CD123 monoclonal antibody (mAb) in a stepwise process of humanization, affinity maturation,&#xD;
      and Fc engineering. To enhance the cytotoxicity of the first-generation antibody CSL360, the&#xD;
      proprietary Xencor (Xmab®) technology was applied and two amino acid mutations (S239D and&#xD;
      I332E) were introduced into the Fc region. These amino acid substitutions led to improved&#xD;
      binding to CD16 (FcγRIIIa) on natural killer (NK) cells and significantly enhanced the&#xD;
      ability to induce ADCC.&#xD;
&#xD;
      The JNJ-56022473 drug product that will be used in this study is produced in a different cell&#xD;
      line with a different process compared with CSL362, the drug product used in the phase I&#xD;
      study CSLCT-AML-11-73 described below. Comparability testing of JNJ-56022473 and CSL362 has&#xD;
      shown the antibodies to behave similarly in biophysical, biochemical, and preclinical&#xD;
      assessments. The primary structure, charge heterogeneity, size heterogeneity, purity, higher&#xD;
      order structure, and process impurities were found to be highly similar between CSL362 and&#xD;
      JNJ56022473. Pharmacodynamic (PD) studies in cynomolgus monkeys showed similar levels of&#xD;
      biological activity between CSL362 and JNJ-56022473 (ie, basophil and pDC depletion; NK cell&#xD;
      number and activity). Additionally, the pharmacokinetic (PK) profiles of JNJ-56022473&#xD;
      following 30 and 100 mg/kg IV dosing of cynomolgus monkeys are highly similar to those of&#xD;
      CSL362. Following the first weekly intravenous dose, mean Cmax and AUC0-167h of JNJ-56022473&#xD;
      are 91% and 94% of those observed for CSL362, respectively.&#xD;
&#xD;
      This is an open-label, single-arm, multicenter, phase II study of JNJ-56022473 in subjects&#xD;
      suffering from MDS or AML. The trial will involve participating sites from Germany and&#xD;
      France. Up to a maximum of 43 subjects will be enrolled in the study.&#xD;
&#xD;
      JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14&#xD;
      days for an initial treatment period of 3 months (6 infusions). Responders will then receive&#xD;
      up to 20 additional infusions whereas for non-responders the initial treatment will be&#xD;
      followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus,&#xD;
      the individual study duration for a subject will be approx. 1 year. A follow up visit will be&#xD;
      performed after 3 months after last study drug administration for all patients to track&#xD;
      pregnancy status according to IB.&#xD;
&#xD;
      For patients who still benefit from the treatment and are graded as responders after the time&#xD;
      period defined above, treatment will continue as long as medically indicated. End of study as&#xD;
      a whole will be 16 months after LPFV (maximum of 26 treatment cycles plus follow up of three&#xD;
      months). Data obtained after the end of the study (EoS) for patients who still responding&#xD;
      will be reported under separate cover.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Enrollement was stopped due to a recommendation by the IDMC/FDA for a parallel clinical trial&#xD;
    with TALA, where potentielly no efficancy could be determined.&#xD;
  </why_stopped>
  <start_date type="Actual">July 2016</start_date>
  <completion_date type="Actual">October 2018</completion_date>
  <primary_completion_date type="Actual">October 2018</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>Overall hematological response rate</measure>
    <time_frame>3 months</time_frame>
    <description>Overall hematological response rate at 3 months (either CR, PR, marrow-CR, HI, SD)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Toxicity</measure>
    <time_frame>3 or 12 months</time_frame>
    <description>Toxicity as measured by NCI CTCAE 4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free-survival</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall hematological response rate at 12 months</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life EORTC-QLQ30</measure>
    <time_frame>9 or 15 months</time_frame>
    <description>measured by EORTC-QLQ30</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment failure</measure>
    <time_frame>3 or 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (best overall response)</measure>
    <time_frame>3 or 12 months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Myelodysplastic Syndrome (MDS)</condition>
  <condition>Acute Myeloid Leukemia (AML)</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>JNJ-56022473</intervention_name>
    <description>JNJ-56022473 will be supplied as a lyophilized product containing 100mg of active pharmaceutical ingredient (50 mg/mL after reconstitution with 2.0 mL sterile water for injection). The JNJ-56022473 dose administered will be dependent upon the subject's weight at baseline. The JNJ-56022473 dose should be adjusted in case the subject's weight changes by &gt; 10%. JNJ- 56022473 will be administered in 250 mL IV infusion over approximately 180 minutes using an infusion pump.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
    <other_name>CSL362</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bone marrow analyses and CBC with differential</intervention_name>
    <description>Bone marrow analyses and CBC with differential will be performed by a central laboratory. If the marrow cannot be aspirated, a biopsy should be performed.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Flow cytometry analyses</intervention_name>
    <description>Characterization of LSCs and blasts (including CD123 and CD38 expression) will be performed as study-related analyses in the context of this protocol by central flow cytometry using bone marrow samples.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Central biobanking</intervention_name>
    <description>Central biobanking of study samples (bone marrow, peripheral blood as well as a buccal swab) will be carried out in Dresden.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Histopathology analysis</intervention_name>
    <description>A bone marrow biopsy is taken whenever it seems necessary to the investigator.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Cytogenetic analysis</intervention_name>
    <description>The cytogenetic analysis with banding analysis (optional FISH) have to be performed at local labs. Therefore 2 - 5 ml of bone marrow will be collected and analysed.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Serum chemistry</intervention_name>
    <description>For serum chemistry 15 ml (2 x 7,5 ml) of peripheral blood have to be collected.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Automated CBC</intervention_name>
    <description>For CBC a minimum of 3 ml of peripheral blood have to be collected.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pregnancy Test</intervention_name>
    <description>Serum or urine pregnancy testing β-HCG with a sensitivity of at least 25 mIU/mL is to be done not more than 3 days prior to initiation of JNJ-56022473 in female patients with childbearing potential. Furthermore, serum or urine pregnancy testing has to be done after end of treatment (EoT) visit.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥18 years of age&#xD;
&#xD;
          -  Diagnosis of AML or MDS&#xD;
&#xD;
          -  At least ≥ 5% BM blasts at the time of screening (done by central morphology)&#xD;
&#xD;
          -  At least one cytopenia (ANC &lt; 1800/μL or platelet count &lt; 100,000/μL or hemoglobin &lt;&#xD;
             10 g/dL)&#xD;
&#xD;
          -  Failure to achieve complete or partial response or hematological improvement after at&#xD;
             least six (azacitidine) or four (decitabine) 4-week treatment cycles administered&#xD;
             during the past two years OR&#xD;
&#xD;
          -  Relapse after initial complete or partial response or hematological improvement&#xD;
             observed after at least six (azacitidine) or four (decitabine) 4-week treatment cycles&#xD;
             administered during the past two years OR&#xD;
&#xD;
          -  Intolerance to treatment with HMA (hypomethylating agents) defined by drug-related ≥&#xD;
             Grade 3 liver or renal toxicity leading to treatment discontinuation during the past&#xD;
             two years&#xD;
&#xD;
          -  Failed to respond to, relapsed following, not eligible, or opted not to participate in&#xD;
             bone marrow transplantation&#xD;
&#xD;
          -  Off all other treatments for AML/MDS for at least four weeks; Filgrastim (G-CSF) and&#xD;
             erythropoietin are allowed before and during the study as clinically indicated&#xD;
&#xD;
          -  No medical need for or patient opted not to receive induction chemotherapy&#xD;
&#xD;
          -  ECOG performance status of 0-2&#xD;
&#xD;
          -  Willing to adhere to the prohibitions and restrictions specified in the protocol&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous treatment with a CD123 agent or T- or NK cell redirecting therapy&#xD;
&#xD;
          -  Patients having received intensive chemotherapy to treat HMA failure&#xD;
&#xD;
          -  Diagnosis of acute promyelocytic leukemia (APL)&#xD;
&#xD;
          -  WBC &gt; 15 GPT/L&#xD;
&#xD;
          -  Any active malignancy within the past year, except basal cell or squamous cell skin&#xD;
             cancer or carcinoma in situ of the cervix or breast&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic&#xD;
             congestive heart failure, unstable angina pectoris, or cardiac arrhythmia&#xD;
&#xD;
          -  Active infection not adequately responding to appropriate therapy&#xD;
&#xD;
          -  Total bilirubin &gt; 1.5 mg/dL not related to hemolysis or Gilbert's disease&#xD;
&#xD;
          -  ALT/AST &gt; 2.5 x upper limit of normal&#xD;
&#xD;
          -  Serum creatinine &gt; 2.0 mg/dL&#xD;
&#xD;
          -  Patients who are unwilling to follow highly effective contraception requirements&#xD;
             (including condom use for males with sexual partners, and for females: prescription&#xD;
             oral contraceptives, contraceptive injections, intrauterine device, , contraceptive&#xD;
             patch, surgical sterilization or true sexual abstinence) before entry, at least at&#xD;
             screening, throughout the study and within 3 months after last study drug&#xD;
             administration&#xD;
&#xD;
          -  Female patients with reproductive potential who do not have a negative urine β-HCG&#xD;
             pregnancy test at screening and prior to the first study drug administration at visit&#xD;
             1 (day 0) of JNJ-56022473 treatment period.&#xD;
&#xD;
          -  Female patients who are lactating&#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>Uwe Platzbecker, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsklinikum Dresden</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lionel Adés, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Saint Louis Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHU Nantes</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Archet 1</name>
      <address>
        <city>Nice</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Saint Louis</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Toulouse</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Chemnitz gGmbH, Klinik für innere Medizin III</name>
      <address>
        <city>Chemnitz</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Dresden</name>
      <address>
        <city>Dresden</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Heinrich Heine Universität</name>
      <address>
        <city>Dusseldorf</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Marien Hospital GmbH</name>
      <address>
        <city>Dusseldorf</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Technische Universität München, Klinikum rechts der Isar</name>
      <address>
        <city>Munich</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Ulm</name>
      <address>
        <city>Ulm</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Germany</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>December 12, 2016</study_first_submitted>
  <study_first_submitted_qc>December 12, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>October 23, 2018</last_update_submitted>
  <last_update_submitted_qc>October 23, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Myelodysplastic Syndrome (MDS)</keyword>
  <keyword>Acute Myeloid Leukemia (AML)</keyword>
  <keyword>hypomethylating agent (HMA) treatment</keyword>
  <keyword>leukemic stem cell</keyword>
  <keyword>CD123</keyword>
  <keyword>immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</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/NCT02992860
org study id: SAMBA-trial
secondary id: 11274
nct id: NCT02992860
lead sponsor: 
has dmc: Yes
The outcome of HMA-refractory patients with MDS or AML is dismal with a median survival of 5
      months after failure, representing a significant unmet medical need due to the very limited
      treatment options. In this context, a specific targeting of the leukemic stem cell (LSC)
      seems a promising option to selectively combat the leukemic progenitor cells. In fact, CD123
      is overexpressed in AML and MDS progenitors making it an attractive target for
      immunotherapy-based approaches. JNJ-56022473 is a promising compound that has been engineered
      with regard to this strategy and the current phase II trial has the aim to evaluate the
      overall hematological response rate at 3 months in HMA refractory/relapsed AML and MDS
      patients.
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies of
      the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis and
      progressive bone marrow failure. Clinically, patients suffer from fatigue and are at high
      risk of infections or bleeding. Also, MDS patients are endangered by progression to secondary
      acute myeloid leukemia (AML), a disorder of early hematopoietic progenitor cells
      characterised by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow,
      and/or other tissues.

      Up to now, allogeneic transplantation is considered the only curative option for both MDS and
      AML patients. However, as MDS and AML mainly manifest in the 7th and 8th decade of life, only
      a limited number of patients tolerating bone marrow transplantation and are therefore
      eligible for this procedure. In fact, comorbid conditions are common among the elderly such
      as heart disease, renal insufficiency and vascular disease thus influencing the ability to
      withstand exhausting transplantation procedures.

      Hence in recent years, novel therapeutic strategies have been developed and hypomethylating
      agents (HMAs) azacitidine and decitabine have emerged as new therapeutic options. In 2009,
      azacitidine was the first HMA in use having received approval for treatment of MDS and AML
      patients with 20-30% blasts. In 2012, also the sister compound decitabine got approval for
      treatment of AML patients ≥ 65 years of age and in 2015, azacitidine's approval was extended
      to AML patients ≥ 65 years of age that are considered unfit for allogeneic transplantation
      with > 30% blasts.

      However, despite the efficacy and reported activity, only 50% of patients respond to the
      treatment with HMAs and the majority of them do relapse. Also the outcome of HMA- refractory
      patients is dismal with a median survival of 5 months after failure and hence MDS and AML
      patients with HMA failure represent a significant unmet medical need due to the poor
      prognosis and very limited treatment options.

      In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising
      option to selectively combat the leukemic cells. In fact, CD123 (also known as
      interleukin-3-Rα) is expressed in different hematological malignancies, among others in MDS
      and AML. Interestingly, CD123 is expressed by the majority of AML blasts and it is also
      overexpressed by CD34+ CD38- LSCs compared with normal hematopoietic stem cells and other
      normal tissues. These features make CD123 an attractive target for anti-leukemia therapy.
      Recent data suggests that treatment with HMA can induce expression of CD123 on AML tumors
      opening up the potential that HMA failure patients may have even higher expression levels of
      CD123.

      Indeed, JNJ-56022473 is a promising compound that has been engineered with regard to this
      strategy. JNJ-56022473 is a humanized monoclonal antibody that targets the alpha chain of the
      interleukin-3-receptor and is optimized at the Fcγ region for enhanced activation of
      antibody- dependent cell-mediated cytotoxicity (ADCC) via natural killer cells.

      Recently, JNJ-56022473 has been evaluated in a phase I study with AML patients at high risk
      for early relapse. There was a clear dose dependency on depletion of peripheral CD123 cell
      populations such as pDC and basophile with complete and sustained depletion seen in pts at
      doses ≥3 mg/kg Given the encouraging results of this phase I trial we now propose a phase II
      trial to evaluate JNJ-56022473 in AML patients as well as in MDS patients that have failed or
      are refractory to HMA- treatment.

      The clinical trial will be accompanied by a translational research program which aims at
      elucidating specific immune responses mediated by JNJ-56022473, in particular by descriptive
      and functional analyses. In this context bone marrow and peripheral blood will be collected
      during the study as well as before and after therapy.

      Constitutive overexpression of the α-subunit of the interleukin-3 receptor i.e. IL-3Rα, is a
      hallmark of the early AML progenitor cell population (i.e. leukemic stem cells) as well as
      leukemic blasts and IL-3Rα is also overexpressed in myelodysplastic syndromes. In fact, CD123
      is unique to the IL-3 receptor and is responsible for the high specificity and low affinity
      binding of IL-3. Upon ligand binding, the α-subunit CD123 associates with the βc-subunit
      (CD131) to form a high-affinity receptor complex initiating an intracellular signaling
      cascade through phosphorylation and activation of at least 3 distinct signal transduction
      pathways: the JAK/STAT-kinase, MAP-kinase-, and PI3-kinase-pathways. Under physiological
      conditions, activation of the IL-3 receptor induces proliferative, anti-apoptotic, and
      differentiating signals.

      JNJ-56022473 (CSL362) is a second generation antibody developed from the murine 7G3 anti-
      CD123 monoclonal antibody (mAb) in a stepwise process of humanization, affinity maturation,
      and Fc engineering. To enhance the cytotoxicity of the first-generation antibody CSL360, the
      proprietary Xencor (Xmab®) technology was applied and two amino acid mutations (S239D and
      I332E) were introduced into the Fc region. These amino acid substitutions led to improved
      binding to CD16 (FcγRIIIa) on natural killer (NK) cells and significantly enhanced the
      ability to induce ADCC.

      The JNJ-56022473 drug product that will be used in this study is produced in a different cell
      line with a different process compared with CSL362, the drug product used in the phase I
      study CSLCT-AML-11-73 described below. Comparability testing of JNJ-56022473 and CSL362 has
      shown the antibodies to behave similarly in biophysical, biochemical, and preclinical
      assessments. The primary structure, charge heterogeneity, size heterogeneity, purity, higher
      order structure, and process impurities were found to be highly similar between CSL362 and
      JNJ56022473. Pharmacodynamic (PD) studies in cynomolgus monkeys showed similar levels of
      biological activity between CSL362 and JNJ-56022473 (ie, basophil and pDC depletion; NK cell
      number and activity). Additionally, the pharmacokinetic (PK) profiles of JNJ-56022473
      following 30 and 100 mg/kg IV dosing of cynomolgus monkeys are highly similar to those of
      CSL362. Following the first weekly intravenous dose, mean Cmax and AUC0-167h of JNJ-56022473
      are 91% and 94% of those observed for CSL362, respectively.

      This is an open-label, single-arm, multicenter, phase II study of JNJ-56022473 in subjects
      suffering from MDS or AML. The trial will involve participating sites from Germany and
      France. Up to a maximum of 43 subjects will be enrolled in the study.

      JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14
      days for an initial treatment period of 3 months (6 infusions). Responders will then receive
      up to 20 additional infusions whereas for non-responders the initial treatment will be
      followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus,
      the individual study duration for a subject will be approx. 1 year. A follow up visit will be
      performed after 3 months after last study drug administration for all patients to track
      pregnancy status according to IB.

      For patients who still benefit from the treatment and are graded as responders after the time
      period defined above, treatment will continue as long as medically indicated. End of study as
      a whole will be 16 months after LPFV (maximum of 26 treatment cycles plus follow up of three
      months). Data obtained after the end of the study (EoS) for patients who still responding
      will be reported under separate cover.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall hematological response rate
time frame: 3 months
description: Overall hematological response rate at 3 months (either CR, PR, marrow-CR, HI, SD)
measure: Toxicity
time frame: 3 or 12 months
description: Toxicity as measured by NCI CTCAE 4.03
measure: Overall survival
time frame: 1 year
measure: Progression-free-survival
time frame: 1 year
measure: Overall hematological response rate at 12 months
time frame: 1 year
measure: Quality of life EORTC-QLQ30
time frame: 9 or 15 months
description: measured by EORTC-QLQ30
measure: Time to treatment failure
time frame: 3 or 12 months
measure: Duration of response (best overall response)
time frame: 3 or 12 months
arm group label: Treatment Arm
arm group type: Experimental
description: JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
intervention type: Drug
intervention name: JNJ-56022473
description: JNJ-56022473 will be supplied as a lyophilized product containing 100mg of active pharmaceutical ingredient (50 mg/mL after reconstitution with 2.0 mL sterile water for injection). The JNJ-56022473 dose administered will be dependent upon the subject's weight at baseline. The JNJ-56022473 dose should be adjusted in case the subject's weight changes by > 10%. JNJ- 56022473 will be administered in 250 mL IV infusion over approximately 180 minutes using an infusion pump.
arm group label: Treatment Arm
other name: CSL362
intervention type: Procedure
intervention name: Bone marrow analyses and CBC with differential
description: Bone marrow analyses and CBC with differential will be performed by a central laboratory. If the marrow cannot be aspirated, a biopsy should be performed.
arm group label: Treatment Arm
intervention type: Other
intervention name: Flow cytometry analyses
description: Characterization of LSCs and blasts (including CD123 and CD38 expression) will be performed as study-related analyses in the context of this protocol by central flow cytometry using bone marrow samples.
arm group label: Treatment Arm
intervention type: Other
intervention name: Central biobanking
description: Central biobanking of study samples (bone marrow, peripheral blood as well as a buccal swab) will be carried out in Dresden.
arm group label: Treatment Arm
intervention type: Procedure
intervention name: Histopathology analysis
description: A bone marrow biopsy is taken whenever it seems necessary to the investigator.
arm group label: Treatment Arm
intervention type: Genetic
intervention name: Cytogenetic analysis
description: The cytogenetic analysis with banding analysis (optional FISH) have to be performed at local labs. Therefore 2 - 5 ml of bone marrow will be collected and analysed.
arm group label: Treatment Arm
intervention type: Procedure
intervention name: Serum chemistry
description: For serum chemistry 15 ml (2 x 7,5 ml) of peripheral blood have to be collected.
arm group label: Treatment Arm
intervention type: Procedure
intervention name: Automated CBC
description: For CBC a minimum of 3 ml of peripheral blood have to be collected.
arm group label: Treatment Arm
intervention type: Procedure
intervention name: Pregnancy Test
description: Serum or urine pregnancy testing β-HCG with a sensitivity of at least 25 mIU/mL is to be done not more than 3 days prior to initiation of JNJ-56022473 in female patients with childbearing potential. Furthermore, serum or urine pregnancy testing has to be done after end of treatment (EoT) visit.
arm group label: Treatment Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Uwe Platzbecker, Prof.
role: Principal Investigator
affiliation: Universitätsklinikum Dresden
last name: Lionel Adés, Dr.
role: Principal Investigator
affiliation: Hospital Saint Louis Paris
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country: France
country: Germany
responsible party type: Sponsor
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
sharing ipd: No