<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/NCT04499339</url>
  </required_header>
  <id_info>
    <org_study_id>CARAMBA-1</org_study_id>
    <secondary_id>2019-001264-30</secondary_id>
    <nct_id>NCT04499339</nct_id>
  </id_info>
  <brief_title>A Phase I/IIa Clinical Trial to Assess Feasibility, Safety and Antitumor Activity of Autologous SLAMF7 CAR-T Cells in Multiple Myeloma</brief_title>
  <official_title>A Phase I/IIa Clinical Trial to Assess Feasibility, Safety and Antitumor Activity of Autologous SLAMF7 CAR-T Cells in Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wuerzburg University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Union</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Wuerzburg University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multiple myeloma (MM) is a rare hematologic malignancy of aberrant plasma cells.&#xD;
&#xD;
      There is a high and currently unmet medical need for novel, innovative treatment concepts to&#xD;
      improve the therapeutic outcome and prognosis of patients suffering from MM.&#xD;
&#xD;
      There is definitive evidence that MM is susceptible to immune-based therapies from&#xD;
      pre-clinical investigations and early clinical trials.&#xD;
&#xD;
      CARAMBA-1 is a first-in-human clinical trial of adoptive immunotherapy with autologous&#xD;
      signaling lymphocytic activation molecule F7 (SLAMF7) chimeric antigen receptor (CAR)-T cells&#xD;
      in patients with advanced MM that have exhausted conventional therapies.&#xD;
&#xD;
      The CARAMBA-1 clinical trial is an open-label, non-randomized, multicenter clinical trial&#xD;
      which combines a phase I dose-escalation part with a phase IIa dose-expansion part to assess&#xD;
      feasibility, safety and anti-myeloma activity of SLAMF7 CAR-T cells.&#xD;
&#xD;
      The CARAMBA project and the CARAMBA-1 clinical trial are supported by the European Union in&#xD;
      the Horizon 2020 research and innovation program.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multiple myeloma (MM) is a rare hematologic malignancy of aberrant plasma cells.&#xD;
&#xD;
      There is a high and currently unmet medical need for novel, innovative treatment concepts to&#xD;
      improve the therapeutic outcome and prognosis of patients suffering from MM.&#xD;
&#xD;
      There is definitive evidence that MM is susceptible to immune-based therapies from&#xD;
      pre-clinical investigations and early clinical trials.&#xD;
&#xD;
      CARAMBA-1 is a first-in human clinical trial of adoptive immunotherapy with autologous SLAMF7&#xD;
      CAR-T cells in patients with advanced MM that have exhausted conventional therapies.&#xD;
&#xD;
      The CARAMBA-1 clinical trial is an open-label, non-randomized, multicenter clinical trial&#xD;
      which combines a phase I dose-escalation part with a phase IIa dose-expansion part to assess&#xD;
      feasibility, safety and anti-myeloma activity of SLAMF7 CAR-T cells.&#xD;
&#xD;
      SLAMF7 CAR-T cells are manufactured using virus-free gene-transfer using the Sleeping Beauty&#xD;
      transposon system.&#xD;
&#xD;
      The CAR-T cell product is formulated to contain equal proportions of CD8 cytotoxic and CD4&#xD;
      helper SLAMF7 CAR-T cells.&#xD;
&#xD;
      The CARAMBA project and the CARAMBA-1 clinical trial are supported by the European Union in&#xD;
      the Horizon 2020 research and innovation program.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 22, 2020</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">March 2024</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>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety determination of the treatment with SLAMF7 CAR-T in phase I</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Type, frequency and severity of AEs in phase I</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Determination of the maximum tolerated dose (MTD) and the recommended phase IIa dose of SLAMF7 CAR-T in patients with MM</measure>
    <time_frame>through study Phase I completion, an average of 2 years</time_frame>
    <description>For the primary endpoint in phase I, the maximum tolerated dose will be determined and recommended for phase IIa.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety determination of the treatment with SLAMF7 CAR-T in phases I and IIa</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>Type, frequency and severity of AEs in phase I and IIa</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of the efficacy, defined as overall response rate (ORR) after treatment with SLAMF7 CAR-T in patients with MM</measure>
    <time_frame>through study completion, an average of 2 years</time_frame>
    <description>In Phase IIa the efficacy will be evaluated, defined as ORR.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">38</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>All eligible patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SLAMF7 CAR-T</intervention_name>
    <description>Single infusion of autologous SLAMF7 CAR-T cells</description>
    <arm_group_label>All eligible patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed informed consent form.&#xD;
&#xD;
          2. Patient is ≥18 years of age.&#xD;
&#xD;
          3. Patient is willing and able to adhere to the protocol requirements.&#xD;
&#xD;
          4. Patient with diagnosis of MM who has been treated with at least 2 prior lines of&#xD;
             treatment, including at least one cycle of high-dose chemotherapy with autologous&#xD;
             hematopoietic stem cell transplantation if the patient was eligible, and exposure to&#xD;
             an immunomodulatory imide drug (e.g. lenalidomide and/or pomalidomide), a proteasome&#xD;
             inhibitor, and an anti-CD38 antibody.&#xD;
&#xD;
             (Note: Induction therapy, up to 2 cycles of high-dose chemotherapy with autologous&#xD;
             hematopoietic stem cell transplantation, and subsequent consolidation and/or&#xD;
             maintenance therapy are considered one line of treatment).&#xD;
&#xD;
          5. At least one of the following subcriteria must be measured in the patient:&#xD;
&#xD;
               -  Serum M-protein greater or equal to 0.5 g/dL&#xD;
&#xD;
               -  Urine M-protein greater or equal to 200 mg/24 h&#xD;
&#xD;
               -  Serum free light chain (FLC) assay: involved FLC level greater or equal to 10&#xD;
                  mg/dL (100 mg/L) provided serum FLC ratio is abnormal&#xD;
&#xD;
               -  A biopsy-proven evaluable plasmacytoma&#xD;
&#xD;
               -  Bone marrow plasma cells &gt;10% of total bone marrow cells (&gt;30% if bone marrow&#xD;
                  plasma cells are the only marker of measurable disease)&#xD;
&#xD;
          6. Patients previously treated with an anti-SLAMF7 antibody are eligible.&#xD;
&#xD;
          7. Karnofsky performance status ≥60%. If patient has a Karnofsky performance status &lt;60%&#xD;
             (e.g. after a spinal cord injury) but is judged to be medically fit by the&#xD;
             investigator, patient is eligible.&#xD;
&#xD;
          8. Female patients of childbearing potential must:&#xD;
&#xD;
               1. have a negative pregnancy test (blood) at screening.&#xD;
&#xD;
               2. either commit to true abstinence from heterosexual contact or agree to use, and&#xD;
                  be able to comply with, effective measures of contraception without interruption,&#xD;
                  from screening through 1 year following the investigantional medicinal product&#xD;
                  (IMP) infusion. A highly effective method of contraception or birth control&#xD;
                  (failure rate less than 1% per year when used consistently and correctly) must be&#xD;
                  practiced. The patient should be informed of the potential risks associated with&#xD;
                  becoming pregnant while enrolled in this clinical trial. Reliable methods for&#xD;
                  this trial are: combined (estrogen and progestogen containing) hormonal&#xD;
                  contraception associated with inhibition of ovulation (oral, intravaginal,&#xD;
                  transdermal), progestogen-only hormonal contraception associated with inhibition&#xD;
                  of ovulation (oral, injectable, implantable), intrauterine device, intrauterine&#xD;
                  hormone-releasing system, bilateral tubal occlusion, sexual abstinence or&#xD;
                  vasectomized sexual partner. Abstinence is only accepted as true abstinence: when&#xD;
                  this is in line with the preferred and usual lifestyle of the patient. (Periodic&#xD;
                  abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods and&#xD;
                  withdrawal] are not acceptable methods of contraception.) Postmenopausal (no&#xD;
                  menses for at least 1 year without alternative medical cause) or surgically&#xD;
                  sterile female patients (tubal ligation, hysterectomy or bilateral oophorectomy)&#xD;
                  may be enrolled.&#xD;
&#xD;
               3. Agree to abstain from breast feeding during the study participation and for 1&#xD;
                  year after the IMP infusion.&#xD;
&#xD;
          9. Male patients must practice true abstinence or agree to use a condom during sexual&#xD;
             contact with a pregnant female or a female of childbearing potential for at least 1&#xD;
             year after IMP infusion, even if he has undergone a successful vasectomy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient has undergone a prior allogeneic stem cell transplant with either standard or&#xD;
             reduced intensity conditioning ≤12 months prior to leukapheresis.&#xD;
&#xD;
          2. Patient has undergone a prior allogeneic stem cell transplant with either standard or&#xD;
             reduced intensity conditioning &gt;12 months, and suffers on chronic Graft-versus-Host&#xD;
             Disease and/or is on systemic immune-suppressants.&#xD;
&#xD;
          3. Patient with diagnosis of MM&#xD;
&#xD;
               1. in first relapse following an autologous stem cell transplantation or&#xD;
&#xD;
               2. in second relapse that subsequently achieves a complete response that is&#xD;
                  considered being a candidate for an allogeneic stem cell transplantation, unless&#xD;
                  the patient explicitly denies undergoing an allogeneic stem cell transplantation.&#xD;
&#xD;
          4. Patient has received anti-CD38 and/or anti-SLAMF7 antibodies ≤8 weeks prior to&#xD;
             leukapheresis.&#xD;
&#xD;
          5. Ongoing treatment with systemic immune-suppressants (e.g. systemic cyclosporine or&#xD;
             systemic steroids at any dose).&#xD;
&#xD;
             (Note: Physiologic steroid replacement therapy, topical immune-suppressants as e.g.&#xD;
             cyclosporine/tacrolimus eye drops and topical steroids are permitted.)&#xD;
&#xD;
          6. Echocardiogram with left ventricular ejection fraction &lt;45%.&#xD;
&#xD;
          7. Inadequate renal function defined by creatinine clearance (CrCl) ≤45 mL/min using&#xD;
             Cockcroft-Gault equation.&#xD;
&#xD;
          8. Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine&#xD;
             aminotransferase (ALT) &gt;2.5 x upper limit of normal (ULN) and total bilirubin &gt;1.5 x&#xD;
             ULN (unless due to Gilbert's syndrome and direct bilirubin is ≤1.5 x ULN; unless due&#xD;
             to intrahepatic myeloma lesions as demonstrated by MRI or positron emission tomography&#xD;
             (PET)/computed tomography (CT) not older than 4 weeks prior to screening).&#xD;
&#xD;
          9. International ratio (INR) or partial thromboplastin time (PTT) &gt;1.5 x ULN, unless on a&#xD;
             stable dose of anti-coagulant.&#xD;
&#xD;
         10. Evidence of human immunodeficiency virus (HIV) infection.&#xD;
&#xD;
         11. Seropositive for and with evidence of active viral infection with hepatitis B virus&#xD;
             (HBV), excluding&#xD;
&#xD;
               -  Patients who are hepatitis B surface antigen negative and HBV viral DNA negative&#xD;
&#xD;
               -  Patients who had hepatitis B but have received an antiviral treatment and show&#xD;
                  non-detectable viral DNA for 6 months&#xD;
&#xD;
               -  Patients who are seropositive because of hepatitis B virus vaccine&#xD;
&#xD;
               -  Patients with known HBV infection but undetectable HBV viral load and on&#xD;
                  anti-viral therapy to prevent HBV reactivation.&#xD;
&#xD;
         12. Seropositive for and with active viral infection with hepatitis C virus (HCV),&#xD;
             excluding&#xD;
&#xD;
             - Patients who had hepatitis C but had received an antiviral treatment and show no&#xD;
             detectable HCV viral RNA for 6 months.&#xD;
&#xD;
         13. Seropositive for syphilis on treponema pallidum hemagglutination test, excluding&#xD;
&#xD;
             - Patients with negative treponema pallidum antibody absorption test result&#xD;
&#xD;
         14. Patients with active infection (e.g. asymptomatic and symptomatic severe acute&#xD;
             respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) or other serious medical or&#xD;
             psychiatric disorder on investigators decision.&#xD;
&#xD;
         15. Pregnant or lactating women.&#xD;
&#xD;
         16. Current or previous (within 30 days of enrollment) treatment with another IMP.&#xD;
&#xD;
         17. Known abuse of alcohol, drugs, or medicinal products.&#xD;
&#xD;
         18. Employees of the sponsor, or employees or relatives of the investigator.&#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>Prof. Michael Hudecek</last_name>
    <role>Study Director</role>
    <affiliation>University Hospital Wuerzburg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Lille</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Early Clinical Trial Unit University Hospital Wuerzburg</name>
      <address>
        <city>Würzburg</city>
        <zip>97080</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trials Unit, Clinica Universidad de Navarra</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Germany</country>
    <country>Spain</country>
  </location_countries>
  <link>
    <url>https://www.caramba-cart.eu/</url>
    <description>CARAMBA project homepage</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 24, 2020</study_first_submitted>
  <study_first_submitted_qc>July 31, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>June 20, 2023</last_update_submitted>
  <last_update_submitted_qc>June 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>SLAMF7</keyword>
  <keyword>Chimeric antigen receptor</keyword>
  <keyword>CAR</keyword>
  <keyword>CAR-T cell</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>virus-free gene transfer</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>
  <!-- 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/NCT04499339
org study id: CARAMBA-1
secondary id: 2019-001264-30
nct id: NCT04499339
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Multiple myeloma (MM) is a rare hematologic malignancy of aberrant plasma cells.

      There is a high and currently unmet medical need for novel, innovative treatment concepts to
      improve the therapeutic outcome and prognosis of patients suffering from MM.

      There is definitive evidence that MM is susceptible to immune-based therapies from
      pre-clinical investigations and early clinical trials.

      CARAMBA-1 is a first-in-human clinical trial of adoptive immunotherapy with autologous
      signaling lymphocytic activation molecule F7 (SLAMF7) chimeric antigen receptor (CAR)-T cells
      in patients with advanced MM that have exhausted conventional therapies.

      The CARAMBA-1 clinical trial is an open-label, non-randomized, multicenter clinical trial
      which combines a phase I dose-escalation part with a phase IIa dose-expansion part to assess
      feasibility, safety and anti-myeloma activity of SLAMF7 CAR-T cells.

      The CARAMBA project and the CARAMBA-1 clinical trial are supported by the European Union in
      the Horizon 2020 research and innovation program.
Multiple myeloma (MM) is a rare hematologic malignancy of aberrant plasma cells.

      There is a high and currently unmet medical need for novel, innovative treatment concepts to
      improve the therapeutic outcome and prognosis of patients suffering from MM.

      There is definitive evidence that MM is susceptible to immune-based therapies from
      pre-clinical investigations and early clinical trials.

      CARAMBA-1 is a first-in human clinical trial of adoptive immunotherapy with autologous SLAMF7
      CAR-T cells in patients with advanced MM that have exhausted conventional therapies.

      The CARAMBA-1 clinical trial is an open-label, non-randomized, multicenter clinical trial
      which combines a phase I dose-escalation part with a phase IIa dose-expansion part to assess
      feasibility, safety and anti-myeloma activity of SLAMF7 CAR-T cells.

      SLAMF7 CAR-T cells are manufactured using virus-free gene-transfer using the Sleeping Beauty
      transposon system.

      The CAR-T cell product is formulated to contain equal proportions of CD8 cytotoxic and CD4
      helper SLAMF7 CAR-T cells.

      The CARAMBA project and the CARAMBA-1 clinical trial are supported by the European Union in
      the Horizon 2020 research and innovation program.
allocation: N/A
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety determination of the treatment with SLAMF7 CAR-T in phase I
time frame: through study completion, an average of 2 years
description: Type, frequency and severity of AEs in phase I
measure: Determination of the maximum tolerated dose (MTD) and the recommended phase IIa dose of SLAMF7 CAR-T in patients with MM
time frame: through study Phase I completion, an average of 2 years
description: For the primary endpoint in phase I, the maximum tolerated dose will be determined and recommended for phase IIa.
measure: Safety determination of the treatment with SLAMF7 CAR-T in phases I and IIa
time frame: through study completion, an average of 2 years
description: Type, frequency and severity of AEs in phase I and IIa
measure: Evaluation of the efficacy, defined as overall response rate (ORR) after treatment with SLAMF7 CAR-T in patients with MM
time frame: through study completion, an average of 2 years
description: In Phase IIa the efficacy will be evaluated, defined as ORR.
arm group label: All eligible patients
arm group type: Experimental
intervention type: Drug
intervention name: SLAMF7 CAR-T
description: Single infusion of autologous SLAMF7 CAR-T cells
arm group label: All eligible patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Prof. Michael Hudecek
role: Study Director
affiliation: University Hospital Wuerzburg
facility: 
facility: 
facility: 
country: France
country: Germany
country: Spain
url: https://www.caramba-cart.eu/
description: CARAMBA project homepage
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell