xml: <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/NCT06002659</url>
    </required_header>
    <id_info>
      <org_study_id>ELC301-CARMA-01</org_study_id>
      <secondary_id>2022-004157-31</secondary_id>
      <nct_id>NCT06002659</nct_id>
    </id_info>
    <brief_title>CAR20(NAP)-T Therapy for B Cell Lymphoma (CARMA-01 Study)</brief_title>
    <acronym>CARMA-01</acronym>
    <official_title>A Phase I/IIa Multicenter Study Evaluating the Safety and Efficacy of CAR20(NAP)-T in Patients With Relapsed/Refractory B Cell Lymphoma (CARMA-01 Study)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Uppsala University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Elicera Therapeutics</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Uppsala University Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Karolinska University Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Uppsala University</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>
        The purpose is to study the safety, tolerability, pharmacokinetics, pharmacodynamics and&#xD;
        efficacy of CAR20(NAP)-T for patients with B-cell malignancies.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        A cancer patient's T cells can be isolated and engineered to express a chimeric antigen&#xD;
        receptor (CAR), which re-directs the T cells to recognize and kill tumor cells expressing&#xD;
        that particular antigen. CD19-targeted CAR-T cell therapy has shown good effects for B cell&#xD;
        malignancies, even cure, in otherwise therapy refractory patients.&#xD;
  &#xD;
        Antigen escape, i.e., the downregulation of the antigen targeted by the CAR due to the&#xD;
        selective pressure caused by the CAR-T cell therapy is a challenge. For patients treated with&#xD;
        CD19 CAR-T cell therapy, about 30% of the patients are resistant to treatment and about 20%&#xD;
        of patients relapse after an initial response.&#xD;
  &#xD;
        CAR20(NAP)-T cells target CD20 and upon target recognition secrete a bacterial-derived&#xD;
        pluripotent immune-stimulating factor named NAP (Helicobacter pylori Neutrophil-activating&#xD;
        protein). Secretion of NAP in the tumor microenvironment can induce an endogenous bystander&#xD;
        immune response, that counteracts antigen escape and thereby improves the therapeutic&#xD;
        outcome.&#xD;
  &#xD;
        CAR20(NAP)-T is an investigational agent not yet approved by authorities.&#xD;
  &#xD;
        Design:&#xD;
  &#xD;
        The study is designed as 3+3 dose escalation phase I, and a dose expansion Phase IIa. The&#xD;
        safety, tolerability, PK/PD, and efficacy will be evaluated.Dose escalation is to be based on&#xD;
        the incidence of dose-limiting toxicity (DLTs). The investigator or sub-investigator will&#xD;
        decide if the AE is related to IMP-treatment on a case-by-case basis depending on the&#xD;
        character of the DLT symptoms. Investigator or sub-investigator has a possibility to classify&#xD;
        various toxicity observed in patient as DLT.The Recommended phase II dose (RP2D) is decided&#xD;
        based on safety, PK/PD data as well as preliminary clinical activity data from the Phase I&#xD;
        dose escalation. After setting the RP2D, additional patients will be treated at RP2D to make&#xD;
        sure at least 6 patients will be treated at RP2D dose level already at the phase I part.&#xD;
  &#xD;
        Protocol treatment:&#xD;
  &#xD;
        The enrolled patient will undergo a leukapheresis procedure to harvest enough T cells for IMP&#xD;
        production. During CAR20(NAP)-T manufacturing, the patient may receive bridging therapy to&#xD;
        control tumor burden. All patients will receive pre-conditioning chemotherapy&#xD;
        (cyclophosphamide and fludarabine) followed by one dose of CAR20(NAP)-T cell infusion&#xD;
        intravenously. The patient will then be followed by doctor/study nurse for evaluation of the&#xD;
        health status and side effects. At follow-up visits, blood samples will be obtained and CT&#xD;
        imaging will be performed. Patient will actively participate in the study for about 24 months&#xD;
        when the final follow-up visit will be scheduled.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">December 1, 2023</start_date>
    <completion_date type="Anticipated">December 30, 2027</completion_date>
    <primary_completion_date type="Anticipated">December 30, 2027</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>Incidence of dose limiting toxicity</measure>
      <time_frame>First infusion up to 30 days</time_frame>
      <description>The incidence of dose limiting toxicity (DLT). Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Adverse events</measure>
      <time_frame>24 months</time_frame>
      <description>The nature, frequency, severity, and tolerability of adverse events (AEs) including clinically significant laboratory data, and their relation to dosage.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Pharmacodynamic (PD) and pharmacokinetic (PK)</measure>
      <time_frame>Either 24 month or 15 years during long-term follow up if clinically indicated</time_frame>
      <description>PD is assessed by determine circulating B cell level; PK is assessed by determine circulating CAR20(NAP)-T cells.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Objective response rate [ORR]</measure>
      <time_frame>24 months</time_frame>
      <description>ORR is defined as the incidence of a complete response or a partial response by the revised Lugano classification as determined by the study investigators. All patients that do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression free survival [PFS]</measure>
      <time_frame>24 months</time_frame>
      <description>PFS is defined as the time from the IMP treatment date to the date of disease progression per the revised Lugano classification or death from any cause.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Best Objective Response</measure>
      <time_frame>24 months</time_frame>
      <description>the incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as best response to treatment.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration of Response (DOR)</measure>
      <time_frame>24 months</time_frame>
      <description>DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per the revised Lugano classification or death regardless of cause. Patients not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall Survival (OS)</measure>
      <time_frame>either 24 months or 15 years during long-term follow up if clinically indicated</time_frame>
      <description>defined as the time from IMP treatment to the date of death. Patients alive by the analysis data cutoff date will be censored at their last contact date. The overall survival rate will be reported at different cut-off time points.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Anti-NAP response</measure>
      <time_frame>either 24 months or 15 years during long-term follow up if clinically indicated</time_frame>
      <description>Determine anti-NAP immune response</description>
    </other_outcome>
    <other_outcome>
      <measure>Bystander immunity activation</measure>
      <time_frame>either 24 months or 15 years during long-term follow up if clinically indicated</time_frame>
      <description>Assess induced tumor specific endogenous T-cell immune response</description>
    </other_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">18</enrollment>
    <condition>B-cell Lymphoma</condition>
    <arm_group>
      <arm_group_label>Treatment</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>CAR20(NAP)-T treatment</description>
    </arm_group>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>CAR20(NAP)-T</intervention_name>
      <description>Autologous CAR-T cells targeting CD20 and upon target recognition express and secrete NAP</description>
      <arm_group_label>Treatment</arm_group_label>
      <other_name>ELC-301</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Cyclophosphamide</intervention_name>
      <description>pre-conditioning chemotherapy</description>
      <arm_group_label>Treatment</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Fludarabine</intervention_name>
      <description>pre-conditioning chemotherapy</description>
      <arm_group_label>Treatment</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Key Inclusion Criteria:&#xD;
  &#xD;
            -  Signed informed consent.&#xD;
  &#xD;
            -  Relapsed or refractory CD20+ diffuse large B-cell lymphoma, mantle cell lymphoma or&#xD;
               indolent lymphoma.&#xD;
  &#xD;
            -  The patient should have been treated with at least two lines of therapy and have no&#xD;
               curative treatment option, specifically&#xD;
  &#xD;
                 -  Relapsed or refractory CD20+ B-cell lymphoma that are not eligible to receive&#xD;
                    clinically approved CD19-directed CAR T cell treatment.&#xD;
  &#xD;
                 -  Relapsed or refractory CD20+ B-cell lymphoma who are CD19 negative.&#xD;
  &#xD;
                 -  Relapsed or refractory B-cell lymphoma who relapse after CD19 CAR T cell&#xD;
                    treatment.&#xD;
  &#xD;
            -  In phase I age &gt;18 years, in phase II all ages&#xD;
  &#xD;
            -  Measurable disease per Lugano classification.&#xD;
  &#xD;
            -  Performance status ECOG 0-2.&#xD;
  &#xD;
            -  Adequate bone marrow function as evidenced by:&#xD;
  &#xD;
                 -  Absolute neutrophil count (ANC) ≥ 1x10^9/l/L&#xD;
  &#xD;
                 -  Platelet ≥ 50x 10^9/l&#xD;
  &#xD;
                 -  Absolute lymphocyte count ≥ 0,1x10^9/L&#xD;
  &#xD;
            -  Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:&#xD;
  &#xD;
                 -  Creatinine clearance (Cockcroft Gault) ≥ 30 mL/min&#xD;
  &#xD;
                 -  Serum Alanine aminotransferase/Aspartate aminotransferase (ALT/AST) ≤ 2.5 Upper&#xD;
                    limit of normal (ULN) and S-Bilirubin &lt;1.5x UNL&#xD;
  &#xD;
                 -  Cardiac ejection fraction ≥ 40%&#xD;
  &#xD;
            -  Functional venous for administration of IMP.&#xD;
  &#xD;
            -  Fertile individuals must consent to use contraceptives during participation in the&#xD;
               trial.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Other CD20-positive lymphomas i.e Burkitt lymphoma, primary CNS lymphoma,&#xD;
               plasmablastic lymphoma or CLL transformed to DLBCL/HGBL (Richter transformation)&#xD;
  &#xD;
            -  Any significant medical or psychiatric illness that would prevent the subject from&#xD;
               giving informed consent or from following the study procedures.&#xD;
  &#xD;
            -  Known human immunodeficiency virus (HIV) infection.&#xD;
  &#xD;
            -  Impending organ-compromising disease.&#xD;
  &#xD;
            -  Rapidly progressing disease&#xD;
  &#xD;
            -  Active and/or severe infection (e.g., tuberculosis, sepsis and opportunistic&#xD;
               infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV)&#xD;
               infection.&#xD;
  &#xD;
            -  Other serious underlying medical conditions, which, in the Investigator's judgment,&#xD;
               could impair the ability of the subject to perform the treatment.&#xD;
  &#xD;
            -  Treatment with an investigational product within 30 days prior to enrolment&#xD;
  &#xD;
            -  Potential sign of hypersensitivity reaction to tocilizumab or any of the agents used&#xD;
               in this study&#xD;
  &#xD;
            -  Systemic corticosteroid treatment (&gt;10mg/day) &lt;5 days prior to IMP treatment or &lt;7&#xD;
               days prior leukapheresis.&#xD;
  &#xD;
            -  Pregnancy&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>N/A</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Di Yu, PhD</last_name>
      <role>Study Director</role>
      <affiliation>Uppsala University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Gunilla Enblad, MD/PhD</last_name>
      <phone>+46186110000</phone>
      <email>gunilla.enblad@igp.uu.se</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Di Yu, PhD</last_name>
      <phone>+46707204196</phone>
      <email>di.yu@igp.uu.se</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Karolinska University Hospital</name>
        <address>
          <city>Stockholm</city>
          <country>Sweden</country>
        </address>
      </facility>
      <contact>
        <last_name>Stephan Mielke</last_name>
      </contact>
      <investigator>
        <last_name>Stephan Mielke, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Uppsala University Hospital</name>
        <address>
          <city>Uppsala</city>
          <country>Sweden</country>
        </address>
      </facility>
      <contact>
        <last_name>Gunilla Enblad</last_name>
      </contact>
      <investigator>
        <last_name>Gunilla Enblad, MD/PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Sweden</country>
    </location_countries>
    <reference>
      <citation>Jin C, Ma J, Ramachandran M, Yu D, Essand M. CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers. Nat Biomed Eng. 2022 Jul;6(7):830-841. doi: 10.1038/s41551-022-00875-5. Epub 2022 Apr 4.</citation>
      <PMID>35379957</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>January 6, 2023</study_first_submitted>
    <study_first_submitted_qc>August 15, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 21, 2023</study_first_posted>
    <last_update_submitted>August 15, 2023</last_update_submitted>
    <last_update_submitted_qc>August 15, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>CAR T cell</keyword>
    <keyword>B cell lymphoma</keyword>
    <keyword>CD20</keyword>
    <keyword>HP-NAP</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lymphoma</mesh_term>
      <mesh_term>Lymphoma, B-Cell</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Cyclophosphamide</mesh_term>
      <mesh_term>Fludarabine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06002659
  org study id: ELC301-CARMA-01
  secondary id: 2022-004157-31
  nct id: NCT06002659
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The purpose is to study the safety, tolerability, pharmacokinetics, pharmacodynamics and
        efficacy of CAR20(NAP)-T for patients with B-cell malignancies.
  A cancer patient's T cells can be isolated and engineered to express a chimeric antigen
        receptor (CAR), which re-directs the T cells to recognize and kill tumor cells expressing
        that particular antigen. CD19-targeted CAR-T cell therapy has shown good effects for B cell
        malignancies, even cure, in otherwise therapy refractory patients.
  
        Antigen escape, i.e., the downregulation of the antigen targeted by the CAR due to the
        selective pressure caused by the CAR-T cell therapy is a challenge. For patients treated with
        CD19 CAR-T cell therapy, about 30% of the patients are resistant to treatment and about 20%
        of patients relapse after an initial response.
  
        CAR20(NAP)-T cells target CD20 and upon target recognition secrete a bacterial-derived
        pluripotent immune-stimulating factor named NAP (Helicobacter pylori Neutrophil-activating
        protein). Secretion of NAP in the tumor microenvironment can induce an endogenous bystander
        immune response, that counteracts antigen escape and thereby improves the therapeutic
        outcome.
  
        CAR20(NAP)-T is an investigational agent not yet approved by authorities.
  
        Design:
  
        The study is designed as 3+3 dose escalation phase I, and a dose expansion Phase IIa. The
        safety, tolerability, PK/PD, and efficacy will be evaluated.Dose escalation is to be based on
        the incidence of dose-limiting toxicity (DLTs). The investigator or sub-investigator will
        decide if the AE is related to IMP-treatment on a case-by-case basis depending on the
        character of the DLT symptoms. Investigator or sub-investigator has a possibility to classify
        various toxicity observed in patient as DLT.The Recommended phase II dose (RP2D) is decided
        based on safety, PK/PD data as well as preliminary clinical activity data from the Phase I
        dose escalation. After setting the RP2D, additional patients will be treated at RP2D to make
        sure at least 6 patients will be treated at RP2D dose level already at the phase I part.
  
        Protocol treatment:
  
        The enrolled patient will undergo a leukapheresis procedure to harvest enough T cells for IMP
        production. During CAR20(NAP)-T manufacturing, the patient may receive bridging therapy to
        control tumor burden. All patients will receive pre-conditioning chemotherapy
        (cyclophosphamide and fludarabine) followed by one dose of CAR20(NAP)-T cell infusion
        intravenously. The patient will then be followed by doctor/study nurse for evaluation of the
        health status and side effects. At follow-up visits, blood samples will be obtained and CT
        imaging will be performed. Patient will actively participate in the study for about 24 months
        when the final follow-up visit will be scheduled.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Incidence of dose limiting toxicity
  time frame: First infusion up to 30 days
  description: The incidence of dose limiting toxicity (DLT). Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
  measure: Adverse events
  time frame: 24 months
  description: The nature, frequency, severity, and tolerability of adverse events (AEs) including clinically significant laboratory data, and their relation to dosage.
  measure: Pharmacodynamic (PD) and pharmacokinetic (PK)
  time frame: Either 24 month or 15 years during long-term follow up if clinically indicated
  description: PD is assessed by determine circulating B cell level; PK is assessed by determine circulating CAR20(NAP)-T cells.
  measure: Objective response rate [ORR]
  time frame: 24 months
  description: ORR is defined as the incidence of a complete response or a partial response by the revised Lugano classification as determined by the study investigators. All patients that do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.
  measure: Progression free survival [PFS]
  time frame: 24 months
  description: PFS is defined as the time from the IMP treatment date to the date of disease progression per the revised Lugano classification or death from any cause.
  measure: Best Objective Response
  time frame: 24 months
  description: the incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as best response to treatment.
  measure: Duration of Response (DOR)
  time frame: 24 months
  description: DOR is defined as the date of their first objective response (which is subsequently confirmed) to disease progression per the revised Lugano classification or death regardless of cause. Patients not meeting the criteria for progression or death by the analysis data cutoff date will be censored at their last evaluable disease assessment date and their response will be noted as ongoing.
  measure: Overall Survival (OS)
  time frame: either 24 months or 15 years during long-term follow up if clinically indicated
  description: defined as the time from IMP treatment to the date of death. Patients alive by the analysis data cutoff date will be censored at their last contact date. The overall survival rate will be reported at different cut-off time points.
  measure: Anti-NAP response
  time frame: either 24 months or 15 years during long-term follow up if clinically indicated
  description: Determine anti-NAP immune response
  measure: Bystander immunity activation
  time frame: either 24 months or 15 years during long-term follow up if clinically indicated
  description: Assess induced tumor specific endogenous T-cell immune response
  arm group label: Treatment
  arm group type: Experimental
  description: CAR20(NAP)-T treatment
  intervention type: Biological
  intervention name: CAR20(NAP)-T
  description: Autologous CAR-T cells targeting CD20 and upon target recognition express and secrete NAP
  arm group label: Treatment
  other name: ELC-301
  intervention type: Drug
  intervention name: Cyclophosphamide
  description: pre-conditioning chemotherapy
  arm group label: Treatment
  intervention type: Drug
  intervention name: Fludarabine
  description: pre-conditioning chemotherapy
  arm group label: Treatment
  criteria: 
  gender: All
  minimum age: N/A
  maximum age: N/A
  healthy volunteers: No
  last name: Di Yu, PhD
  role: Study Director
  affiliation: Uppsala University
  last name: Gunilla Enblad, MD/PhD
  phone: +46186110000
  email: gunilla.enblad@igp.uu.se
  last name: Di Yu, PhD
  phone: +46707204196
  email: di.yu@igp.uu.se
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  investigator: 
  country: Sweden
  citation: Jin C, Ma J, Ramachandran M, Yu D, Essand M. CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers. Nat Biomed Eng. 2022 Jul;6(7):830-841. doi: 10.1038/s41551-022-00875-5. Epub 2022 Apr 4.
  PMID: 35379957
  responsible party type: Sponsor
  mesh term: Lymphoma
  mesh term: Lymphoma, B-Cell
  mesh term: Cyclophosphamide
  mesh term: Fludarabine
  sharing ipd: No