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/NCT06027983</url>
    </required_header>
    <id_info>
      <org_study_id>ACEHER2</org_study_id>
      <nct_id>NCT06027983</nct_id>
    </id_info>
    <brief_title>ADDC-R - Epo-R T Cells With Trastuzumab in HER2+ Advanced Breast Cancer and Other Solid Tumors</brief_title>
    <official_title>Phase IB Followed by Phase II Study of Trastuzumab Combined With Autologous T Cells Expressing an Antibody-dependent Cell Cytotoxicity Receptor (ADCC-R) and an Erythropoietin Receptor (Epo-R) in HER2+ Advanced Breast Cancer and Other Solid Tumors</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>National University Hospital, Singapore</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>National University Hospital, Singapore</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This phase Ib study aims to assess the safety and feasibility of combination of ADCC-R-Epo-R&#xD;
        T cells with trastuzumab in patients with HER2+ solid tumors, with further expansion of study&#xD;
        population in HER2+ metastatic breast cancer once safety has been established.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Hypothesis&#xD;
  &#xD;
        Investigator hypothesize that trastuzumab-mediated ADCC will be augmented by the infusion of&#xD;
        autologous ADCC-R-Epo-R T-cells. Investigator further hypothesize that infused ADCC-R Epo-R&#xD;
        T-cells can expand in vivo in the absence of prior lymphodepletion, supported by either&#xD;
        endogenous levels of Epo or exogenous Epo administration.&#xD;
  &#xD;
        Primary Objectives&#xD;
  &#xD;
          1. To determine the safety of autologous ADCC-R-Epo-R T-cells in patients with HER2+&#xD;
             advanced solid tumors&#xD;
  &#xD;
          2. To determine the clinical benefit rate (CBR) of autologous ADCC-R-Epo-R T-cells in&#xD;
             patients with HER2+ advanced breast cancer&#xD;
  &#xD;
        Secondary Objectives&#xD;
  &#xD;
          1. To determine the expansion and persistence of autologous ADCC-R-Epo-R T-cells after a&#xD;
             single infusion in patients with advanced solid tumors&#xD;
  &#xD;
          2. To determine anti-tumor efficacy in terms of objective response rate (ORR) and&#xD;
             progression-free survival (PFS) of autologous ADCC-R-Epo-R T-cells in patients with&#xD;
             HER2+ advanced breast cancer&#xD;
  &#xD;
        Exploratory Objectives&#xD;
  &#xD;
          1. To determine if endogenous levels of Epo can stimulate and support the expansion of&#xD;
             ADCC-R-Epo-R T-cells in vivo&#xD;
  &#xD;
          2. To investigate if exogenous administration of Epo can support the persistence of&#xD;
             ADCC-R-Epo-R T-cells in vivo when endogenous Epo is not sufficient&#xD;
  &#xD;
          3. To study the presence of ADCC-R-Epo-R T-cells in tumors and tumor microenvironment using&#xD;
             serial tumor biopsies&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">November 1, 2023</start_date>
    <completion_date type="Anticipated">December 31, 2027</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2025</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>
      <intervention_model_description>This is a single arm, open-label, phase Ib safety lead in, followed by phase II study. The phase Ib segment will be carried out in a standard 3+3 dose escalation design. In the phase II, dose expansion will be carried out to a total of 10 patients at recommended phase II dose in both phase Ib and II.&#xD;
  Phase Ib: Patients with advanced solid tumors will be enrolled in a 3+3 dose escalation fashion, with projected enrolment of between 6-30 patients to determine RP2D. Once the RP2D is confirmed, the study will proceed to phase II.&#xD;
  Phase II: Up to a total of 10 patients with HER2+ advanced breast cancer will be enrolled.&#xD;
  For patients who are in Dose level 3 - 5 will require additional Trastuzumab,erythropoietin beta and Lymphodepletion.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Time to treatment failure</measure>
      <time_frame>3 years</time_frame>
      <description>defined as the time from the date of study enrolment to the date of the first of the following events: early discontinuation of study therapy, progressive disease, or death due to any cause. Time to treatment failure will be censored at the date of the last follow-up visit for patients who did not discontinue early, who are still alive, and who have not progressed.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Progression-free survival</measure>
      <time_frame>3 Years</time_frame>
      <description>is defined as the time from the date of study enrolment to the first date of documented disease progression. Progression-free survival will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, progression-free survival will be censored at the date of the last follow-up visit.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Duration of tumour response</measure>
      <time_frame>3 Years</time_frame>
      <description>Among tumor responders, the duration of tumor response is measured from the date of enrolment until the first date of documented disease progression or death due to any cause, whichever occurs first. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.</description>
    </primary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">36</enrollment>
    <condition>HER2+ Advanced Breast Cancer</condition>
    <condition>Other Solid Tumors</condition>
    <arm_group>
      <arm_group_label>ADCC-R-Epo-R T-cells</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Eligible patients will undergo apheresis prior to cycle 1 therapy. Treatment comprises of trastuzumab followed by ADCC-R-Epo-R T-cells in cycle 1. Subcutaneous Erythropoetin beta (SC Epo) will be administered during cycle 1 in dose levels 3, 4, and 5.&#xD;
  Lymphodepletion will be carried out in dose level 5, with fludarabine and cyclophosphamide.&#xD;
  During Cycle 2 onwards till disease progression, patients will receive IV or SC trastuzumab only, every 3 weeks.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>ADCC-R-Epo-R T-cells + Trastuzumab</intervention_name>
      <description>ADCC-R-Epo-R T-cells will be administered by infusion. Trastuzumab will be administered intravenously.</description>
      <arm_group_label>ADCC-R-Epo-R T-cells</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Erythropoietin beta</intervention_name>
      <description>Administered as Subcutaneously</description>
      <arm_group_label>ADCC-R-Epo-R T-cells</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Fludarabine and Cyclophosphosphamide</intervention_name>
      <description>3-day chemotherapy regimen of fludarabine and cyclophosphamide for lymphodepletion</description>
      <arm_group_label>ADCC-R-Epo-R T-cells</arm_group_label>
      <other_name>Lymphodepletion</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          Patients may be included in the study only if they meet all of the following criteria:&#xD;
  &#xD;
            -  Age ≥ 21 years.&#xD;
  &#xD;
            -  Histologically confirmed diagnosis of HER2-positive cancer defined by&#xD;
               immunohistochemistry (IHC) to be HER2 IHC3+ or HER2 IHC2+ and FISH positive. If&#xD;
               immunohistochemistry is not available, FISH method is acceptable. The HER2&#xD;
               positivities by FISH is determined as FISH amplification ratio positive by&#xD;
               institutional guidelines. Tumor subtype for each phase include :&#xD;
  &#xD;
            -  Phase I: HER2-positive breast or gastric cancer or other treatment-refractory&#xD;
               HER2-positive solid tumors&#xD;
  &#xD;
            -  Phase II : HER2-positive breast carcinoma&#xD;
  &#xD;
            -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1.&#xD;
  &#xD;
            -  Has measurable or evaluable disease based on RECIST 1.1 criteria&#xD;
  &#xD;
            -  Estimated life expectancy of at least 12 weeks.&#xD;
  &#xD;
            -  Prior lines of therapy:&#xD;
  &#xD;
            -  HER2-positive breast cancer - patient must have failed at least two lines of anti-HER2&#xD;
               based therapy for advanced/metastatic cancer. Patients with documented relapse while&#xD;
               receiving or within 6 months of completion of adjuvant or neoadjuvant trastuzumab for&#xD;
               HER2-positive breast cancer will be considered as 1 prior line of therapy.&#xD;
  &#xD;
            -  HER2-positive gastric cancer - patient must have failed at least one line of anti-HER2&#xD;
               based therapy.&#xD;
  &#xD;
            -  Other refractory HER2-positive solid tumors (non-breast, non-gastric) - have no&#xD;
               standard therapies or have failed or unable to tolerate standard therapies&#xD;
  &#xD;
            -  Has recovered from acute toxicities from prior anti-cancer therapies&#xD;
  &#xD;
            -  Left ventricular ejection fraction ≥50%&#xD;
  &#xD;
            -  Adequate organ function including the following:&#xD;
  &#xD;
               o Bone marrow: Absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L&#xD;
               Platelets ≥ 100 x 109/L Haemoglobin ≥ 8 x 109/L&#xD;
  &#xD;
               o Hepatic: Bilirubin ≤ 1.5 x upper limit of normal (ULN), ALT or AST≤ 2.5x ULN, (or ≤5&#xD;
               X with liver metastases)&#xD;
  &#xD;
               o Renal: Creatinine ≤ 1.5x ULN&#xD;
  &#xD;
            -  Signed informed consent from patient or legal representative.&#xD;
  &#xD;
            -  Able to comply with study-related procedures.&#xD;
  &#xD;
            -  Specific to cohorts 3, 4 and 5 : Patients who have a history of VTE are eligible if as&#xD;
               long as they are receiving therapeutic/prophylactic doses of anticoagulation.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Patients will be excluded from the study for any of the following reasons:&#xD;
  &#xD;
            -  Treatment within the last 30 days with any investigational drug.&#xD;
  &#xD;
            -  Concurrent administration of any other tumour therapy, including cytotoxic&#xD;
               chemotherapy, hormonal therapy, and immunotherapy.&#xD;
  &#xD;
            -  Major surgery within 28 days of study drug administration.&#xD;
  &#xD;
            -  Active infection that in the opinion of the investigator would compromise the&#xD;
               patient's ability to tolerate therapy.&#xD;
  &#xD;
            -  Pregnancy.&#xD;
  &#xD;
            -  Breast feeding.&#xD;
  &#xD;
            -  Serious concomitant disorders that would compromise the safety of the patient or&#xD;
               compromise the patient's ability to complete the study, at the discretion of the&#xD;
               investigator.&#xD;
  &#xD;
            -  Active bleeding disorder or bleeding site.&#xD;
  &#xD;
            -  Non-healing wound.&#xD;
  &#xD;
            -  Poorly controlled diabetes mellitus.&#xD;
  &#xD;
            -  Second primary malignancy that is clinically detectable at the time of consideration&#xD;
               for study enrolment.&#xD;
  &#xD;
            -  Symptomatic brain metastasis.&#xD;
  &#xD;
            -  History of significant neurological or mental disorder, including seizures or&#xD;
               dementia,&#xD;
  &#xD;
            -  History of autoimmune disease or use of gamma immunoglobulin&#xD;
  &#xD;
            -  Unable to comply with study procedures&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>21 Years</minimum_age>
      <maximum_age>99 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Soo Chin Lee</last_name>
      <role>Principal Investigator</role>
      <affiliation>National University Hospital, Singapore</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Soo Chin Lee</last_name>
      <phone>+65 6908 2222</phone>
      <email>soo_chin_lee@nuhs.edu.sg</email>
    </overall_contact>
    <results_reference>
      <citation>Lee SC, Shimasaki N, Lim JSJ, Wong A, Yadav K, Yong WP, Tan LK, Koh LP, Poon MLM, Tan SH, Ow SGW, Bharwani L, Yap YS, Foo MZQ, Coustan-Smith E, Sundar R, Tan HL, Chong WQ, Kumarakulasinghe NB, Lieow JLM, Koe PJX, Goh BC, Campana D. Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Clin Cancer Res. 2020 Sep 1;26(17):4494-4502. doi: 10.1158/1078-0432.CCR-20-0768. Epub 2020 Jun 10.</citation>
      <PMID>32522887</PMID>
    </results_reference>
    <results_reference>
      <citation>Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K, Davidoff AM, Chng WJ, Campana D. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 2014 Jan 1;74(1):93-103. doi: 10.1158/0008-5472.CAN-13-1365. Epub 2013 Nov 6.</citation>
      <PMID>24197131</PMID>
    </results_reference>
    <results_reference>
      <citation>Vinanica N, Yong A, Wong D, Png YT, Seow SV, Imamura M, Campana D. Specific stimulation of T lymphocytes with erythropoietin for adoptive immunotherapy. Blood. 2020 Feb 27;135(9):668-679. doi: 10.1182/blood.2019001645.</citation>
      <PMID>31697835</PMID>
    </results_reference>
    <verification_date>June 2023</verification_date>
    <study_first_submitted>August 31, 2023</study_first_submitted>
    <study_first_submitted_qc>August 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 7, 2023</study_first_posted>
    <last_update_submitted>September 14, 2023</last_update_submitted>
    <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Breast Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Trastuzumab</mesh_term>
      <mesh_term>Fludarabine</mesh_term>
      <mesh_term>Epoetin Alfa</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/NCT06027983
  org study id: ACEHER2
  nct id: NCT06027983
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  This phase Ib study aims to assess the safety and feasibility of combination of ADCC-R-Epo-R
        T cells with trastuzumab in patients with HER2+ solid tumors, with further expansion of study
        population in HER2+ metastatic breast cancer once safety has been established.
  Hypothesis
  
        Investigator hypothesize that trastuzumab-mediated ADCC will be augmented by the infusion of
        autologous ADCC-R-Epo-R T-cells. Investigator further hypothesize that infused ADCC-R Epo-R
        T-cells can expand in vivo in the absence of prior lymphodepletion, supported by either
        endogenous levels of Epo or exogenous Epo administration.
  
        Primary Objectives
  
          1. To determine the safety of autologous ADCC-R-Epo-R T-cells in patients with HER2+
             advanced solid tumors
  
          2. To determine the clinical benefit rate (CBR) of autologous ADCC-R-Epo-R T-cells in
             patients with HER2+ advanced breast cancer
  
        Secondary Objectives
  
          1. To determine the expansion and persistence of autologous ADCC-R-Epo-R T-cells after a
             single infusion in patients with advanced solid tumors
  
          2. To determine anti-tumor efficacy in terms of objective response rate (ORR) and
             progression-free survival (PFS) of autologous ADCC-R-Epo-R T-cells in patients with
             HER2+ advanced breast cancer
  
        Exploratory Objectives
  
          1. To determine if endogenous levels of Epo can stimulate and support the expansion of
             ADCC-R-Epo-R T-cells in vivo
  
          2. To investigate if exogenous administration of Epo can support the persistence of
             ADCC-R-Epo-R T-cells in vivo when endogenous Epo is not sufficient
  
          3. To study the presence of ADCC-R-Epo-R T-cells in tumors and tumor microenvironment using
             serial tumor biopsies
  allocation: N/A
  intervention model: Sequential Assignment
  intervention model description: This is a single arm, open-label, phase Ib safety lead in, followed by phase II study. The phase Ib segment will be carried out in a standard 3+3 dose escalation design. In the phase II, dose expansion will be carried out to a total of 10 patients at recommended phase II dose in both phase Ib and II.
  Phase Ib: Patients with advanced solid tumors will be enrolled in a 3+3 dose escalation fashion, with projected enrolment of between 6-30 patients to determine RP2D. Once the RP2D is confirmed, the study will proceed to phase II.
  Phase II: Up to a total of 10 patients with HER2+ advanced breast cancer will be enrolled.
  For patients who are in Dose level 3 - 5 will require additional Trastuzumab,erythropoietin beta and Lymphodepletion.
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Time to treatment failure
  time frame: 3 years
  description: defined as the time from the date of study enrolment to the date of the first of the following events: early discontinuation of study therapy, progressive disease, or death due to any cause. Time to treatment failure will be censored at the date of the last follow-up visit for patients who did not discontinue early, who are still alive, and who have not progressed.
  measure: Progression-free survival
  time frame: 3 Years
  description: is defined as the time from the date of study enrolment to the first date of documented disease progression. Progression-free survival will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, progression-free survival will be censored at the date of the last follow-up visit.
  measure: Duration of tumour response
  time frame: 3 Years
  description: Among tumor responders, the duration of tumor response is measured from the date of enrolment until the first date of documented disease progression or death due to any cause, whichever occurs first. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.
  arm group label: ADCC-R-Epo-R T-cells
  arm group type: Experimental
  description: Eligible patients will undergo apheresis prior to cycle 1 therapy. Treatment comprises of trastuzumab followed by ADCC-R-Epo-R T-cells in cycle 1. Subcutaneous Erythropoetin beta (SC Epo) will be administered during cycle 1 in dose levels 3, 4, and 5.
  Lymphodepletion will be carried out in dose level 5, with fludarabine and cyclophosphamide.
  During Cycle 2 onwards till disease progression, patients will receive IV or SC trastuzumab only, every 3 weeks.
  intervention type: Drug
  intervention name: ADCC-R-Epo-R T-cells + Trastuzumab
  description: ADCC-R-Epo-R T-cells will be administered by infusion. Trastuzumab will be administered intravenously.
  arm group label: ADCC-R-Epo-R T-cells
  intervention type: Drug
  intervention name: Erythropoietin beta
  description: Administered as Subcutaneously
  arm group label: ADCC-R-Epo-R T-cells
  intervention type: Drug
  intervention name: Fludarabine and Cyclophosphosphamide
  description: 3-day chemotherapy regimen of fludarabine and cyclophosphamide for lymphodepletion
  arm group label: ADCC-R-Epo-R T-cells
  other name: Lymphodepletion
  criteria: 
  gender: All
  minimum age: 21 Years
  maximum age: 99 Years
  healthy volunteers: No
  last name: Soo Chin Lee
  role: Principal Investigator
  affiliation: National University Hospital, Singapore
  last name: Soo Chin Lee
  phone: +65 6908 2222
  email: soo_chin_lee@nuhs.edu.sg
  citation: Lee SC, Shimasaki N, Lim JSJ, Wong A, Yadav K, Yong WP, Tan LK, Koh LP, Poon MLM, Tan SH, Ow SGW, Bharwani L, Yap YS, Foo MZQ, Coustan-Smith E, Sundar R, Tan HL, Chong WQ, Kumarakulasinghe NB, Lieow JLM, Koe PJX, Goh BC, Campana D. Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Clin Cancer Res. 2020 Sep 1;26(17):4494-4502. doi: 10.1158/1078-0432.CCR-20-0768. Epub 2020 Jun 10.
  PMID: 32522887
  citation: Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K, Davidoff AM, Chng WJ, Campana D. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 2014 Jan 1;74(1):93-103. doi: 10.1158/0008-5472.CAN-13-1365. Epub 2013 Nov 6.
  PMID: 24197131
  citation: Vinanica N, Yong A, Wong D, Png YT, Seow SV, Imamura M, Campana D. Specific stimulation of T lymphocytes with erythropoietin for adoptive immunotherapy. Blood. 2020 Feb 27;135(9):668-679. doi: 10.1182/blood.2019001645.
  PMID: 31697835
  responsible party type: Sponsor
  mesh term: Breast Neoplasms
  mesh term: Trastuzumab
  mesh term: Fludarabine
  mesh term: Epoetin Alfa
  sharing ipd: No