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/NCT05981014</url>
    </required_header>
    <id_info>
      <org_study_id>【2021】04-01</org_study_id>
      <nct_id>NCT05981014</nct_id>
    </id_info>
    <brief_title>Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes as Neoadjuvant Therapy for HER2-Negative Breast Cancer</brief_title>
    <official_title>An Open-Label Phase I/II Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes as Neoadjuvant Therapy for HER2-Negative Breast Cancer</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Sun Yat-Sen Memorial Hospital of Sun Yat-Sen 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>
        RATIONALE: Patients with HER2-negative breast cancer not responding to initial neoadjuvant&#xD;
        chemotherapy might have lower chances for a pathologic complete response (pCR) at definitive&#xD;
        surgery, indicating worse prognosis. Adoptive cell therapy has demonstrated efficacy in&#xD;
        advanced breast cancer, but whether the addition of adoptive cell therapy to neoadjuvant&#xD;
        chemotherapy could increase the pCR rate remains unclear. Tumor-draining lymph node-derived&#xD;
        lymphocytes (LNLs) that have abundant tumor-reactive T cells, but not exhausted T cells, are&#xD;
        easy to produce. It is not yet known whether LNL treatment is safe and effective in patients&#xD;
        with HER2-negative breast cancer not responding to neoadjuvant chemotherapy.&#xD;
  &#xD;
        PURPOSE: This open-label phase I/II trial is to investigate the safety and efficacy of&#xD;
        autologous LNL in patients with HER2-negative breast cancer not responding to neoadjuvant&#xD;
        chemotherapy.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Recruiting</overall_status>
    <start_date type="Anticipated">August 1, 2023</start_date>
    <completion_date type="Anticipated">May 31, 2035</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2030</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>Randomized</allocation>
      <intervention_model>Sequential Assignment</intervention_model>
      <intervention_model_description>Phase I: Single-arm, dose-escalation and dose-expansion study Phase II: Two-arm parallel assignment</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Phase I: Incidence of Dose-Limiting Toxicity (DLT)</measure>
      <time_frame>From the LNL infusion up to 28 days post-infusion</time_frame>
      <description>Adverse events are reported based upon Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. DLT will be defined as a non-hematologic Grade 3 or higher adverse event, occurring within the 28 days immediately after LNL infusion, that is probably or definitely related to LNL infusion, and lasts more than 28 days or does not resolve to Grade&lt;3 despite treatment with dexamethasone at 10 mg per 12 hours IV for 7 days (or other corticosteroid at equivalent dose), and/or tocilizumab at 8mg/kg IV for three times.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Phase I: Incidence of Grade≥3 Treatment-Emergent Adverse Event (TEAE)</measure>
      <time_frame>From the LNL infusion up to 28 days post-infusion</time_frame>
      <description>Adverse events are reported based upon CTCAE version 5.0 criteria. The incidence of Grade≥3 TEAE occurring within the 28 days immediately after LNL infusion will be summarized with descriptive statistics.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Phase II: Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery</measure>
      <time_frame>Up to approximately 18~29 weeks</time_frame>
      <description>pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the local pathologist at the time of definitive surgery.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Phase I: Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery</measure>
      <time_frame>Up to approximately 26~29 weeks</time_frame>
      <description>pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the local pathologist at the time of definitive surgery.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I and phase II: Objective Response Rate (ORR)</measure>
      <time_frame>Up to approximately 26~29 weeks</time_frame>
      <description>Objective response rate is defined as the percentage of participants in the analysis population who have a complete response (CR) or partial response (PR) during the study. The percentage of participants who experienced a CR or PR assessed by modified RECIST criteria by breast MRI is presented.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I and phase II: 6-month, 1-year and 2-year Event-Free Survival (EFS)</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>Event-free survival is defined as the time from enrollment (phase I) or randomization (phase II) to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast) after surgery or death due to any cause. Patients who terminate the study without evidence of any of the above events will be censored at the date of their last follow-up tumor assessment. Patients who start a new anti-tumor therapy (with the exception of adjuvant endocrine therapy in ER or PgR positive tumors after surgery) in the absence of disease progression or recurrence will be censored at their last follow-up tumor assessment before the start of the new therapy.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I and phase II: Overall Survival (OS)</measure>
      <time_frame>Up to approximately five years</time_frame>
      <description>Overall survival is defined as the time from enrollment (phase I) or randomization (phase II) to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I: Levels of multiple different cytokines in blood samples before and after LNL infusion.</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>To evaluate the pharmacokinetics and pharmacodynamics of LNL, levels of multiple different cytokines in blood samples including Granzyme B, IFN-γ, GM-CSF, IL-2, IL-4, IL-6, etc. will be measured using cytokine chips, ELISA or flow cytometry at various time points before and after LNL infusion.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I: Distribution of T cell subsets in blood samples before and after LNL infusion.</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>To evaluate the pharmacokinetics and pharmacodynamics of LNL, distribution of T cell subsets in blood samples will be measured using flow cytometry at various time points before and after LNL infusion.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I: Distribution of T-cell receptor (TCR) clonotype in blood samples before and after LNL infusion.</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>To evaluate the pharmacokinetics and pharmacodynamics of LNL, distribution of T-cell receptor (TCR) clonotype in blood samples will be measured using TCR sequencing at various time points before and after LNL infusion.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase II: Incidence of Grade≥3 Treatment-Emergent Adverse Event (TEAE)</measure>
      <time_frame>From the LNL infusion up to 28 days post-infusion</time_frame>
      <description>Adverse events are reported based upon CTCAE version 5.0 criteria. The incidence of Grade≥3 TEAE occurring within the 28 days immediately after LNL infusion will be summarized with descriptive statistics.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">196</enrollment>
    <condition>Breast Neoplasms</condition>
    <arm_group>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants in both phase I and phase II portions receive two cycles of doxorubicin or epirubicin, plus cyclophosphamide (AC or EC), followed by neoadjuvant LNL treatment, which consists of non-myeloablative lymphocyte depleting regimen of chemotherapy with cyclophosphamide and fludarabine, followed by infusion of LNL and interleukin-2. After LNL treatment, participants receive four-cycles of nab-paclitaxel as neoadjuvant therapy prior to definitive surgery. The choice of doxorubicin or epirubicin should be the same as the prior neoadjuvant chemotherapy.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Phase II: Chemotherapy</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>The single-arm phase I study did not have this arm. Participants in phase II portion receive two cycles of doxorubicin or epirubicin, plus cyclophosphamide (AC or EC), followed by four-cycles of nab-paclitaxel as neoadjuvant therapy prior to definitive surgery. The choice of doxorubicin or epirubicin should be the same as the prior neoadjuvant chemotherapy.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Sentinel Lymph Node Biopsy (SLNB)</intervention_name>
      <description>A sample of the participant's tumor-draining lymph nodes will be collected and sent to the biotherapy center for LNL isolation and expansion.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <other_name>SLNB</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Doxorubicin</intervention_name>
      <description>Doxorubicin will be administered at 60 mg/m^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <arm_group_label>Phase II: Chemotherapy</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Epirubicin</intervention_name>
      <description>Epirubicin will be administered at 100 mg/m^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <arm_group_label>Phase II: Chemotherapy</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Cyclophosphamide</intervention_name>
      <description>Cyclophosphamide will be administered at 600 mg/m^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <arm_group_label>Phase II: Chemotherapy</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Cyclophosphamide</intervention_name>
      <description>Cyclophosphamide will be administered at 60 mg/kg IV daily over approximately two hours for two days. Cyclophosphamide will be initiated seven days prior to the anticipated LNL transfer, and the precise timing will depend on the rate of in vitro LNL growth.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Fludarabine</intervention_name>
      <description>After administration of cyclophosphamide, fludarabine will then be infused at 25 mg/m^2 intravenous piggyback (IVPB) daily over approximately 30 minutes for five days, starting five days prior to LNL transfer.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Tumor-draining lymph node-derived lymphocyte (LNL)</intervention_name>
      <description>In the dose-escalation portion of phase I study, participants receive ascending dose (1×10^9~18×10^9), single Infusion of LNL on day 0. In the dose-expansion portion of phase I study, participants receive single infusion of LNL at the recommended phase 2 dose (RP2D).&#xD;
  In the phase II study, participants receive single infusion of LNL at the RP2D.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <other_name>LNL</other_name>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Interleukin-2</intervention_name>
      <description>Eight to twelve hours after completing the LNL infusion, all participants will receive intermediate-dose decrescendo IL-2 IV.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <other_name>IL-2</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Nab-paclitaxel</intervention_name>
      <description>Nab-paclitaxel will be administered at 260 mg/m^2 IV on Day 1 of Cycles 3-6 of the neoadjuvant chemotherapy of the study.</description>
      <arm_group_label>Phase I and phase II: Chemotherapy + LNL treatment</arm_group_label>
      <arm_group_label>Phase II: Chemotherapy</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          In order to be eligible for participation in this trial, the participant must:&#xD;
  &#xD;
            1. Have signed the informed consent to study participation.&#xD;
  &#xD;
            2. Be a female subject and aged between 18 and 70 years.&#xD;
  &#xD;
            3. Provide a core needle biopsy which is histologically confirmed as invasive breast&#xD;
               cancer. Excisional biopsy or surgical biopsy is not allowed.&#xD;
  &#xD;
            4. Have received two cycles of doxorubicin or epirubicin, plus cyclophosphamide, and had&#xD;
               stable disease (SD) confirmed by breast MRI.&#xD;
  &#xD;
            5. Have breast cancer defined as the following combined primary tumor (T), regional lymph&#xD;
               node (N), and distant metastasis (M) staging per AJCC for breast cancer staging&#xD;
               criteria version 8 based on breast MRI assessment:&#xD;
  &#xD;
               The minimum size of the primary tumor was 1 cm in largest diameter by breast MRI,&#xD;
               N0-3, M0.&#xD;
  &#xD;
            6. Have HER2-negative breast cancer, defined as 0-1+ by immunohistochemistry or 2+ by&#xD;
               immunohistochemistry without HER2 amplification by FISH.&#xD;
  &#xD;
            7. Have known hormone receptor status (estrogen receptor [ER], progesterone receptor&#xD;
               [PgR]), Ki67 value and, if institutional standard permits, known tumor grade.&#xD;
  &#xD;
            8. Have not received prior therapies for breast cancer, including but not limited to,&#xD;
               chemotherapy (except two cycles of doxorubicin or epirubicin, plus cyclophosphamide),&#xD;
               radiotherapy, hormonal therapy, targeted therapy, biological therapy and surgery.&#xD;
  &#xD;
            9. Have accessible tumor-draining lymph nodes by surgery to grow LNL. Participants have&#xD;
               not received sentinel lymph node biopsy (SLNB) and ipsilateral axillary lymph node&#xD;
               dissection (ALND) for the breast cancer lesion.&#xD;
  &#xD;
           10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
  &#xD;
           11. Demonstrate adequate normal organ function:&#xD;
  &#xD;
               NOTE: Blood component or cytokine therapy is not allowed within 14 days before&#xD;
               surgery.&#xD;
  &#xD;
                 1. Routine blood test:&#xD;
  &#xD;
                      -  Absolute neutrophil count (ANC) ≥1.5×10^9/L&#xD;
  &#xD;
                      -  Lymphocyte count (LC) &gt;0.5×10^9/L&#xD;
  &#xD;
                      -  Platelets (PLT) ≥100×10^9/L&#xD;
  &#xD;
                      -  Hemoglobin (Hb) ≥90 g/L&#xD;
  &#xD;
                 2. Liver function test:&#xD;
  &#xD;
                      -  AST and ALT ≤2.5 ×ULN (≤5×ULN for participants with liver metastases)&#xD;
  &#xD;
                      -  ALP ≤2.5 ×ULN (≤5×ULN for participants with liver or bone metastases)&#xD;
  &#xD;
                      -  Total bilirubin ≤1.5×ULN (≤3.0 mg/dL for participants with Gilbert's&#xD;
                         syndrome)&#xD;
  &#xD;
                 3. Renal function test:&#xD;
  &#xD;
                    • Calculated creatinine clearance (CrCL) ≥45 mL/min OR creatinine ≤1.5 × ULN&#xD;
  &#xD;
                 4. Coagulation function test:&#xD;
  &#xD;
                      -  APTT ≤1.5 ×ULN&#xD;
  &#xD;
                      -  INR or PT ≤1.5×ULN&#xD;
  &#xD;
                 5. Doppler echocardiography:&#xD;
  &#xD;
                    • Left ventricular ejection fraction (LVEF) ≥50%&#xD;
  &#xD;
                 6. Pulmonary function test:&#xD;
  &#xD;
                      -  FEV1≥60%&#xD;
  &#xD;
           12. Female participants of childbearing potential must be willing to use an adequate&#xD;
               method of contraception for the course of the study through one year (or longer as&#xD;
               specified by local institutional guidelines) after the last dose of study treatment.&#xD;
               Female subjects of childbearing potential must have a negative serum pregnancy test&#xD;
               within 7 days prior to LNL infusion.&#xD;
  &#xD;
           13. Have recovered from prior therapy-related adverse events to Grade≤1 per CTCAE version&#xD;
               5.0 criteria or met the criteria of normal organ function specified above prior to the&#xD;
               surgery for obtaining the lymph nodes, except for second-degree peripheral nerve&#xD;
               injury, alopecia, leukoderma, hypothyroidism controlled by thyroid hormone replacement&#xD;
               therapy, type 1 diabetes controlled by insulin therapy, and other irreversible toxic&#xD;
               events that would not be exacerbated by LNL infusion as judged by the investigator&#xD;
               (e.g., hearing loss).&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          The participant must be excluded from participating in this trial if the participant:&#xD;
  &#xD;
            1. Has metastatic breast cancer.&#xD;
  &#xD;
            2. Has a known additional malignancy within the last 5 years. Exceptions include basal&#xD;
               cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone&#xD;
               potentially curative therapy, in situ cervical cancer, and ductal carcinoma in situ&#xD;
               that has undergone radical mastectomy.&#xD;
  &#xD;
            3. Has a known history of cardiovascular disease, including but not limited to, (1)&#xD;
               congestive heart failure (New York Heart Association [NYHA] functional classification&#xD;
               Class &gt; 2), (2) unstable angina pectoris, (3) myocardial infarction in the past 3&#xD;
               months, (4) supraventricular arrhythmia or ventricular arrhythmia that requires&#xD;
               treatments.&#xD;
  &#xD;
            4. Has interstitial pneumonia or active pneumonia that has clinical implications, or&#xD;
               other respiratory diseases that seriously affect pulmonary function.&#xD;
  &#xD;
            5. Has an active infection requiring systemic therapy or has an unexplained fever of&#xD;
               &gt;38.5℃ except fevers caused by cancer.&#xD;
  &#xD;
            6. Has arterial and/or venous thrombotic events in the past 5 months, e.g.,&#xD;
               cerebrovascular accident, deep vein thrombosis or pulmonary embolism.&#xD;
  &#xD;
            7. Has a known psychiatric, alcohol abuse or substance abuse disorders.&#xD;
  &#xD;
            8. Is pregnant or breastfeeding.&#xD;
  &#xD;
            9. Has an active autoimmune disease, a history of autoimmune disease, or autoimmune&#xD;
               disease that has required systemic treatment (e.g., with use of prednisone at a dose&#xD;
               of &gt;10mg per day or other corticosteroids at an equivalent dose). Replacement therapy&#xD;
               (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for&#xD;
               adrenal or pituitary insufficiency) is allowed.&#xD;
  &#xD;
           10. Has a history of congenital immunodeficiency or acquired immunodeficiency (e.g.,&#xD;
               positive serology test for HIV).&#xD;
  &#xD;
           11. Has tuberculosis in the past one year, or has a history of active tuberculosis more&#xD;
               than one year but did not receive regular treatments.&#xD;
  &#xD;
           12. Has known active hepatitis B or hepatitis C. Participants that are hepatitis B surface&#xD;
               antigen (HBsAg) or hepatitis B core antigen (HBcAg) positive may participate provided&#xD;
               that the HBV DNA level is normal. Participants that are hepatitis C antibody positive&#xD;
               may participate provided that the HCV DNA level is normal. Carriers of HBV or HCV must&#xD;
               receive anti-virus therapy, and take regular DNA copy number tests during this trial.&#xD;
  &#xD;
           13. Has received a live vaccine within 4 weeks prior to enrollment, or plans to receive a&#xD;
               live vaccine during this trial.&#xD;
  &#xD;
           14. Has a history of allogeneic bone marrow or organ transplant.&#xD;
  &#xD;
           15. Has received the study-related drugs including anthracycline, cyclophosphamide,&#xD;
               taxane, fludarabine, interleukin-2, except two cycles of doxorubicin or epirubicin,&#xD;
               plus cyclophosphamide.&#xD;
  &#xD;
           16. Has a history of hypersensitivity or allergy to the drugs in this study and any of&#xD;
               their components including but not limited to, LNL, doxorubicin/epirubicin,&#xD;
               cyclophosphamide, nab-paclitaxel, fludarabine, interleukin-2, dimethyl sulphoxide&#xD;
               (DMSO), human serum albumin (HSA), dextran-40 and antibiotics (β-lactam antibiotics,&#xD;
               gentamicin).&#xD;
  &#xD;
           17. Has contraindication for use of IL-2, including but not limited to, refractory or&#xD;
               intractable epilepsy, and active gastrointestinal bleeding.&#xD;
  &#xD;
           18. Has a history of Grade≥2 neuropathy.&#xD;
  &#xD;
           19. Has received long half-life angiogenesis inhibitors within four weeks prior to&#xD;
               enrollment, e.g., bevacizumab.&#xD;
  &#xD;
           20. Is receiving any medication prohibited in combination with study treatments as&#xD;
               described in the respective product labels, unless medication was stopped within 7&#xD;
               days prior to enrollment.&#xD;
  &#xD;
           21. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
               that might confound the results of the study, interfere with participation for the&#xD;
               full duration of the study, or render study participation not compatible with the&#xD;
               participant's best interest, in the opinion of the investigator.&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Erwei Song, M.D., Ph.D.</last_name>
      <role>Principal Investigator</role>
      <affiliation>Sun Yat-sen Memorial Hospital,Sun Yat-sen University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Shicheng Su, M.D., Ph.D.</last_name>
      <phone>+86 13632394954</phone>
      <email>lnl_trial@126.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Erwei Song, M.D., Ph.D.</last_name>
      <phone>+86 13719237746</phone>
      <email>lnl_trial@126.com</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Sun Yat-sen Memorial Hospital, Sun Yat-sen University</name>
        <address>
          <city>Guangzhou</city>
          <state>Guangdong</state>
          <zip>510120</zip>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Shicheng Su, M.D., Ph.D.</last_name>
        <phone>+86 13632394954</phone>
        <email>lnl_trial@126.com</email>
      </contact>
      <contact_backup>
        <last_name>Erwei Song, M.D., Ph.D.</last_name>
        <phone>+86 13719237746</phone>
        <email>lnl_trial@126.com</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 17, 2023</study_first_submitted>
    <study_first_submitted_qc>July 31, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 8, 2023</study_first_posted>
    <last_update_submitted>July 31, 2023</last_update_submitted>
    <last_update_submitted_qc>July 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University</investigator_affiliation>
      <investigator_full_name>Erwei Song, M.D., Ph.D.</investigator_full_name>
      <investigator_title>Director of Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University</investigator_title>
    </responsible_party>
    <keyword>HER2-Negative</keyword>
    <keyword>Neoadjuvant Chemotherapy</keyword>
    <keyword>Lymph Node</keyword>
    <keyword>Lymphocytes</keyword>
    <keyword>Adoptive Cell Therapy</keyword>
    <keyword>Doxorubicin</keyword>
    <keyword>Epirubicin</keyword>
    <keyword>Cyclophosphamide</keyword>
    <keyword>Nab-paclitaxel</keyword>
    <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>Paclitaxel</mesh_term>
      <mesh_term>Cyclophosphamide</mesh_term>
      <mesh_term>Doxorubicin</mesh_term>
      <mesh_term>Fludarabine</mesh_term>
      <mesh_term>Interleukin-2</mesh_term>
      <mesh_term>Epirubicin</mesh_term>
    </intervention_browse>
    <!-- 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/NCT05981014
  org study id: 【2021】04-01
  nct id: NCT05981014
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  RATIONALE: Patients with HER2-negative breast cancer not responding to initial neoadjuvant
        chemotherapy might have lower chances for a pathologic complete response (pCR) at definitive
        surgery, indicating worse prognosis. Adoptive cell therapy has demonstrated efficacy in
        advanced breast cancer, but whether the addition of adoptive cell therapy to neoadjuvant
        chemotherapy could increase the pCR rate remains unclear. Tumor-draining lymph node-derived
        lymphocytes (LNLs) that have abundant tumor-reactive T cells, but not exhausted T cells, are
        easy to produce. It is not yet known whether LNL treatment is safe and effective in patients
        with HER2-negative breast cancer not responding to neoadjuvant chemotherapy.
  
        PURPOSE: This open-label phase I/II trial is to investigate the safety and efficacy of
        autologous LNL in patients with HER2-negative breast cancer not responding to neoadjuvant
        chemotherapy.
  allocation: Randomized
  intervention model: Sequential Assignment
  intervention model description: Phase I: Single-arm, dose-escalation and dose-expansion study Phase II: Two-arm parallel assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Phase I: Incidence of Dose-Limiting Toxicity (DLT)
  time frame: From the LNL infusion up to 28 days post-infusion
  description: Adverse events are reported based upon Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. DLT will be defined as a non-hematologic Grade 3 or higher adverse event, occurring within the 28 days immediately after LNL infusion, that is probably or definitely related to LNL infusion, and lasts more than 28 days or does not resolve to Grade<3 despite treatment with dexamethasone at 10 mg per 12 hours IV for 7 days (or other corticosteroid at equivalent dose), and/or tocilizumab at 8mg/kg IV for three times.
  measure: Phase I: Incidence of Grade≥3 Treatment-Emergent Adverse Event (TEAE)
  time frame: From the LNL infusion up to 28 days post-infusion
  description: Adverse events are reported based upon CTCAE version 5.0 criteria. The incidence of Grade≥3 TEAE occurring within the 28 days immediately after LNL infusion will be summarized with descriptive statistics.
  measure: Phase II: Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery
  time frame: Up to approximately 18~29 weeks
  description: pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the local pathologist at the time of definitive surgery.
  measure: Phase I: Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery
  time frame: Up to approximately 26~29 weeks
  description: pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the local pathologist at the time of definitive surgery.
  measure: Phase I and phase II: Objective Response Rate (ORR)
  time frame: Up to approximately 26~29 weeks
  description: Objective response rate is defined as the percentage of participants in the analysis population who have a complete response (CR) or partial response (PR) during the study. The percentage of participants who experienced a CR or PR assessed by modified RECIST criteria by breast MRI is presented.
  measure: Phase I and phase II: 6-month, 1-year and 2-year Event-Free Survival (EFS)
  time frame: Up to approximately two years
  description: Event-free survival is defined as the time from enrollment (phase I) or randomization (phase II) to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast) after surgery or death due to any cause. Patients who terminate the study without evidence of any of the above events will be censored at the date of their last follow-up tumor assessment. Patients who start a new anti-tumor therapy (with the exception of adjuvant endocrine therapy in ER or PgR positive tumors after surgery) in the absence of disease progression or recurrence will be censored at their last follow-up tumor assessment before the start of the new therapy.
  measure: Phase I and phase II: Overall Survival (OS)
  time frame: Up to approximately five years
  description: Overall survival is defined as the time from enrollment (phase I) or randomization (phase II) to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.
  measure: Phase I: Levels of multiple different cytokines in blood samples before and after LNL infusion.
  time frame: Up to approximately two years
  description: To evaluate the pharmacokinetics and pharmacodynamics of LNL, levels of multiple different cytokines in blood samples including Granzyme B, IFN-γ, GM-CSF, IL-2, IL-4, IL-6, etc. will be measured using cytokine chips, ELISA or flow cytometry at various time points before and after LNL infusion.
  measure: Phase I: Distribution of T cell subsets in blood samples before and after LNL infusion.
  time frame: Up to approximately two years
  description: To evaluate the pharmacokinetics and pharmacodynamics of LNL, distribution of T cell subsets in blood samples will be measured using flow cytometry at various time points before and after LNL infusion.
  measure: Phase I: Distribution of T-cell receptor (TCR) clonotype in blood samples before and after LNL infusion.
  time frame: Up to approximately two years
  description: To evaluate the pharmacokinetics and pharmacodynamics of LNL, distribution of T-cell receptor (TCR) clonotype in blood samples will be measured using TCR sequencing at various time points before and after LNL infusion.
  measure: Phase II: Incidence of Grade≥3 Treatment-Emergent Adverse Event (TEAE)
  time frame: From the LNL infusion up to 28 days post-infusion
  description: Adverse events are reported based upon CTCAE version 5.0 criteria. The incidence of Grade≥3 TEAE occurring within the 28 days immediately after LNL infusion will be summarized with descriptive statistics.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  arm group type: Experimental
  description: Participants in both phase I and phase II portions receive two cycles of doxorubicin or epirubicin, plus cyclophosphamide (AC or EC), followed by neoadjuvant LNL treatment, which consists of non-myeloablative lymphocyte depleting regimen of chemotherapy with cyclophosphamide and fludarabine, followed by infusion of LNL and interleukin-2. After LNL treatment, participants receive four-cycles of nab-paclitaxel as neoadjuvant therapy prior to definitive surgery. The choice of doxorubicin or epirubicin should be the same as the prior neoadjuvant chemotherapy.
  arm group label: Phase II: Chemotherapy
  arm group type: Active Comparator
  description: The single-arm phase I study did not have this arm. Participants in phase II portion receive two cycles of doxorubicin or epirubicin, plus cyclophosphamide (AC or EC), followed by four-cycles of nab-paclitaxel as neoadjuvant therapy prior to definitive surgery. The choice of doxorubicin or epirubicin should be the same as the prior neoadjuvant chemotherapy.
  intervention type: Procedure
  intervention name: Sentinel Lymph Node Biopsy (SLNB)
  description: A sample of the participant's tumor-draining lymph nodes will be collected and sent to the biotherapy center for LNL isolation and expansion.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  other name: SLNB
  intervention type: Drug
  intervention name: Doxorubicin
  description: Doxorubicin will be administered at 60 mg/m^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  arm group label: Phase II: Chemotherapy
  intervention type: Drug
  intervention name: Epirubicin
  description: Epirubicin will be administered at 100 mg/m^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  arm group label: Phase II: Chemotherapy
  intervention type: Drug
  intervention name: Cyclophosphamide
  description: Cyclophosphamide will be administered at 600 mg/m^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  arm group label: Phase II: Chemotherapy
  intervention type: Drug
  intervention name: Cyclophosphamide
  description: Cyclophosphamide will be administered at 60 mg/kg IV daily over approximately two hours for two days. Cyclophosphamide will be initiated seven days prior to the anticipated LNL transfer, and the precise timing will depend on the rate of in vitro LNL growth.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  intervention type: Drug
  intervention name: Fludarabine
  description: After administration of cyclophosphamide, fludarabine will then be infused at 25 mg/m^2 intravenous piggyback (IVPB) daily over approximately 30 minutes for five days, starting five days prior to LNL transfer.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  intervention type: Biological
  intervention name: Tumor-draining lymph node-derived lymphocyte (LNL)
  description: In the dose-escalation portion of phase I study, participants receive ascending dose (1×10^9~18×10^9), single Infusion of LNL on day 0. In the dose-expansion portion of phase I study, participants receive single infusion of LNL at the recommended phase 2 dose (RP2D).
  In the phase II study, participants receive single infusion of LNL at the RP2D.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  other name: LNL
  intervention type: Biological
  intervention name: Interleukin-2
  description: Eight to twelve hours after completing the LNL infusion, all participants will receive intermediate-dose decrescendo IL-2 IV.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  other name: IL-2
  intervention type: Drug
  intervention name: Nab-paclitaxel
  description: Nab-paclitaxel will be administered at 260 mg/m^2 IV on Day 1 of Cycles 3-6 of the neoadjuvant chemotherapy of the study.
  arm group label: Phase I and phase II: Chemotherapy + LNL treatment
  arm group label: Phase II: Chemotherapy
  criteria: 
  gender: Female
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: No
  last name: Erwei Song, M.D., Ph.D.
  role: Principal Investigator
  affiliation: Sun Yat-sen Memorial Hospital,Sun Yat-sen University
  last name: Shicheng Su, M.D., Ph.D.
  phone: +86 13632394954
  email: lnl_trial@126.com
  last name: Erwei Song, M.D., Ph.D.
  phone: +86 13719237746
  email: lnl_trial@126.com
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
  investigator full name: Erwei Song, M.D., Ph.D.
  investigator title: Director of Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
  mesh term: Breast Neoplasms
  mesh term: Paclitaxel
  mesh term: Cyclophosphamide
  mesh term: Doxorubicin
  mesh term: Fludarabine
  mesh term: Interleukin-2
  mesh term: Epirubicin