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/NCT05981001</url>
    </required_header>
    <id_info>
      <org_study_id>【2021】03-01</org_study_id>
      <nct_id>NCT05981001</nct_id>
    </id_info>
    <brief_title>Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes for Advanced HER2-Negative Breast Cancer</brief_title>
    <official_title>An Open-Label Phase I/II Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes for Advanced 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 advanced breast cancer have limited choice on targeted&#xD;
        therapies, and often show only modest responses to available immunotherapies. Adoptive cell&#xD;
        therapy with tumor-infiltrating lymphocytes has difficulties in preparing enough cells from&#xD;
        solid tumors and overcoming the exhaustion and dysfunction of T cells, which limit its&#xD;
        clinical use. Tumor-draining lymph node-derived lymphocytes (LNLs) that have abundant&#xD;
        tumor-specific T cells, rather than exhausted T cells, are easier to produce. It is not yet&#xD;
        known whether LNL treatment is safe and effective in patients with advanced HER2-negative&#xD;
        breast cancer.&#xD;
  &#xD;
        PURPOSE: This open-label phase I/II trial is to study the safety and efficacy of autologous&#xD;
        LNL in patients with advanced HER2-negative breast cancer.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Recruiting</overall_status>
    <start_date type="Anticipated">August 1, 2023</start_date>
    <completion_date type="Anticipated">April 30, 2035</completion_date>
    <primary_completion_date type="Anticipated">April 30, 2032</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&#xD;
  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: Progression-Free-Survival (PFS)</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>Progression-free survival is defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Phase I: PFS</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>Progression-free survival is defined as the time from enrollment to the first documented PD per RECIST 1.1 or death due to any cause, whichever occurs first.</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 and phase II: Objective Response Rate (ORR)</measure>
      <time_frame>Up to approximately two years</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). The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I and phase II: Disease Control Rate (DCR)</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>Disease control rate is defined as the percentage of participants who have achieved CR or PR or have demonstrated stable disease (SD) for at least 24 weeks, per RECIST 1.1.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Phase I and phase II: Duration of Response (DOR)</measure>
      <time_frame>Up to approximately two years</time_frame>
      <description>For participants who demonstrate a confirmed CR or confirmed PR per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until PD per RECIST 1.1 or death due to any cause, whichever occurs first.</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">170</enrollment>
    <condition>Breast Neoplasms</condition>
    <arm_group>
      <arm_group_label>Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants in both phase I and phase II portions receive 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 camrelizumab PLUS one of two background chemotherapy regimens at investigator's discretion: (1) nab-paclitaxel, OR (2) gemcitabine/carboplatin.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Phase II: Camrelizumab + 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 camrelizumab PLUS one of two background chemotherapy regimens at investigator's discretion: (1) nab-paclitaxel, OR (2) gemcitabine/carboplatin.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Surgery for harvesting tumor-draining lymph nodes</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: LNL treatment + Camrelizumab + 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: LNL treatment + Camrelizumab + Chemotherapy</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: LNL treatment + Camrelizumab + Chemotherapy</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: LNL treatment + Camrelizumab + Chemotherapy</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: LNL treatment + Camrelizumab + Chemotherapy</arm_group_label>
      <other_name>IL-2</other_name>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Camrelizumab</intervention_name>
      <description>Camrelizumab will be administered at a fixed dose of 200mg IV on Day 1 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.</description>
      <arm_group_label>Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy</arm_group_label>
      <arm_group_label>Phase II: Camrelizumab + Chemotherapy</arm_group_label>
      <other_name>SHR-1210</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Nab-paclitaxel</intervention_name>
      <description>Nab-paclitaxel will be administered at 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.</description>
      <arm_group_label>Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy</arm_group_label>
      <arm_group_label>Phase II: Camrelizumab + Chemotherapy</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Gemcitabine</intervention_name>
      <description>Gemcitabine will be administered at 1000 mg/m^2 IV on Days 1 and 8 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.</description>
      <arm_group_label>Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy</arm_group_label>
      <arm_group_label>Phase II: Camrelizumab + Chemotherapy</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Carboplatin</intervention_name>
      <description>Carboplatin will be administered at area under the concentration-time curve 2 (AUC 2) IV on Days 1 and 8 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.</description>
      <arm_group_label>Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy</arm_group_label>
      <arm_group_label>Phase II: Camrelizumab + 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. Have locally advanced or recurrent inoperable HER2-negative breast cancer (Stage&#xD;
               IIIB~IIIC) which cannot be treated with curative intent OR have metastatic breast&#xD;
               cancer (Stage IV). HER2-negative breast cancer is defined by the most recent ASCO/CAP&#xD;
               guidelines. Participants should appear clinically stable in the opinion of the&#xD;
               investigator.&#xD;
  &#xD;
            4. Participants with estrogen receptor (ER)-positive and/or progesterone receptor&#xD;
               (PR)-positive breast cancer have failed at least one line of hormonal therapy or&#xD;
               CDK4/6 inhibitor, or are appropriate candidates for chemotherapy. Participants with&#xD;
               ER-positive and/or PR-positive breast cancer may have received unlimited prior&#xD;
               chemotherapy. Participants with triple-negative breast cancer (TNBC) may have received&#xD;
               unlimited prior treatments for breast cancer.&#xD;
  &#xD;
            5. Have not received the chemotherapeutic drugs and immune checkpoint inhibitor intended&#xD;
               to be used in this study in the prior treatments for the Stage IIIB, IIIC or IV breast&#xD;
               cancer. Participants who received the same chemotherapeutic drugs and/or immune&#xD;
               checkpoint inhibitor in the (neo)adjuvant setting as in this study are eligible, only&#xD;
               if ≥12 months have elapsed between the completion of treatment with curative intent&#xD;
               (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy&#xD;
               administration, whichever occurred last) and the enrollment of this study.&#xD;
  &#xD;
            6. Have not received any prior adoptive cell therapy.&#xD;
  &#xD;
            7. Be suitable for treatment with nab-paclitaxel or gemcitabine/carboplatin and&#xD;
               camrelizumab as judged by the investigator.&#xD;
  &#xD;
            8. Have accessible tumor-draining lymph nodes by surgery to grow LNL.&#xD;
  &#xD;
            9. Have measurable disease based on RECIST 1.1. Target lesions situated in a previously&#xD;
               irradiated area are considered measurable, only if they have shown unequivocal&#xD;
               progression based on RECIST 1.1 after radiation therapy.&#xD;
  &#xD;
           10. Have provided recently or newly obtained biopsy from a locally advanced or recurrent&#xD;
               inoperable or metastatic tumor lesion for pathological examination of molecular&#xD;
               subtype and PD-L1 expression, unless contraindicated due to site inaccessibility&#xD;
               and/or participant safety concerns.&#xD;
  &#xD;
           11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
  &#xD;
           12. Have life expectancy ≥4 months.&#xD;
  &#xD;
           13. 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;
           14. 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;
           15. Have a specified washout period from prior anticancer therapies to the enrollment:&#xD;
  &#xD;
                 -  Angiogenesis inhibitors: 4 weeks&#xD;
  &#xD;
                 -  Chemotherapy or targeted therapy: 3 weeks&#xD;
  &#xD;
                 -  Radiotherapy: 2 weeks&#xD;
  &#xD;
                 -  Hormonal therapy: one week&#xD;
  &#xD;
           16. 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, except for&#xD;
               second-degree peripheral nerve injury, alopecia, leukoderma, hypothyroidism controlled&#xD;
               by thyroid hormone replacement therapy, type 1 diabetes controlled by insulin therapy,&#xD;
               and other irreversible toxic events that would not be exacerbated by LNL infusion as&#xD;
               judged by the investigator (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 rapidly progressing tumors, as judged by the investigator.&#xD;
  &#xD;
            2. Has known active CNS metastases and/or carcinomatous meningitis except for previously&#xD;
               treated and radiographically stable CNS metastases, or CNS metastases without&#xD;
               medication requirement and corticosteroid dependence. To demonstrate radiographic&#xD;
               stability of brain metastases, a minimum of 2 post-treatment brain imaging assessments&#xD;
               are required: (1) The first brain imaging must be acquired after treatment of brain&#xD;
               metastases has been completed; (2) The second brain imaging must be obtained during&#xD;
               screening and 4 weeks after the previous post-treatment brain imaging.&#xD;
  &#xD;
            3. Has spinal cord compression not relieved by surgery or radiotherapy. Participants with&#xD;
               previously treated spinal cord compression may participate provided that the&#xD;
               compression-related symptoms are relieved within more than one week prior to surgery&#xD;
               for tumor-draining lymph nodes.&#xD;
  &#xD;
            4. Has uncontrolled pleural effusion, pericardial effusion or ascites. Participants with&#xD;
               indwelling catheter may participate.&#xD;
  &#xD;
            5. Has uncontrolled cancer pain as judged by the investigator. Participants requiring&#xD;
               pain medication must have a treatment plan before enrollment. Symptomatic lesions&#xD;
               suitable for palliative radiotherapy should be treated before enrollment.&#xD;
  &#xD;
            6. 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;
            7. 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;
            8. Has interstitial pneumonia or active pneumonia that has clinical implication, or other&#xD;
               respiratory diseases that seriously affect pulmonary function.&#xD;
  &#xD;
            9. Has an active infection requiring systemic therapy or has an unexplained fever of&#xD;
               &gt;38.5℃ except fevers caused by cancer.&#xD;
  &#xD;
           10. 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;
           11. Is currently participating in a clinical study and receiving an investigational agent&#xD;
               and/or using an investigational device, or has participated in a clinical study and&#xD;
               received an investigational agent and/or used an investigational device within 4 weeks&#xD;
               prior to enrollment.&#xD;
  &#xD;
               Note: Subjects who have entered the follow-up phase of a clinical study may&#xD;
               participate as long as 4 weeks have elapsed since the last dose of the investigational&#xD;
               agent and/or removal of the device.&#xD;
  &#xD;
           12. Has a known psychiatric, alcohol abuse or substance abuse disorders.&#xD;
  &#xD;
           13. Is pregnant or breastfeeding.&#xD;
  &#xD;
           14. 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;
           15. Has a history of congenital immunodeficiency or acquired immunodeficiency (e.g.,&#xD;
               positive serology test for HIV).&#xD;
  &#xD;
           16. 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;
           17. 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;
           18. Has received a live vaccine within 4 weeks prior to enrollment, or plans to receive a&#xD;
               live vaccine during this trial.&#xD;
  &#xD;
           19. Has a history of allogeneic bone marrow or organ transplant.&#xD;
  &#xD;
           20. 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, cyclophosphamide, fludarabine,&#xD;
               interleukin-2, dimethyl sulphoxide (DMSO), human serum albumin (HSA), dextran-40,&#xD;
               antibiotics (β-lactam antibiotics, gentamicin), camrelizumab, nab-paclitaxel or&#xD;
               gemcitabine/carboplatin).&#xD;
  &#xD;
           21. Has contraindication for use of IL-2, including but not limited to, refractory or&#xD;
               intractable epilepsy, and active gastrointestinal bleeding.&#xD;
  &#xD;
           22. Has a history of Grade≥2 neuropathy.&#xD;
  &#xD;
           23. 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;
           24. 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>Lymph Node</keyword>
    <keyword>Lymphocytes</keyword>
    <keyword>Adoptive Cell Therapy</keyword>
    <keyword>Camrelizumab</keyword>
    <keyword>Chemotherapy</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>Carboplatin</mesh_term>
      <mesh_term>Gemcitabine</mesh_term>
      <mesh_term>Fludarabine</mesh_term>
      <mesh_term>Interleukin-2</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/NCT05981001
  org study id: 【2021】03-01
  nct id: NCT05981001
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  RATIONALE: Patients with HER2-negative advanced breast cancer have limited choice on targeted
        therapies, and often show only modest responses to available immunotherapies. Adoptive cell
        therapy with tumor-infiltrating lymphocytes has difficulties in preparing enough cells from
        solid tumors and overcoming the exhaustion and dysfunction of T cells, which limit its
        clinical use. Tumor-draining lymph node-derived lymphocytes (LNLs) that have abundant
        tumor-specific T cells, rather than exhausted T cells, are easier to produce. It is not yet
        known whether LNL treatment is safe and effective in patients with advanced HER2-negative
        breast cancer.
  
        PURPOSE: This open-label phase I/II trial is to study the safety and efficacy of autologous
        LNL in patients with advanced HER2-negative breast cancer.
  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: Progression-Free-Survival (PFS)
  time frame: Up to approximately two years
  description: Progression-free survival is defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first.
  measure: Phase I: PFS
  time frame: Up to approximately two years
  description: Progression-free survival is defined as the time from enrollment to the first documented PD per RECIST 1.1 or death due to any cause, whichever occurs first.
  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 and phase II: Objective Response Rate (ORR)
  time frame: Up to approximately two years
  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). The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented.
  measure: Phase I and phase II: Disease Control Rate (DCR)
  time frame: Up to approximately two years
  description: Disease control rate is defined as the percentage of participants who have achieved CR or PR or have demonstrated stable disease (SD) for at least 24 weeks, per RECIST 1.1.
  measure: Phase I and phase II: Duration of Response (DOR)
  time frame: Up to approximately two years
  description: For participants who demonstrate a confirmed CR or confirmed PR per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until PD per RECIST 1.1 or death due to any cause, whichever occurs first.
  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: LNL treatment + Camrelizumab + Chemotherapy
  arm group type: Experimental
  description: Participants in both phase I and phase II portions receive 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 camrelizumab PLUS one of two background chemotherapy regimens at investigator's discretion: (1) nab-paclitaxel, OR (2) gemcitabine/carboplatin.
  arm group label: Phase II: Camrelizumab + Chemotherapy
  arm group type: Active Comparator
  description: The single-arm phase I study did not have this arm. Participants in phase II portion receive camrelizumab PLUS one of two background chemotherapy regimens at investigator's discretion: (1) nab-paclitaxel, OR (2) gemcitabine/carboplatin.
  intervention type: Procedure
  intervention name: Surgery for harvesting tumor-draining lymph nodes
  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: LNL treatment + Camrelizumab + 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: LNL treatment + Camrelizumab + Chemotherapy
  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: LNL treatment + Camrelizumab + Chemotherapy
  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: LNL treatment + Camrelizumab + Chemotherapy
  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: LNL treatment + Camrelizumab + Chemotherapy
  other name: IL-2
  intervention type: Biological
  intervention name: Camrelizumab
  description: Camrelizumab will be administered at a fixed dose of 200mg IV on Day 1 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.
  arm group label: Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy
  arm group label: Phase II: Camrelizumab + Chemotherapy
  other name: SHR-1210
  intervention type: Drug
  intervention name: Nab-paclitaxel
  description: Nab-paclitaxel will be administered at 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.
  arm group label: Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy
  arm group label: Phase II: Camrelizumab + Chemotherapy
  intervention type: Drug
  intervention name: Gemcitabine
  description: Gemcitabine will be administered at 1000 mg/m^2 IV on Days 1 and 8 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.
  arm group label: Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy
  arm group label: Phase II: Camrelizumab + Chemotherapy
  intervention type: Drug
  intervention name: Carboplatin
  description: Carboplatin will be administered at area under the concentration-time curve 2 (AUC 2) IV on Days 1 and 8 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.
  arm group label: Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy
  arm group label: Phase II: Camrelizumab + 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: Carboplatin
  mesh term: Gemcitabine
  mesh term: Fludarabine
  mesh term: Interleukin-2