Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes as Neoadjuvant Therapy for HER2-Negative Breast Cancer
An Open-Label Phase I/II Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes as Neoadjuvant Therapy for HER2-Negative Breast Cancer
1 other identifier
interventional
196
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Aug 2023
Longer than P75 for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 17, 2023
CompletedStudy Start
First participant enrolled
August 1, 2023
CompletedFirst Posted
Study publicly available on registry
August 8, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2030
ExpectedStudy Completion
Last participant's last visit for all outcomes
May 31, 2035
August 8, 2023
July 1, 2023
7.4 years
July 17, 2023
July 31, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
Phase I: Incidence of Dose-Limiting Toxicity (DLT)
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.
From the LNL infusion up to 28 days post-infusion
Phase I: Incidence of Grade≥3 Treatment-Emergent Adverse Event (TEAE)
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.
From the LNL infusion up to 28 days post-infusion
Phase II: Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery
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.
Up to approximately 18~29 weeks
Secondary Outcomes (8)
Phase I: Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery
Up to approximately 26~29 weeks
Phase I and phase II: Objective Response Rate (ORR)
Up to approximately 26~29 weeks
Phase I and phase II: 6-month, 1-year and 2-year Event-Free Survival (EFS)
Up to approximately two years
Phase I and phase II: Overall Survival (OS)
Up to approximately five years
Phase I: Levels of multiple different cytokines in blood samples before and after LNL infusion.
Up to approximately two years
- +3 more secondary outcomes
Study Arms (2)
Phase I and phase II: Chemotherapy + LNL treatment
EXPERIMENTALParticipants 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.
Phase II: Chemotherapy
ACTIVE COMPARATORThe 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.
Interventions
A sample of the participant's tumor-draining lymph nodes will be collected and sent to the biotherapy center for LNL isolation and expansion.
Doxorubicin will be administered at 60 mg/m\^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.
Epirubicin will be administered at 100 mg/m\^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.
Cyclophosphamide will be administered at 600 mg/m\^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.
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.
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.
Eight to twelve hours after completing the LNL infusion, all participants will receive intermediate-dose decrescendo IL-2 IV.
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.
Eligibility Criteria
You may qualify if:
- In order to be eligible for participation in this trial, the participant must:
- Have signed the informed consent to study participation.
- Be a female subject and aged between 18 and 70 years.
- Provide a core needle biopsy which is histologically confirmed as invasive breast cancer. Excisional biopsy or surgical biopsy is not allowed.
- Have received two cycles of doxorubicin or epirubicin, plus cyclophosphamide, and had stable disease (SD) confirmed by breast MRI.
- Have breast cancer defined as the following combined primary tumor (T), regional lymph node (N), and distant metastasis (M) staging per AJCC for breast cancer staging criteria version 8 based on breast MRI assessment:
- The minimum size of the primary tumor was 1 cm in largest diameter by breast MRI, N0-3, M0.
- Have HER2-negative breast cancer, defined as 0-1+ by immunohistochemistry or 2+ by immunohistochemistry without HER2 amplification by FISH.
- Have known hormone receptor status (estrogen receptor \[ER\], progesterone receptor \[PgR\]), Ki67 value and, if institutional standard permits, known tumor grade.
- Have not received prior therapies for breast cancer, including but not limited to, chemotherapy (except two cycles of doxorubicin or epirubicin, plus cyclophosphamide), radiotherapy, hormonal therapy, targeted therapy, biological therapy and surgery.
- Have accessible tumor-draining lymph nodes by surgery to grow LNL. Participants have not received sentinel lymph node biopsy (SLNB) and ipsilateral axillary lymph node dissection (ALND) for the breast cancer lesion.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Demonstrate adequate normal organ function:
- NOTE: Blood component or cytokine therapy is not allowed within 14 days before surgery.
- Routine blood test:
- +19 more criteria
You may not qualify if:
- The participant must be excluded from participating in this trial if the participant:
- Has metastatic breast cancer.
- Has a known additional malignancy within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, and ductal carcinoma in situ that has undergone radical mastectomy.
- Has a known history of cardiovascular disease, including but not limited to, (1) congestive heart failure (New York Heart Association \[NYHA\] functional classification Class \> 2), (2) unstable angina pectoris, (3) myocardial infarction in the past 3 months, (4) supraventricular arrhythmia or ventricular arrhythmia that requires treatments.
- Has interstitial pneumonia or active pneumonia that has clinical implications, or other respiratory diseases that seriously affect pulmonary function.
- Has an active infection requiring systemic therapy or has an unexplained fever of \>38.5℃ except fevers caused by cancer.
- Has arterial and/or venous thrombotic events in the past 5 months, e.g., cerebrovascular accident, deep vein thrombosis or pulmonary embolism.
- Has a known psychiatric, alcohol abuse or substance abuse disorders.
- Is pregnant or breastfeeding.
- Has an active autoimmune disease, a history of autoimmune disease, or autoimmune disease that has required systemic treatment (e.g., with use of prednisone at a dose of \>10mg per day or other corticosteroids at an equivalent dose). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed.
- Has a history of congenital immunodeficiency or acquired immunodeficiency (e.g., positive serology test for HIV).
- Has tuberculosis in the past one year, or has a history of active tuberculosis more than one year but did not receive regular treatments.
- Has known active hepatitis B or hepatitis C. Participants that are hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg) positive may participate provided that the HBV DNA level is normal. Participants that are hepatitis C antibody positive may participate provided that the HCV DNA level is normal. Carriers of HBV or HCV must receive anti-virus therapy, and take regular DNA copy number tests during this trial.
- Has received a live vaccine within 4 weeks prior to enrollment, or plans to receive a live vaccine during this trial.
- Has a history of allogeneic bone marrow or organ transplant.
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Guangzhou, Guangdong, 510120, China
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Erwei Song, M.D., Ph.D.
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Director of Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study Record Dates
First Submitted
July 17, 2023
First Posted
August 8, 2023
Study Start
August 1, 2023
Primary Completion (Estimated)
December 31, 2030
Study Completion (Estimated)
May 31, 2035
Last Updated
August 8, 2023
Record last verified: 2023-07