Phase I Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes as Neoadjuvant Therapy for HER2-Negative Breast Cancer

NCT06121570 | Recruiting Phase 1 DMC

• 1 other identifier: [2021] 04-01
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 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 phase I trial is mainly to investigate the safety of autologous LNL in patients with HER2-negative breast cancer not responding to neoadjuvant chemotherapy.

Conditions

Breast Neoplasms

Keywords

HER2-Negative; Neoadjuvant Chemotherapy; Lymph Node; Lymphocytes; Adoptive Cell Therapy; Doxorubicin; Epirubicin; Cyclophosphamide; Nab-paclitaxel

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Secondary Outcomes (7)

• Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 at the time of definitive surgery

  Up to approximately 26~29 weeks

• Objective Response Rate (ORR)

  Up to approximately 26~29 weeks

• 6-month, 1-year and 2-year Event-Free Survival (EFS)

  Up to approximately two years

• Overall Survival (OS)

  Up to approximately five years

• Levels of multiple different cytokines in blood samples before and after LNL infusion.

  Up to approximately two years

Study Arms (1)

Chemotherapy + LNL treatment

EXPERIMENTAL

Participants 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.

Procedure: Sentinel Lymph Node Biopsy (SLNB); Drug: Doxorubicin; Drug: Epirubicin; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Tumor-draining lymph node-derived lymphocyte (LNL); Biological: Interleukin-2; Drug: Nab-paclitaxel

Interventions

Sentinel Lymph Node Biopsy (SLNB) PROCEDURE

A sample of the participant's tumor-draining lymph nodes will be collected and sent to the biotherapy center for LNL isolation and expansion.

Also known as: SLNB

Chemotherapy + LNL treatment

Doxorubicin DRUG

Doxorubicin will be administered at 60 mg/m\^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.

Chemotherapy + LNL treatment

Epirubicin DRUG

Epirubicin will be administered at 100 mg/m\^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.

Chemotherapy + LNL treatment

Cyclophosphamide DRUG

Cyclophosphamide will be administered at 600 mg/m\^2 IV on Day 1 of Cycles 1-2 of the neoadjuvant chemotherapy of the study.

Chemotherapy + LNL treatment

Fludarabine DRUG

Fludarabine will be administered at 30 mg/m\^2 IV daily for three days. Fludarabine will be initiated five days prior to the anticipated LNL transfer, and the precise timing will depend on the rate of in vitro LNL growth.

Chemotherapy + LNL treatment

Tumor-draining lymph node-derived lymphocyte (LNL) BIOLOGICAL

Participants receive single infusion of LNL at the recommended phase 2 dose (RP2D).

Also known as: LNL

Chemotherapy + LNL treatment

Interleukin-2 BIOLOGICAL

Eight to twelve hours after completing the LNL infusion, all participants will receive intermediate-dose decrescendo IL-2 IV.

Also known as: IL-2

Chemotherapy + LNL treatment

Nab-paclitaxel DRUG

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.

Chemotherapy + LNL treatment

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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 before receiving neoadjuvant chemotherapy:
• 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, immunotherapy 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:

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 that is progressing or requires active treatment within the last 5 years. Exceptions include basal or squamous cell carcinoma of the skin, and thyroid cancer that has undergone potentially curative therapy or in situ cervical cancer.
• 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 \>10 mg 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.

Sponsors & Collaborators

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: lead

Study Sites (1)

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Guangzhou, Guangdong, 510120, China

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Sentinel Lymph Node Biopsy; Doxorubicin; Epirubicin; Cyclophosphamide; fludarabine; Interleukin-2; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Biopsy; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Lymph Node Excision; Investigative Techniques; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Erwei Song, M.D., Ph.D.

  Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Shicheng Su, M.D., Ph.D.

CONTACT

+86 13632394954; lnl_trial@126.com

Erwei Song, M.D., Ph.D.

CONTACT

+86 13719237746; lnl_trial@126.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• 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: October 26, 2023
• First Posted: November 8, 2023
• Study Start: November 1, 2023
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2031
• Last Updated: November 8, 2023

Record last verified: 2023-11

Locations

CN (1)