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

NCT06121557 | Recruiting Phase 1 DMC

• 1 other identifier: [2021] 03-01
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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 phase I trial is mainly to study the safety of autologous LNL in patients with advanced HER2-negative breast cancer.

Conditions

Breast Neoplasms

Keywords

HER2-Negative; Lymph Node; Lymphocytes; Adoptive Cell Therapy; Camrelizumab; Chemotherapy; Antibody-Drug Conjugate; Poly(ADP-ribose) Polymerase Inhibitor

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 (8)

• Objective Response Rate (ORR)

  Up to approximately two years

• Disease Control Rate (DCR)

  Up to approximately two years

• Duration of Response (DOR)

  Up to approximately two years

• Progression-Free Survival (PFS)

  Up to approximately two years

• Overall Survival (OS)

  Up to approximately five years

Study Arms (1)

LNL treatment + Camrelizumab + another anti-tumor drug

EXPERIMENTAL

Participants 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 another anti-tumor drug chosen from chemotherapeutic drug, ADC, or PARP inhibitor at investigator's discretion.

Procedure: Surgery for harvesting tumor-draining lymph nodes; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Tumor-draining lymph node-derived lymphocyte (LNL); Biological: Interleukin-2; Biological: Camrelizumab; Drug: Chemotherapeutic drug, ADC or PARP inhibitor

Interventions

Surgery for harvesting tumor-draining lymph nodes 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.

LNL treatment + Camrelizumab + another anti-tumor drug

Cyclophosphamide DRUG

Cyclophosphamide will be administered at 500 mg/m\^2 IV daily for three days. Cyclophosphamide 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.

LNL treatment + Camrelizumab + another anti-tumor drug

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.

LNL treatment + Camrelizumab + another anti-tumor drug

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

In the dose-escalation portion, participants receive ascending dose (1×10\^9\~18×10\^9), single Infusion of LNL on day 0. In the dose-expansion portion, participants receive single infusion of LNL at the recommended phase 2 dose (RP2D).

Also known as: LNL

LNL treatment + Camrelizumab + another anti-tumor drug

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

LNL treatment + Camrelizumab + another anti-tumor drug

Camrelizumab BIOLOGICAL

Camrelizumab will be administered at a dose of 200mg (3mg/kg for participants whose weight is below 50kg) IV on Day 1 of each 21-day cycle until unacceptable toxic effects or disease progression or other termination criteria appeared.

Also known as: SHR-1210

LNL treatment + Camrelizumab + another anti-tumor drug

Chemotherapeutic drug, ADC or PARP inhibitor DRUG

Another anti-tumor drug chosen from chemotherapeutic drug, ADC, or PARP inhibitor will be administered at investigator's discretion.

LNL treatment + Camrelizumab + another anti-tumor drug

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.
• Have locally advanced or recurrent inoperable HER2-negative breast cancer (Stage IIIB\~IIIC) which cannot be treated with curative intent OR have metastatic breast cancer (Stage IV). HER2-negative breast cancer is defined by the most recent ASCO/CAP guidelines. Participants should appear clinically stable in the opinion of the investigator.
• Participants with estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancer have failed at least one line of hormonal therapy or CDK4/6 inhibitor, or are appropriate candidates for chemotherapy. Participants with ER-positive and/or PR-positive breast cancer may have received unlimited prior chemotherapy. Participants with triple-negative breast cancer (TNBC) may have received unlimited prior treatments for breast cancer.
• Have not received any prior adoptive cell therapy.
• Be suitable for treatment with camrelizumab and another anti-tumor drug chosen from chemotherapeutic drug, ADC, or PARP inhibitor as judged by the investigator.
• Have accessible tumor-draining lymph nodes by surgery to grow LNL.
• Have measurable disease based on RECIST 1.1. Target lesions situated in a previously irradiated area are considered measurable, only if they have shown unequivocal progression based on RECIST 1.1 after radiation therapy.
• Have provided recently or newly obtained biopsy from a locally advanced or recurrent inoperable or metastatic tumor lesion for pathological examination of molecular subtype and PD-L1 expression, unless contraindicated due to site inaccessibility and/or participant safety concerns.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Have life expectancy ≥4 months.
• 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 rapidly progressing tumors, as judged by the investigator.
• Has known active CNS metastases and/or carcinomatous meningitis except for previously treated and radiographically stable CNS metastases, or CNS metastases without medication requirement and corticosteroid dependence. To demonstrate radiographic stability of brain metastases, a minimum of 2 post-treatment brain imaging assessments are required: (1) The first brain imaging must be acquired after treatment of brain metastases has been completed; (2) The second brain imaging must be obtained during screening and 4 weeks after the previous post-treatment brain imaging.
• Has spinal cord compression not relieved by surgery or radiotherapy. Participants with previously treated spinal cord compression may participate provided that the compression-related symptoms are relieved within more than one week prior to surgery for tumor-draining lymph nodes.
• Has uncontrolled pleural effusion, pericardial effusion or ascites. Participants with indwelling catheter may participate.
• Has uncontrolled cancer pain as judged by the investigator. Participants requiring pain medication must have a treatment plan before enrollment. Symptomatic lesions suitable for palliative radiotherapy should be treated before enrollment.
• 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 implication, 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.
• Is currently participating in a clinical study and receiving an investigational agent and/or using an investigational device, or has participated in a clinical study and received an investigational agent and/or used an investigational device within 4 weeks prior to enrollment.
• Note: Subjects who have entered the follow-up phase of a clinical study may participate as long as 4 weeks have elapsed since the last dose of the investigational agent and/or removal of the device.
• Has a known psychiatric, alcohol abuse or substance abuse disorders.
• Is pregnant or breastfeeding.

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

Surgical Procedures, Operative; Cyclophosphamide; fludarabine; Interleukin-2; camrelizumab; arginine decarboxylase; Poly(ADP-ribose) Polymerase Inhibitors

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents; Therapeutic Uses

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

Model Details: Single-arm, dose-escalation and dose-expansion study

Study Record Dates

• First Submitted: October 26, 2023
• First Posted: November 8, 2023
• Study Start: November 1, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2031
• Last Updated: November 8, 2023

Record last verified: 2023-11

Locations

CN (1)