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

NCT05981001 | Recruiting Phase 1 DMC

• 1 other identifier: 【2021】03-01
• Study Type: interventional
• Target: 170
• 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 open-label phase I/II trial is to study the safety and efficacy 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

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: Progression-Free-Survival (PFS)

  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.

  Up to approximately two years

Secondary Outcomes (9)

• Phase I: PFS

  Up to approximately two years

• Phase I and phase II: Overall Survival (OS)

  Up to approximately five years

• Phase I and phase II: Objective Response Rate (ORR)

  Up to approximately two years

• Phase I and phase II: Disease Control Rate (DCR)

  Up to approximately two years

• Phase I and phase II: Duration of Response (DOR)

  Up to approximately two years

Study Arms (2)

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy

EXPERIMENTAL

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.

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: Nab-paclitaxel; Drug: Gemcitabine; Drug: Carboplatin

Phase II: Camrelizumab + Chemotherapy

ACTIVE COMPARATOR

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.

Biological: Camrelizumab; Drug: Nab-paclitaxel; Drug: Gemcitabine; Drug: Carboplatin

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.

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy

Cyclophosphamide DRUG

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.

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy

Fludarabine DRUG

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.

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy

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

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.

Also known as: LNL

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy

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

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy

Camrelizumab BIOLOGICAL

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.

Also known as: SHR-1210

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy; Phase II: Camrelizumab + Chemotherapy

Nab-paclitaxel DRUG

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.

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy; Phase II: Camrelizumab + Chemotherapy

Gemcitabine DRUG

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.

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy; Phase II: Camrelizumab + Chemotherapy

Carboplatin DRUG

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.

Phase I and phase II: LNL treatment + Camrelizumab + Chemotherapy; Phase II: Camrelizumab + Chemotherapy

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 the chemotherapeutic drugs and immune checkpoint inhibitor intended to be used in this study in the prior treatments for the Stage IIIB, IIIC or IV breast cancer. Participants who received the same chemotherapeutic drugs and/or immune checkpoint inhibitor in the (neo)adjuvant setting as in this study are eligible, only if ≥12 months have elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and the enrollment of this study.
• Have not received any prior adoptive cell therapy.
• Be suitable for treatment with nab-paclitaxel or gemcitabine/carboplatin and camrelizumab 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.

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 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 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; 130-nm albumin-bound paclitaxel; Gemcitabine; Carboplatin

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; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes

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: 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

Model Details: Phase I: Single-arm, dose-escalation and dose-expansion study Phase II: Two-arm parallel assignment

Study Record Dates

• First Submitted: July 17, 2023
• First Posted: August 8, 2023
• Study Start: August 1, 2023
• Primary Completion (Estimated): April 30, 2032
• Study Completion (Estimated): April 30, 2035
• Last Updated: August 8, 2023

Record last verified: 2023-07

Locations

CN (1)