Trial Title:
Phase I Study of Autologous Tumor-Draining Lymph Node-Derived Lymphocytes for Advanced HER2-Negative Breast Cancer
NCT ID:
NCT06121557
Condition:
Breast Neoplasms
Conditions: Official terms:
Breast Neoplasms
Cyclophosphamide
Fludarabine
Interleukin-2
Poly(ADP-ribose) Polymerase Inhibitors
Conditions: Keywords:
HER2-Negative
Lymph Node
Lymphocytes
Adoptive Cell Therapy
Camrelizumab
Chemotherapy
Antibody-Drug Conjugate
Poly(ADP-ribose) Polymerase Inhibitor
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Single-arm, dose-escalation and dose-expansion study
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
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:
LNL treatment + Camrelizumab + another anti-tumor drug
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
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.
Arm group label:
LNL treatment + Camrelizumab + another anti-tumor drug
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
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.
Arm group label:
LNL treatment + Camrelizumab + another anti-tumor drug
Intervention type:
Biological
Intervention name:
Tumor-draining lymph node-derived lymphocyte (LNL)
Description:
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).
Arm group label:
LNL treatment + Camrelizumab + another anti-tumor drug
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:
LNL treatment + Camrelizumab + another anti-tumor drug
Other name:
IL-2
Intervention type:
Biological
Intervention name:
Camrelizumab
Description:
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.
Arm group label:
LNL treatment + Camrelizumab + another anti-tumor drug
Other name:
SHR-1210
Intervention type:
Drug
Intervention name:
Chemotherapeutic drug, ADC or PARP inhibitor
Description:
Another anti-tumor drug chosen from chemotherapeutic drug, ADC, or PARP inhibitor will be
administered at investigator's discretion.
Arm group label:
LNL treatment + Camrelizumab + another anti-tumor drug
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
In order to be eligible for participation in this trial, the participant must:
1. Have signed the informed consent to study participation.
2. Be a female subject and aged between 18 and 70 years.
3. 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.
4. 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.
5. Have not received any prior adoptive cell therapy.
6. Be suitable for treatment with camrelizumab and another anti-tumor drug chosen from
chemotherapeutic drug, ADC, or PARP inhibitor as judged by the investigator.
7. Have accessible tumor-draining lymph nodes by surgery to grow LNL.
8. 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.
9. 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.
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
11. Have life expectancy ≥4 months.
12. Demonstrate adequate normal organ function:
NOTE: Blood component or cytokine therapy is not allowed within 14 days before
surgery.
1. Routine blood test:
- Absolute neutrophil count (ANC) ≥1.5×10^9/L
- Lymphocyte count (LC) >0.5×10^9/L
- Platelets (PLT) ≥100×10^9/L
- Hemoglobin (Hb) ≥90 g/L
2. Liver function test:
- AST and ALT ≤2.5×ULN (≤5×ULN for participants with liver metastases)
- ALP ≤2.5×ULN (≤5×ULN for participants with liver or bone metastases)
- Total bilirubin ≤1.5×ULN (≤3.0 mg/dL for participants with Gilbert's
syndrome)
3. Renal function test:
· Calculated creatinine clearance (CrCL) ≥45 mL/min OR creatinine ≤1.5×ULN
4. Coagulation function test:
- APTT ≤1.5×ULN
- INR or PT ≤1.5×ULN
5. Doppler echocardiography:
· Left ventricular ejection fraction (LVEF) ≥50%
6. Pulmonary function test:
- FEV1 ≥60%
13. Female participants of childbearing potential must be willing to use an adequate
method of contraception for the course of the study through one year (or longer as
specified by local institutional guidelines) after the last dose of study treatment.
Female subjects of childbearing potential must have a negative serum pregnancy test
within 7 days prior to LNL infusion.
14. Have a specified washout period from prior anti-tumor therapies to the enrollment:
- Angiogenesis inhibitors: 4 weeks
- Chemotherapy or targeted therapy: 3 weeks
- Radiotherapy: 2 weeks
- Hormonal therapy: one week
Have recovered from prior therapy-related adverse events to Grade≤1 per CTCAE version 5.0
criteria or met the criteria of normal organ function specified above, except for
second-degree peripheral nerve injury, alopecia, leukoderma, hypothyroidism controlled by
thyroid hormone replacement therapy, type 1 diabetes controlled by insulin therapy, and
other irreversible toxic events that would not be exacerbated by LNL infusion as judged
by the investigator (e.g., hearing loss).
Exclusion Criteria:
The participant must be excluded from participating in this trial if the participant:
1. Has rapidly progressing tumors, as judged by the investigator.
2. 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.
3. 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.
4. Has uncontrolled pleural effusion, pericardial effusion or ascites. Participants
with indwelling catheter may participate.
5. 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.
6. 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.
7. 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.
8. Has interstitial pneumonia or active pneumonia that has clinical implication, or
other respiratory diseases that seriously affect pulmonary function.
9. Has an active infection requiring systemic therapy or has an unexplained fever of
>38.5℃ except fevers caused by cancer.
10. Has arterial and/or venous thrombotic events in the past 5 months, e.g.,
cerebrovascular accident, deep vein thrombosis or pulmonary embolism.
11. 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.
12. Has a known psychiatric, alcohol abuse or substance abuse disorders.
13. Is pregnant or breastfeeding.
14. 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.
15. Has a history of congenital immunodeficiency or acquired immunodeficiency (e.g.,
positive serology test for HIV).
16. Has tuberculosis in the past one year, or has a history of active tuberculosis more
than one year but did not receive regular treatments.
17. 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.
18. Has received a live vaccine within 4 weeks prior to enrollment, or plans to receive
a live vaccine during this trial.
19. Has a history of allogeneic bone marrow or organ transplant.
20. Has a history of hypersensitivity or allergy to the drugs in this study and any of
their components including but not limited to, LNL, cyclophosphamide, fludarabine,
interleukin-2, dimethyl sulphoxide (DMSO), human serum albumin (HSA), dextran-40,
antibiotics (β-lactam antibiotics, gentamicin), camrelizumab, or another anti-tumor
drug that the investigator intends to choose.
21. Has contraindication for use of IL-2, including but not limited to, refractory or
intractable epilepsy, and active gastrointestinal bleeding.
22. Has a history of Grade≥2 neuropathy.
23. Is receiving any medication prohibited in combination with study treatment as
described in the respective product labels, unless medication was stopped within 7
days prior to enrollment.
24. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with
participation for the full duration of the study, or render study participation not
compatible with the participant's best interest, in the opinion of the investigator.
Gender:
Female
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Address:
City:
Guangzhou
Zip:
510120
Country:
China
Status:
Recruiting
Contact:
Last name:
Shicheng Su, M.D., Ph.D.
Phone:
+86 13632394954
Email:
lnl_trial@126.com
Contact backup:
Last name:
Erwei Song, M.D., Ph.D.
Phone:
+86 13719237746
Email:
lnl_trial@126.com
Start date:
November 1, 2023
Completion date:
December 31, 2031
Lead sponsor:
Agency:
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Agency class:
Other
Source:
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06121557
