TNBC, Triple Negative Breast Cancer
Conditions
Keywords
chemo-resistance, neoadjuvant SBRT
Brief summary
The goal of this clinical trial is to test whether a "rescue" strategy can turn chemotherapy-resistant triple-negative breast cancer (TNBC) into a curable state. Patients whose tumors fail to shrink after 2 cycles of standard neoadjuvant chemotherapy will receive a short, high-precision course of stereotactic body radiotherapy (SBRT, 24 Gy in 3 daily fractions) to the breast primary tumor, followed by 4 cycles of toripalimab (an anti-PD-1 antibody) combined with albumin-bound paclitaxel plus carboplatin. The main questions are: Can this SBRT-immuno-chemo triplet raise the pathologic complete response (pCR; no invasive cancer in breast or nodes at surgery)? Can it produce an objective radiologic response (ORR) in at least half of the patients, allowing more breast-conserving operations and fewer mastectomies? Secondary objectives include safety, changes in tumor-infiltrating lymphocytes (TILs), event-free survival, and exploratory biomarkers (whole-exome and RNA-seq, PBMC immunoprofiling) to discover signatures of benefit. Participants will undergo image-guided core biopsies before and after SBRT, provide serial blood samples, and have definitive surgery 3-5 weeks after the last cycle.
Detailed description
This is a single-arm, single-center, phase II exploratory trial designed for chemotherapy-refractory, early-stage triple-negative breast cancer (Stage II-III). After two cycles of standard neoadjuvant chemotherapy (taxane ± anthracycline ± platinum), patients with stable disease (SD) or progressive disease (PD) by RECIST 1.1 are eligible. Intervention sequence: Day 1-3: SBRT 8 Gy × 3 fractions to the intact breast primary (total 24 Gy) under daily image guidance. Day 4: first dose of toripalimab 240 mg IV. Day 21 (±3 d): start cycle 2 of toripalimab 240 mg d1 + albumin-bound paclitaxel 125 mg/m² d1,8 + carboplatin AUC 6 d1, q21 d × 4 cycles (immunotherapy always given first on day 1). Surgery: within 3-5 weeks after cycle 4; sentinel-node or axillary dissection per institutional standard. Adjuvant radiation (standard whole-breast/chest-wall plus nodal fields) is delivered post-operatively, but no further boost to the primary tumour bed is required. Endpoints Primary: pCR rate (ypT0/is ypN0) in the intent-to-treat population. Secondary: ORR by RECIST 1.1 after 4 cycles, change in TILs (H&E-based, % stromal area), safety (CTCAE v5.0), event-free survival, overall survival, and rate of breast-conserving surgery. Exploratory: genomic scars, PD-L1, interferon signature, TCR clonality, ctDNA dynamics.
Interventions
RADIATIONSBRT
24 Gy in 3 daily fractions (8 Gy each) to the breast primary tumor, started within 1 week after confirmation of chemotherapy resistance.
DRUGToripalimab (anti-PD-1 antibody)
240 mg intravenous infusion every 21 days for 4 cycles
DRUGChemotherapy switch
Albumin-bound paclitaxel 125 mg/m² (days 1 \& 8) plus carboplatin AUC 6 (day 1)
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Female, age 18-75 years, newly diagnosed invasive breast cancer. * Histologically confirmed triple-negative phenotype: ER \< 1 %, PR \< 1 % by IHC, HER2 negative (IHC 0/1+ or IHC 2+ with ISH negative). * Clinical stage II-III (T2-4 or N1-3, M0). * Completed 2 cycles of standard neoadjuvant chemotherapy (taxane ± anthracycline ± platinum) and assessed as non-responder: stable disease (SD) or progressive disease (PD) by RECIST 1.1. * ECOG performance status 0 or 1. * Radiation oncologist confirms suitability for SBRT and subsequent standard post-operative radiotherapy. * Adequate organ function within 14 days before enrollment: WBC ≥ 2 000/µL, ANC ≥ 1 500/µL, platelets ≥ 100 000/µL, Hb ≥ 9 g/dL; Serum creatinine ≤ 2 mg/dL or GFR ≥ 40 mL/min; AST/ALT ≤ 2.5 × ULN, total bilirubin ≤ ULN (≤ 3 mg/dL if Gilbert syndrome); INR ≤ 1.5 (on anticoagulation allowed if therapeutic range) * Negative HIV, HBV surface antigen, and HCV antibody (or HBV DNA / HCV RNA negative if false-positive).
Exclusion criteria
* Inflammatory breast cancer. * Any other malignancy requiring treatment within the past 3 years (except adequately treated basal-cell skin carcinoma or cervical CIS). * Active autoimmune disease, immunodeficiency, or systemic steroids \> 10 mg/day prednisone equivalent within 2 years. * Clinically significant cardiovascular disease (unstable angina, NYHA III/IV heart failure, recent MI). * Prior radiotherapy to the breast or chest wall. * Active infection requiring systemic therapy. * Known intolerance or hypersensitivity to toripalimab, paclitaxel, or carboplatin. * Pregnant or lactating women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| pCR rate | At definitive surgery, 3-5 weeks after completion of cycle 4 (week 15 from study entry) | Pathological complete response (pCR), percentage of patients with no invasive residual tumor in breast and lymph nodes (ypT0/is ypN0) at surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR Rate | After cycle 4, within 2 weeks before surgery (week 13). | Proportion of patients achieving complete or partial tumor shrinkage by RECIST 1.1 on MRI. |
| Acute and late toxicities | From first SBRT fraction to 30 days post-SBRT (week 5); From first toripalimab dose to 90 days after last dose (week 28) | Acute Radiation Skin Reaction;Immune-Related Adverse Events (irAEs) |
Countries
China
Contacts
CONTACTTing Zhang, phD.
Outcome results
None listed