RECLAIM: A Phase II, Open-Label, Single-Arm, Multicenter Clinical Trial of Cromolyn, TQB2102, and Panpulimab for Re-Challenging Immune-Refractory Triple-Negative Breast Cancer

This is a phase II, open-Label, single-arm, multicenter clinical trial investigating the efficacy and safety of cromolyn for potentiating ADC combined with immunotherapy in refractory triple-negative breast cancer. Based on previous findings, the infiltration level of antigen-presenting mast cells (apMCs) was significantly correlated with clinical benefits from immunotherapy. Cromolyn, a mast cell membrane stabilizer, demonstrated promising efficacy in the phase II "Renaissance" clinical study. Among 10 patients with anti-PD-1/PD-L1-resistant TNBC, the combination of cromolyn with chemotherapy and immunotherapy achieved an objective response rate (ORR) of 50%. To further validate these findings, we have designed this study to enroll TNBC patients who have progressed after conventional treatments (including chemotherapy, immunotherapy, ADC, etc.), with the aim of further investigating the synergistic effects of cromolyn sodium combined with ADC and PD-1 monoclonal antibody against refractory TNBC tumors at the clinical level.

Inclusion Criteria:

1. Age: Female, ≥18 years old and ≤70 years old.

2. Diagnosis: Histologically confirmed invasive triple-negative breast cancer (defined as: ER-negative by IHC with <1% positive tumor cells; PR-negative with <1% positive tumor cells; HER2 0-1+ or HER2 2+ with confirmed negative FISH/CISH without amplification).

3. Prior Treatment: Recurrent or metastatic refractory breast cancer with disease progression after prior immunotherapy.

4. Measurable Disease: At least one measurable lesion per RECIST v1.1 (≥20 mm by conventional CT or ≥10 mm by spiral CT; lesion must not have been previously irradiated).

5. Organ Function: Adequate organ function as follows:

   1. Blood Counts: Hemoglobin ≥90 g/L (no transfusion within 14 days); absolute neutrophil count ≥1.5×10⁹/L; platelets ≥75×10⁹/L.
   2. Blood Chemistry: Total bilirubin ≤1.5×ULN; ALT and AST ≤3×ULN (≤5×ULN if liver metastases are present); serum creatinine ≤1×ULN; creatinine clearance >50 mL/min (Cockcroft-Gault formula).

6. Treatment-Free Interval: No radiotherapy, endocrine therapy, molecular targeted therapy, or major surgery within 3 weeks prior to study entry; recovery from prior treatment-related toxicities (surgical wounds fully healed if applicable); absence of peripheral neuropathy or only grade I peripheral neuropathy.

7. Performance Status: ECOG performance status ≤1, and life expectancy ≥3 months.

8. Contraception: Women of childbearing potential must agree to use medically approved contraception during the study treatment period and for at least 3 months after the last dose of the study drug.

9. Consent: Voluntary participation with signed informed consent, good compliance, and willingness to cooperate with follow-up.

Exclusion Criteria:

1. Prior Radiotherapy: Receipt of radiotherapy within 3 weeks before treatment initiation (except for palliative reasons).
2. CNS Metastases: Known history or presence of central nervous system (CNS) metastases at screening. Patients with clinical suspicion of CNS metastases must undergo contrast-enhanced CT or MRI within 28 days prior to the first dose to rule out CNS involvement.
3. Cardiac Disease: History of clinically significant or uncontrolled cardiac conditions, including congestive heart failure, angina, myocardial infarction within the past 6 months, or ventricular arrhythmia.
4. Persistent Toxicity: Ongoing ≥ Grade 1 adverse reactions from previous treatments, except for alopecia or conditions deemed acceptable by the investigator. Such exceptions must be clearly documented in the investigator's notes.
5. Recent Major Surgery: Undergone major surgery (excluding minor outpatient procedures such as vascular access placement) within 3 weeks before the first cycle of study treatment.
6. Pregnancy or Lactation: Patients who are pregnant or breastfeeding.
7. Other Malignancies: History of other malignant tumors within the past 5 years (except cured basal cell carcinoma of the skin or carcinoma in situ of the cervix).
8. Impaired Drug Absorption: Conditions affecting oral drug intake and absorption, such as dysphagia, chronic diarrhea, or intestinal obstruction.
9. Uncontrolled Effusions: Uncontrolled third-space effusions (e.g., significant pleural or ascitic fluid) not manageable by drainage or other methods.
10. Non-Healing Conditions: Long-term non-healing wounds or incompletely healed fractures.
11. Active Viral Hepatitis: Active HBV or HCV infection (HBV-DNA ≥ 500 IU/mL) or chronic hepatitis with abnormal liver function.
12. Allergic History: Known allergy or hypersensitivity to any component of the study regimen, or history of hypersensitivity to other monoclonal antibodies.
13. Eosinophilia/Mastocytosis: Patients with eosinophilia or mastocytosis.
14. Steroid Use: Chronic use of oral corticosteroids. Occasional past use requires a 4-week washout period before enrollment.
15. Prior Use of Specific Therapies: Previous treatment with PD-1/TGF-β bispecific antibody, PD-1/CTLA-4 bispecific antibody, PD-1/VEGF bispecific antibody, or anti-HER2 dual-epitope ADC; or use of ADC agents in ≥2 prior lines of therapy.