QUEEN-APPLE: A Single-Arm, Multicenter, Prospective Phase II Clinical Study of Iparomlimab and Tuvonralimab (QL1706) in Combination With Anlotinib Hydrochloride and Nab-Paclitaxel as First-Line Treatment for Advanced Triple-Negative Breast Cancer

QUEEN-APPLE: A Single-Arm, Multicenter, Prospective Phase II Clinical Study of Iparomlimab and Tuvonralimab (QL1706) in Combination With Anlotinib Hydrochloride and Nab-Paclitaxel as First-Line Treatment for Advanced Triple-Negative Breast Cancer

This study is a single-arm, multicenter, prospective phase II clinical trial designed to evaluate the efficacy and safety of QL1706 in combination with anlotinib hydrochloride and nab-paclitaxel as first-line treatment for advanced triple-negative breast cancer.

A total of 34 participants with first-line advanced triple-negative breast cancer are enrolled in this study:

Enrolled participants receive QL1706 (5 mg/kg, Q3W, day 1) + anlotinib (12 mg per dose, QD, days 1-14, Q3W) + nab-paclitaxel (125 mg/m², days 1 and 8, Q3W), with a 21-day cycle. Treatment continues until disease progression, intolerable toxicity, the investigator's judgment that the participant no longer derives benefit, withdrawal of informed consent by the participant, completion of 2 years of QL1706 treatment, or other reasons specified in the protocol.

The study consists of a screening period (from the signing of informed consent to no more than 28 days before the first dose), a treatment period (including on-treatment visits and end-of-treatment visit), and a follow-up period (including safety follow-up and survival follow-up).

Screening Period:

The screening period begins after the participant signs the informed consent form and ends at enrollment, lasting no more than 28 days. Eligible participants are those with pathologically confirmed, previously untreated first-line triple-negative breast cancer. During screening, participant information, samples, and blood specimens are collected as needed. Participants who meet all inclusion criteria and none of the exclusion criteria are enrolled.

Treatment Period:

Study drugs are administered within 3 days of enrollment. Each treatment cycle is 3 weeks. Study treatment continues until disease progression, intolerable toxicity, initiation of new anti-cancer therapy, loss to follow-up, death, withdrawal of informed consent, or other reasons, with a maximum treatment duration of 2 years (whichever occurs first). Safety assessments are performed every 3 weeks, and tumor imaging evaluations are performed every 6 weeks (±7 days) according to RECIST v1.1 criteria.

Follow-up Period:

When participants discontinue study treatment or withdraw early, they are still required to complete the corresponding assessments as specified in the protocol.

Safety Follow-up: At 30 days (±7 days) after the last dose, participants return to the site for one follow-up visit, during which blood samples are collected and safety examinations are performed.

Survival Follow-up: Every 2 months. Survival status and subsequent treatment information are collected by telephone or other appropriate means.

Inclusion Criteria:

1. Participants voluntarily join the study, sign the informed consent form, and agree to strictly comply with the study protocol requirements.
2. Female patients aged between 18 and 75 years.
3. Confirmed by histopathological examination as advanced triple-negative invasive breast cancer, meeting the following criteria: pathological type triple-negative, specifically: ER negative (IHC <1%), PR negative (IHC <1%), HER2 negative (IHC -/+ or IHC ++ but FISH/CISH negative). Priority is given to pathology from metastatic lesions; if metastatic lesion pathology is not available, primary lesion pathology may be used.
4. TNBC patients with initial diagnosis of stage IV (according to AJCC 8th edition) or recurrent/metastatic disease who are not suitable for surgery, and have not received prior systemic therapy for advanced disease. Prior neoadjuvant and/or adjuvant therapy with taxanes or other anti-tumor treatments is permitted, provided that there was no disease progression during neoadjuvant therapy, and the interval between completion of taxane-based (neo)adjuvant therapy and recurrence/metastasis is ≥6 months.
5. Suitable for nab-paclitaxel treatment.
6. At least one measurable tumor lesion according to RECIST 1.1 criteria.
7. Expected survival ≥3 months.
8. ECOG performance status 0 or 1.
9. Adequate organ function, including:

1)Hematology: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count (PLT) ≥100×10⁹/L; hemoglobin (HB) ≥90 g/L.

2)Liver function: Total bilirubin ≤1.5×ULN; AST and ALT ≤2.5×ULN; if liver metastases are present, ALT and AST must be ≤5×ULN.

3)Renal function: Serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance ≥60 mL/min (calculated by the Cockcroft-Gault formula).

10.Participants of childbearing potential must use appropriate contraception during the study and for 120 days after study completion, have a negative serum pregnancy test within 7 days before study enrollment, and must not be lactating.

Exclusion Criteria:

1. Known history of severe allergic reactions to QL1706, anlotinib, nab-paclitaxel, or any of their excipients.
2. Inability to swallow oral medications, or any gastrointestinal disorder that may interfere with the absorption and metabolism of the study drugs.
3. Symptomatic brain/leptomeningeal metastases and/or spinal cord metastases.
4. Active or potentially relapsing autoimmune disease, with the following exceptions: vitiligo, alopecia, psoriasis, or eczema not requiring systemic treatment; hypothyroidism due to autoimmune thyroiditis requiring only stable-dose hormone replacement therapy; type I diabetes mellitus requiring only stable-dose insulin replacement therapy.
5. Major surgery within 3 weeks before study initiation, or failure to recover from surgery.
6. History of organ transplantation or autologous/allogeneic stem cell transplantation.
7. Known or self-reported human immunodeficiency virus (HIV) infection.
8. HBV-DNA positive or HCV-DNA positive (copy number >10³).
9. Prior treatment with any agent targeting the mechanism of tumor immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies), immune checkpoint agonists (e.g., antibodies targeting ICOS, CD40, CD137, GITR, OX40), or immune cell therapy.
10. Prior treatment with anti-angiogenic targeted therapy.
11. Hypertension that cannot be well controlled with a single antihypertensive medication (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg).
12. Arterial/venous thrombotic events (e.g., cerebrovascular accident including transient ischemic attack, deep vein thrombosis, pulmonary embolism) within 6 months before enrollment.
13. Presence of other malignancies within 5 years before enrollment, except for TNBC.
14. Tumor invasion or compression of surrounding major blood vessels or organs.
15. Active central nervous system (CNS) metastatic lesions.
16. Clinically significant pleural effusion, pericardial effusion, or ascites requiring repeated drainage.
17. History of myocarditis, cardiomyopathy, or malignant arrhythmias.
18. History of significant bleeding tendency or coagulation dysfunction.
19. History of esophageal-gastric varices, severe ulcer, non-healing wound, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months before the first dose.
20. Known active tuberculosis (TB).
21. History of or current non-infectious pneumonitis/interstitial lung disease requiring systemic corticosteroid therapy.
22. Major surgery or severe trauma within 30 days before the first dose, or planned major surgery within 30 days after the first dose; minor local surgery within 3 days before the first dose.
23. Platelet or red blood cell transfusion within 4 weeks before initiation of study drug treatment.
24. Receipt of live vaccine within 4 weeks before the first dose, or planned receipt of live vaccine during the study.
25. Female participants who are pregnant, breastfeeding, or planning to become pregnant during the study.
26. Patients judged by the investigator to be unsuitable for participation in this study.