Phase 2 Clinical Study of Iparomlimab and Tuvonralimab (QL1706) in Combination With Platinum Chemotherapy Versus Platinum Chemotherapy in the Treatment of Second-/Third-line Triple Negative Breast Cancer (TNBC)

Phase 2 Randomized Controlled Clinical Study of Iparomlimab and Tuvonralimab (QL1706) in Combination With Platinum Chemotherapy Versus Platinum Chemotherapy in the Treatment of Second-/Third-line Triple Negative Breast Cancer (TNBC)

This study is an open-label, prospective, phase 2, randomized controlled study to evaluate the efficacy and safety of apolitovorrelizumab (QL1706) in combination with platinum chemotherapy versus platinum chemotherapy in the treatment of advanced unresectable and or metastatic triple negative breast cancer previously treated with first-line or second-line systems. It is planned to enroll 78 subjects in this study. Subjects who meet the inclusion and exclusion criteria are divided into a random ratio of 1:1. The experimental group will receive QL1706 in combination with platinum chemotherapy selected by the investigator, and the control group will receive platinum chemotherapy selected by the investigator. A treatment cycle will be held every 3 weeks until disease progression or intolerable toxicity occurs. After subjects in the control group withdraw from the study, they are allowed to receive other treatments selected by the QL1706 co-investigators based on the subjects 'wishes. Efficacy assessments will be conducted every 6 weeks (42 days ±7 days) after treatment until disease progression, withdrawal of informed consent, death, or start of new antitumor therapy, whichever comes first.

Inclusion Criteria:

• Age ≥18 years, regardless of gender;
• ECOG performance status: 0-1;
• Locally advanced or metastatic triple negative breast cancer confirmed by histopathology that is not suitable for curative treatment and cannot be treated surgically (Defined as negative for HER2, ER and PR expression according to the latest ASCO/CAP guidelines);
• Patients who have previously received first-line or second-line systemic treatment for locally advanced or metastatic breast cancer and have experienced recurrence within 12 months after the end of previous adjuvant therapy are counted as first-line systemic therapy;
• There is radiographic or objective evidence of disease progression at the last systemic treatment before or after the start of study treatment;
• Patients have at least one evaluable lesion (based on CT or MRI according to the RECIST 1.1 criteria);
• Tissue or blood samples for biomarker testing can be provided, tissue samples during the baseline period (try to provide tumor puncture tissue after recent progression, if not, previously archived tissue is also available, 5-10 white slides); blood samples during the baseline period, after 2 cycles of treatment and after progression;
• Good organ function：The bone marrow function must be tested within 14 days before enrollment, white blood cell count (WBC) ≥3.5×109/L, hemoglobin (Hb) ≥90g/L, absolute neutrophil count (ANC) ≥1.5×109/L, and platelets (PLT) ≥80×109/L, and have not received blood transfusion or biological response modifiers (such as granulocytes, erythrocyte growth factor, Shengxuebao, etc.) within 14 days before the first dose. Liver function: Liver function must be tested within 14 years before enrollment. Patients without liver metastasis require serum total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN. Requirements for patients with liver metastases: serum total bilirubin (TBIL) ≤1.5× the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5×ULN; alkaline phosphatase (ALP) ≤5×ULN in patients with liver metastases and no bone metastases, and ALP≤2.5×ULN in patients without liver and bone metastases. Renal function: Renal function should be tested within 14 days before enrollment, with blood creatinine ≤1.5×ULN or creatinine clearance ≥60mL/min (based on the Cockcroft-Gault formula). No serious cardiac dysfunction, left ventricular ejection fraction (LVEF) ≥50%(confirmed by ECHO) .Coagulation function: International normalized ratio (INR) ≤1.5×ULN and activated partial thromboplastin time (APTT) ≤1.5×ULN (unless receiving the*utic anticoagulant drugs).
• Patients of childbearing potential must use effective contraceptive measures during the study until 6 months after the last dose.
• The patient voluntarily joined the study and signed the informed consent form, with good compliance.

Exclusion Criteria:

• Previous use of CTLA-4 monoclonal antibody or PD-1/PD-L1 and CTLA-4 bispecific antibodies (such as cardonilumab, KN046, etc.) or bifunctional combination antibodies (e.g., apolitto vorrelizumab);
• relapse within 6 months after the end of previous (new) adjuvant immune checkpoint inhibitor therapy; or progression-free survival of locally advanced or metastatic breast cancer receiving immune checkpoint inhibitor therapy; 6 months;
• relapse within 6 months after the end of previous (new) adjuvant platinum therapy; Or locally advanced or metastatic breast cancer receiving platinum therapy has a progression-free survival of <3 months (if the drug is discontinued due to non-tumor progression factors, but the duration of discontinuation is ≥3 months before randomization, you can participate in this study);
• Those who have experienced immune-related toxicity that led to permanent drug discontinuation during previous anti-tumor immunotherapy, or have experienced immune-related adverse events (irAEs) of ≥ grade 3 or immune-related myocarditis of ≥ grade 2 and are assessed by the investigator as not suitable for treatment in this study. Grade 3 endocrine abnormalities with stable control of hormone replacement therapy can be enrolled after the investigator assessed that these irAEs will not affect the administration of study drugs and safety assessment;
• Previous history of or concurrent interstitial pneumonia, severe chronic obstructive pulmonary disease, severe pulmonary dysfunction, symptomatic bronchospasm, etc.;
• Previous history of other primary malignant tumors; Note: Except for basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or cervical cancer in situ; Or patients who have received radical treatment and have not relapsed within 5 years of treatment can participate in this trial;
• Have experienced severe allergic reactions to the pharmaceutical or inactive ingredients of the study drug;
• Adverse reactions from previous anti-tumor therapy have not recovered to NCI-CTCAE 5.0 grade evaluation ≤1 (Except for toxicities that are judged by the investigator to have no safety risks, such as hair loss);
• Have active autoimmune disease or have a history of autoimmune disease, are using immunosuppressants, or systemic hormone therapy (prednisone or other equivalent hormone at a dose>10mg/day), and continue to use it within 2 weeks prior to enrollment. Except for the following diseases: Clinically stable autoimmune thyroid disease; Type 1 diabetes treated with hormone replacement therapy; through local treatment (e.g., low-dose topical hormones) are well controlled and no autoimmune skin diseases requiring additional treatment due to acute exacerbation within 12 months prior to screening (such as eczema, psoriasis, chronic lichen simplex, or vitiligo with simple skin lesions accumulating less than 10% of the body surface area);
• Any serious or uncontrollable systemic disease, including hypertension that is not well controlled with drugs, according to the investigator's judgment (systolic blood pressure>160mmHg or diastolic blood pressure>100mmHg), uncontrolled diabetes, and signs of active bleeding, etc.;
• Uncontrolled cardiac disease, including heart failure of NYHA class 2 or above, unstable angina pectoris, myocardial infarction within 1 year, clinically significant supraventricular or ventricular arrhythmia requiring treatment, prolonged QT syndrome, such as QTc>450ms (men) or QTc>470ms (women);
• Evidence of active infection includes but is not limited to hepatitis B (both HBsAg positive and HBVDNA≥2000IU/mL, and hepatitis caused by drugs or other reasons is excluded), hepatitis C (both anti-HCV antibody positive and HCV RNA positive) or human immunodeficiency virus (HIV) infection;
• Women with positive serum pregnancy tests or nursing do not agree to use adequate contraceptive measures during the study and for 6 months after receiving the trial drug;
• Subjects with known central nervous system metastases and/or cancerous meningitis (except for: asymptomatic, or treatment-treated and stable, no new brain metastases or radiographic evidence of expansion of brain metastases has been found for at least 4 weeks after treatment for brain metastases, and steroid or anticonvulsant treatment has been discontinued for at least 14 days before the start of study treatment);
• Other circumstances that the investigator deems unsuitable for participation in this clinical trial.