Prospective registration

A Single-Arm, Multicenter Clinical Study of Eribulin Mesylate in Combination with Ivonescimab as First-Line Treatment for Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer

A Single-Arm, Multicenter Clinical Study of Eribulin Mesylate in Combination with Ivonescimab as First-Line Treatment for Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer

Lu Haiqi 

Lu Haiqi 

No. 3, Qingchun East Road, Hangzhou, Zhejiang Province

No. 3, Qingchun East Road, Hangzhou, Zhejiang Province

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

Yes

Ethics Committee,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine

Yang Yangchi

No. 3, Qingchun East Road, Hangzhou, Zhejiang Province

Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

No. 3, Qingchun East Road, Hangzhou, Zhejiang Province

Independent Research Project (Self-Funded)

Inoperable locally advanced or metastatic triple-negative breast cancer

Interventional study

2

Single arm 

1. Primary Objective: To evaluate the efficacy and safety of eribulin combined with ianalumab as first-line treatment in patients with locally advanced or metastatic triple-negative breast cancer (TNBC). 2. Secondary Objectives: (1) To assess the efficacy of eribulin combined with ianalumab as first-line treatment in patients with locally advanced or metastatic TNBC; (2) To evaluate the correlation between PD-L1 expression in tumor tissue and the efficacy of the study drugs.

1. 18-75 years old (including boundary value), gender is not limited; 2. ECOG physical fitness score (PS) 0-1 points; 3. Subjects need to provide a two-year memory file and/or fresh tumor tissue sample, histologically or cytologically confirmed TNBC (ER, PR and HER2 are all negative) by the central laboratory: (1) Negative ER and PR are defined as: ER less than 1% and PR less than 1% detected by IHC; (2) HER2 negativity is defined as: IHC test 0 (negative/-) or 1, if it is 2, ISH or FISH test must be performed and the result is negative; (3) For patients with ER/PR expression >=1% and < 10%, if the investigator assesses that the patient cannot benefit from endocrine therapy, it is more suitable to be treated according to the treatment principles of TNBC, and enrollment can be considered after full evaluation; (4) For the molecular typing inconsistency between the pathology of metastatic lesions and surgical pathology, the pathological results of the latest metastatic lesions will be used to determine whether to enroll; 4. Patients with locally advanced, recurrent, or metastatic TNBC who have not received prior systemic therapy and are not suitable for radical surgical resection or local therapy, or whose disease progresses after surgical resection or local therapy, must meet the following conditions: (1) The use of anti-tumor therapy (including taxe and/or anthracycline, neoadjuvant therapy must meet the non-progression) period in the previous neoadjuvant and/or adjuvant therapy phase, and the interval between the end time of neoadjuvant and/or adjuvant therapy (the date of the last dose) and the first documented local advancement, recurrence or metastasis is >=12 months; The interval between the end time of adjuvant therapy (date of last dose) of other drugs such as capecitabine (such as PD-1/PD-L1 inhibitors) and the first documented locally advanced, recurrence or metastasis >=6 months; (2) Those who received surgical treatment alone (in the absence of neoadjuvant/adjuvant therapy before/after surgery), the time interval between the date of surgery and the first recorded locally advanced, recurrence or metastasis was >=6 months; 5. At least one measurable (non-brain metastasis) tumor lesion according to the Evaluation Criteria for Efficacy in Solid Tumors (RECIST 1.1) criteria. CT or MR scan, the longest diameter of non-lymph node lesions is at least >=10mm, and the short diameter of lymph node lesions is >=15mm (tumor lesions that have received radiotherapy or other locoregional therapy have clearly documented disease progression after the end of treatment as measurable lesions; If the selected target lesion undergoes pathological biopsy during the screening period, an interval of at least 2 weeks from the time of the first dose is required); 6. Expected survival time>=12 weeks; 7. Have adequate organ and bone marrow function: Laboratory tests meet the following conditions within 1 week prior to enrollment (based on normal values in the laboratory department of each study center): (1) Blood routine: WBC>= 3.0×109/L, ANC>=1.5×10^9/L; PLT >= 90 ×10^9/L; HGB>= 9.0g/dL; (2) Liver function: TBiL<=1.5×ULN; For subjects with liver metastases or evidence of Gilbert's disease, TBiL<=3×ULN; ALT and AST<= 2.5×ULN (subjects with liver metastases<=5×ULN; ALB>=30g/L; For subjects with liver metastasis or bone metastasis, ALP<=5×ULN; (3) Renal function: Scr<=1.5×ULN; or creatinine clearance (Ccr) calculated according to the Cockcroft-Gault formula>=60mL/min; (4) Coagulation function: INR<= and APTT<=1.5×ULN (for subjects receiving anticoagulant therapy, the investigator judged that both INR and APTT are within the safe and effective treatment range); (5) Urine routine: the results show that urine protein <2; If the urine protein >=2, the 24-hour urine protein content should be <1g; 8. Subjects of childbearing potential must have a urine or serological pregnancy test within 72 hours before the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; 9. Subjects (including partners) are willing to take effective contraceptive measures from the screening period to 90 days after the last study dose, such as double-barrier contraceptive methods, condoms, oral or injectable contraceptives, intrauterine devices, etc.; 10. Volunteer to participate in this study and sign the informed consent form. If the subject is unable to read and sign the informed consent form due to incapacity or other reasons, his or her guardian needs to act as an agent for the informed consent process and sign the informed consent form. If the subject does not have the ability to read the informed consent form (e.g., illiterate subjects), the informed consent process needs to be witnessed by a witness and the informed consent form is signed.

1. Thyroid cancer, cervical carcinoma in situ, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin that have been cured after treatment within 5 years before enrollment can be enrolled; 2. Participation in clinical trials or clinical studies of other investigational drugs or investigational devices within 28 days before the first dose; or received anti-tumor therapy within 4 weeks or within 5 half-lives of the drug (whichever is shorter) before the first dose, including but not limited to chemotherapy, radiotherapy (palliative radiotherapy completed at least 2 weeks before study drug treatment is allowed), targeted therapy, immunotherapy, or endocrine therapy; Received proprietary Chinese (herbal) drugs or non-specific immunomodulatory therapy with anti-tumor indications (such as interleukin, interferon, thymus peptide, tumor necrosis factor, etc., excluding IL-11 for the treatment of thrombocytopenia) within 2 weeks before the first dose; 3. Previous treatment adverse events (alopecia, grade <=2 peripheral neurotoxicity and endocrine disease controlled by hormone replacement therapy, etc., except for toxicities judged by the investigator to have no safety risk) have not recovered to grade ≤1 (NCI-CTCAE V5.0); 4. Previous grade 3-4 irAEs or discontinuation of treatment (except for grade 3 endocrine abnormalities controlled by hormone replacement therapy); 5. Subjects with active or history of autoimmune diseases that may recur (such as: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulitis, etc.), or high-risk (such as those who have undergone organ transplantation and need to receive immunosuppressive therapy). However, patients with the following conditions are allowed to be enrolled: (1) Subjects with stable type I diabetes mellitus (HbA1c<=8.0%) after fixed-dose insulin therapy; (2) autoimmune hypothyroidism that only needs hormone replacement therapy; (3) Skin diseases that do not require systemic treatment (such as: eczema, rash occupying less than 10% of the body surface area, psoriasis without ophthalmic symptoms, etc.); 6. Systemic treatment with glucocorticoids (> 10mg/day prednisone or equivalent dose) or other immunosuppressive drugs within 14 days before the first dose. If there is no active autoimmune disease, inhaled, ophthalmological, or topical glucocorticoids or other glucocorticoids at a dose of <=10mg/day prednisone or equivalent dose are allowed (glucocorticoid therapy used to prevent contrast allergy in imaging examinations such as CT is allowed); 7. Known uncontrollable or symptomatic active CNS metastases. However, for subjects with asymptomatic brain metastases, they can be enrolled if they meet the following conditions: (1) Imaging and neurological examinations are stable for more than 4 weeks after receiving relevant treatment; (2) If there is no imaging evaluation, the neurological examination is stable for more than 4 weeks under glucocorticoid therapy, and the prednisone dose used before the first dose of study drug is ≤10mg/day or equivalent dose of other hormones; 8. Presence of brainstem, meningeal metastasis, spinal cord metastasis or compression; 9. Tumor invasion or compression of surrounding important organs (such as aorta, heart and pericardium, superior vena cava, trachea, esophagus, etc.) or there is a risk of esophagotracheal fistula or esophagopleural fistula; Tumor mediastinal lymph node metastasis invades the trachea and main bronchi; 10. Patients with known or suspected active tuberculosis, or patients with infectious pneumonia requiring treatment; 11. Patients with a history of interstitial lung disease or non-infectious pneumonia; 12. Presence of any of the following infections: (1) Active infection within 2 weeks prior to screening, requiring systemic treatment; (2) HIV antibody positive; (3) Active hepatitis B or C. Asymptomatic hepatitis B virus carriers (HBV DNA titer<2000 IU/mL) or cured hepatitis C (negative HCV RNA test) are allowed to be enrolled (if HBVDNA test is positive, antiviral therapy must be administered 14 days before the first dose according to local practice of diagnosis and treatment; If HBsAg positive and/or HBcAb positive, the investigator will assess whether antiviral therapy is required); 13. History of clinically significant cardiovascular and cerebrovascular diseases, including: (1) Congestive heart failure (NYHA class III-IV); (2) Severe/unstable angina, or new onset angina in the last 3 months; (3) Acute myocardial infarction events within 6 months prior to screening; (4) Severe arrhythmias requiring treatment (such as: atrial fibrillation, ventricular tachycardia, complete left bundle branch block, complete block, torsade de pointes or familial/hereditary arrhythmias, long QT syndrome, etc.); (5) Cardiac function: LVEF detected by cardiac ultrasound < 50%; (6) Prolongation of QTcF interval detected by electrocardiogram: 450 ms > males and 470 ms > females (Appendix 4); (7) Acute cerebrovascular disease (such as: cerebral infarction, cerebral hemorrhage, transient ischemia, cerebrovascular accident, hypertensive crisis or hypertensive encephalopathy, etc.) within 6 months before screening; (8) Hypertension that is not well controlled by antihypertensive drugs (resting systolic blood pressure >160mmHg or diastolic blood pressure >100mmHg); (9) Other cardiac damage that may affect the safety evaluation of the study drug (such as myocardial ischemia, cardiomyopathy, etc.); 14. Those who have the following untreated or incomplete treatment within 6 months before screening and have high risk factors for bleeding: (1) Severe symptoms and signs of active gastric ulcer, gastrointestinal bleeding, and coagulation disorders; Imaging (CT/MRI) shows that the tumor has invaded the periphery of important blood vessels, or the tumor is very likely to invade important blood vessels during the follow-up study period, causing fatal major bleeding; (2) Arterial thrombosis or embolism events, or significant vascular diseases (e.g., aortic aneurysm requiring surgical repair, aortic dissection); History of deep vein thrombosis 3 months before screening; (3) Conditions that may cause gastrointestinal bleeding or perforation (such as: duodenal ulcer, intestinal obstruction, Crohn's disease, ulcerative colitis, resection of large gastric and small intestine, etc.); Those who have a history of intestinal perforation or intestinal fistula in the past, and have not healed after surgical treatment; esophageal and gastric varices; 15. Presence of pleural effusion, pericardial effusion or abdominal effusion with clinical symptoms, uncontrollable or requiring repeated drainage as judged by the investigator; 16. Current uncontrolled comorbid diseases, including but not limited to decompensated cirrhosis, nephrotic syndrome, etc.; 17. Previously treated with immune checkpoint inhibitors (including but not limited to anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.) or anti-angiogenesis-related drugs (including but not limited to bevacizumab, anlotinib, apatinib, lenvatinib, sorafenib, sunitinib, regorafenib, fruquintinib, etc.); 18. Individuals who have previously undergone stem cell, bone marrow, or solid organ transplantation; 19. Individuals who have undergone surgical treatment (excluding biopsy) within 4 weeks prior to screening or whose surgical wounds have not completely healed; 20. Individuals who have received blood transfusions, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin, or erythropoietin treatment within 2 weeks prior to the first dose; 21. Individuals with a history of severe allergies or who have experienced grade 3-4 allergic reactions during treatment with other monoclonal antibodies; 22. Individuals who have received live vaccines within 30 days prior to screening or plan to receive them during the study; 23. Individuals with mental disorders, psychological disorders, hereditary diseases, or those with alcohol or drug addiction, which in the investigator's judgment may interfere with study treatment and follow-up, affect study results, impact patient compliance, or put the patient at high risk, are not allowed to enroll; 24. Pregnant or breastfeeding women; 25. Individuals with local or systemic diseases not caused by malignant tumors, or diseases or symptoms secondary to tumors that may lead to higher medical risks and/or uncertainty in survival assessment, such as tumor-related leukemia responses (white blood cell count >20×10^9/L) or cachexia manifestations (e.g., known weight loss of more than 10% within 3 months prior to screening); 26. Individuals unable to comply with the study protocol or whom the investigator deems unsuitable to participate in this study.

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Data collection and management consist of two parts: one is the case record form (CRF), and the other is the electronic collection and management system (EDC).