Study of Paclitaxel Polymeric Micelles Combined With HP and Adebelimab Versus Taxane Combined With HP as First-Line Treatment for Advanced HER2-Positive Breast Cancer

Официальное название

A Multicenter, Randomized, Open-Label, Controlled Phase II Clinical Study of Paclitaxel Polymeric Micelles Combined With Trastuzumab and Pertuzumab (HP) and Adebelimab Versus Taxane Combined With HP as First-Line Treatment for Advanced HER2-Positive Breast Cancer

Обзор

This study is a randomized, open-label, controlled, multicenter Phase II trial conducted in patients with advanced HER2-positive breast cancer, aimed at evaluating the efficacy and safety of paclitaxel polymer micelles for injection combined with trastuzumab and adalimumab versus the paclitaxel-based regimen combined with trastuzumab as first-line treatment. Eligible subjects with histologically or cytologically confirmed advanced HER2-positive breast cancer were enrolled after obtaining informed consent. They were randomly assigned to two groups: the experimental group received paclitaxel polymer micelles for injection combined with trastuzumab, pertuzumab, and adrelumab; the control group received taxanes (paclitaxel, docetaxel, albumin-bound paclitaxel, paclitaxel polymer micelles) combined with trastuzumab and pertuzumab. Each treatment cycle lasted 3 weeks (Q3W), with administration on day 1 (D1) of each cycle. Therapy continued until disease progression (PD), intolerable toxicity, withdrawal of informed consent, initiation of alternative antitumor therapy, death, or any other treatment discontinuation criteria specified in the protocol-whichever occurred first.

Подробное описание

In 2020, the incidence rate of breast cancer among women in China was 59.0 per 100,000, with a mortality rate of 16.6 per 100,000, ranking first and fourth, respectively, among all female malignant tumors nationwide. Currently, for the salvage treatment of human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), the first-line recommended regimen is trastuzumab combined with pertuzumab plus a taxane-based therapy.

Paclitaxel is a broad-spectrum anticancer agent with a unique mechanism of action, exhibiting significant antitumor activity against various malignant tumors, including breast cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, and head and neck cancer. It is widely used in clinical practice for the treatment of these malignancies. Among its formulations, the paclitaxel injection solubilized with polyoxyethylene castor oil was the first to be approved for market. However, polyoxyethylene castor oil can induce human serum complement activation and histamine release, leading to adverse reactions such as renal impairment, neurotoxicity, bone marrow suppression, allergic reactions, and asymptomatic arrhythmias. To prevent allergic reactions, prophylactic medication is required prior to administration; nevertheless, some patients may still experience varying degrees of allergic reactions, causing clinical operational challenges and patient discomfort. Globally, an increasing number of research institutions are dedicated to developing novel paclitaxel formulations aimed at reducing its adverse effects, increasing its clinical dosage, and enhancing its therapeutic efficacy.

Paclitaxel polymer micelles for injection is an innovative paclitaxel dosage form independently developed by China Shanghai Yizhong Pharmaceutical Co., Ltd. This formulation exhibits exceptional in vivo stability and high sensitivity in intratumoral drug release. Compared to other marketed paclitaxel formulations, paclitaxel micelles demonstrate superior safety even with significantly higher clinical dosages, require no antiallergic pretreatment prior to administration, and eliminate the need for specialized infusion devices, ensuring clinical convenience. Phase III clinical trial results for non-small cell lung cancer (NSCLC) demonstrated a markedly improved objective response rate (ORR) and significantly prolonged progression-free survival (PFS). In first-line treatment of advanced NSCLC, it exhibits unique advantages and advanced efficacy in both therapeutic outcomes and safety profiles, making it a novel option for NSCLC chemotherapy.

Studies have demonstrated that PD-L1 expression can be detected in approximately 42% of HER2-positive breast cancer patients. Results from a Phase II clinical trial showed that the overall pathological complete response (pCR) rate reached 61% when immune checkpoint inhibitors were added to the treatment of HER2-positive breast cancer, with even higher pCR rates observed in subgroup analyses. These findings collectively suggest that targeting PD-1/PD-L1 holds promise as a potential therapeutic target for HER2-positive breast cancer. Adecabtagalimab, a humanized anti-PD-L1 monoclonal antibody, specifically binds to the PD-L1 molecule to block the PD-1/PD-L1 pathway responsible for tumor immune tolerance, thereby reactivating the immune system's antitumor activity and achieving therapeutic effects. In March 2023, the National Medical Products Administration approved adecabtagalimab in combination with carboplatin and etoposide for first-line treatment of patients with extensive-stage small cell lung cancer.

Based on previous research findings and the widespread application of paclitaxel in breast cancer treatment, this study aims to develop a clinical protocol comparing paclitaxel polymer micelles for injection combined with dupilumab and adalimumab versus taxane-based regimens combined with dupilumab as first-line therapy for unresectable advanced HER2-positive breast cancer. The goal is to demonstrate that the combination of paclitaxel polymer micelles with dupilumab and adalimumab provides therapeutic benefits in patients with advanced HER2-positive breast cancer while maintaining manageable safety profiles. The primary objective of the study is to evaluate the objective response rate (ORR) between the trial group (paclitaxel polymer micelles + dupilumab + adalimumab) and the control group (taxanes + dupilumab) in first-line treatment of advanced HER2-positive breast cancer. The secondary objectives are to assess progression-free survival (PFS), overall survival (OS), and safety profiles of the trial group versus the control group in this context.

Вмешательства

• Препарат Paclitaxel polymer micelles combined with trastuzumab, pertuzumab, and adrelumab
  1. Paclitaxel polymer micelles for injection: 300 mg/m², administered via intravenous infusion over ≥3.5 hours; 2. Trastuzumab: Initial dose of 8 mg/kg, administered within 1.5 hours; subsequent doses adjusted to 6 mg/kg, administered within 1.5 hours; 3. Pertuzumab: Initial dose of 840 mg, followed by a subsequent dose of 420 mg, administered via intravenous infusion within 1.5 hours; 4. Adalimumab: 20 mg/kg, with infusion duration controlled between 30 to 60 minutes, not exceeding 2 hours.
• Препарат Taxanes combined with trastuzumab and pertuzumab.
  1. Paclitaxel: 175 mg/m², intravenous infusion over 3 hours; or Docetaxel: 75 mg/m², intravenous infusion over 1 hour; or Albumin-bound paclitaxel: 260 mg/m², intravenous infusion over 30 minutes; or Paclitaxel polymer micelles for injection: 300 mg/m², intravenous infusion over ≥3.5 hours. 2. Trastuzumab: Initial dose of 8 mg/kg, administered within 1.5 hours; subsequent doses adjusted to 6 mg/kg, administered within 1.5 hours; 3. Pertuzumab: Initial dose of 840 mg, followed by a subsequent dos

Первичные конечные точки

• Objective response rate （ORR） [Срок оценки: From enrollment to the end of treatment up to approximately 24 months]

Вторичные конечные точки (3)

• Progression-Free Survival (PFS) [Срок оценки: From enrollment to the first evidence of PD or death from any cause up to approximately 24 months]
• Overall Survival (OS) [Срок оценки: From enrollment to the date of death up to approximately 60 months]
• Safety Endpoints [Срок оценки: From enrollment to the end of treatment up to approximately 24 months]

Критерии участия

• Age: ≥18 years, no gender restriction;
• Pathologically confirmed breast cancer: a) Advanced or metastatic breast cancer; b) Locally assessed as HER2-positive (IHC 3+ or IHC 2+ with ISH+);
• For advanced or metastatic breast cancer, patients should have not previously received chemotherapy or HER2-targeted therapy, or have received only first-line endocrine therapy. Subjects receiving chemotherapy or HER2-targeted therapy as neoadjuvant or adjuvant treatment are eligible if the interval from treatment completion to metastasis diagnosis exceeds 6 months;
• PD-L1 testing is positive (combined positive score CPS ≥ 1);
• ECOG score is 0-1;
• Estimated survival is at least 3 months;
• There is at least one measurable lesion assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) (according to RECIST 1.1);
• Basic normal function of major organs such as the heart, lungs, liver, and kidneys;
• Sufficient organ and bone marrow function, meeting the following criteria: (1) Complete blood count must meet: a) Hemoglobin (HB) ≥ 90 g/L; b) Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L; c) Platelet count (PLT) ≥ 75×10⁹/L; (2) Biochemical tests must meet: a) Serum total bilirubin (TBIL) ≤ 1.5× upper limit of normal (ULN); b) ALT and AST ≤ 2.5× ULN; if liver metastases are present, ALT and AST ≤ 5× ULN; c) Cr ≤ 1.5× ULN or creatinine clearance (CCr) ≥ 60 mL/min (Cockcroft-Gault formula);
• Patients voluntarily participate in the study, sign an informed consent form, and demonstrate good compliance.

Критерии исключения

Subjects were ineligible for this trial if they met any of the following criteria:

• Known allergy or intolerance to any study agent or excipient;
• Primary central nervous system malignancy or meningeal metastasis; symptomatic patients with central nervous system metastases; patients with asymptomatic brain metastases or clinically stable conditions requiring no steroid therapy for at least 4 weeks were eligible;
• History of chemotherapy, targeted therapy, or major surgery within 4 weeks prior to first dose; history of endocrine therapy or local radiotherapy within 2 weeks prior to first dose;
• Active or previously documented interstitial lung disease (ILD), pneumonia, or suspected ILD that could not be excluded by imaging during screening; pneumonia that could not be excluded by imaging during screening;
• History of other malignancies within 5 years that could be locally treated and cured (excluding basal cell carcinoma of the skin, superficial or non-invasive bladder cancer, cervical carcinoma in situ, breast ductal carcinoma in situ, papillary thyroid carcinoma, etc.);
• History of live vaccine vaccination within 28 days prior to treatment;
• Active autoimmune diseases (including but not limited to myasthenia gravis, myositis, asthma, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vitiligo, psoriasis, etc.); stable-dose hormone replacement therapy for hypothyroidism was excluded;
• Patients with significant coagulation disorders or other clear evidence of bleeding risk.
• Patients with the following cardiac conditions within 6 months prior to treatment initiation: acute coronary syndrome, coronary artery bypass grafting, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular events; cardiac dysfunction classified ≥ Class II on the New York Heart Association (NYHA) scale or left ventricular ejection fraction (LVEF) <50%; myocardial infarction, severe/unstable angina, cerebrovascular accident/stroke, transient ischemic attack, subarachnoid hemorrhage, or severe cardiac rhythm/conductance abnormalities requiring clinical intervention (e.g., ventricular arrhythmias, second-to-third-degree atrioventricular block, congenital long QT syndrome);
• Patients with active hepatitis B or C virus infection, HIV infection, or active pulmonary tuberculosis;
• Patients with active infections requiring antimicrobial therapy (e.g., antibiotics, antiviral agents, or antifungal drugs);
• Patients with a known history of allogeneic organ transplantation or hematopoietic stem cell transplantation;
• Patients with a history of substance abuse (e.g., psychiatric medications) that cannot be discontinued or those with mental disorders;
• Pregnant or breastfeeding women; or patients of reproductive age who are unwilling or unable to use effective contraceptive measures.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Fudan University Shanghai Cancer center — Шанхай

Публикации

• Wang J, Zhou C, Yao W, Wang Q, Min X, Chen G, Xu X, Li X, Xu F, Fang Y, Yang R, Yu G, Gong Y, Zhao J, Fan Y, Liu Q, Cao L, Yao Y, Liu Y, Li X, Wu J, He Z, Lu K, Jiang L, Hu C, Zhao W, Zhang B, Shi W, Zhang X, Cheng Y; CAPSTONE-1 Study Group. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomis PMID 35576956
• Ahn HK, Sim SH, Suh KJ, Kim MH, Jeong JH, Kim JY, Lee DW, Ahn JH, Chae H, Lee KH, Kim JH, Lee KS, Sohn JH, Choi YL, Im SA, Jung KH, Park YH. Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2022 Sep 1;8(9):1271-1277. doi: PMID 35797012
• Schettini F, Prat A. Dissecting the biological heterogeneity of HER2-positive breast cancer. Breast. 2021 Oct;59:339-350. doi: 10.1016/j.breast.2021.07.019. Epub 2021 Aug 5. PMID 34392185
• Janjigian YY, Kawazoe A, Yanez P, Li N, Lonardi S, Kolesnik O, Barajas O, Bai Y, Shen L, Tang Y, Wyrwicz LS, Xu J, Shitara K, Qin S, Van Cutsem E, Tabernero J, Li L, Shah S, Bhagia P, Chung HC. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730. doi: 10.1038/s41586-021-04161-3. Epub 2021 Dec 15. PMID 34912120
• Xu B, Li W, Zhang Q, Li Q, Wang X, Li H, Sun T, Yin Y, Zheng H, Feng J, Zhu H, Siddiqui A, Macharia H, Knott A. Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): final analysis of a phase III, randomized, double-blind, placebo-controlled study. Breast Cancer Res Treat. 2023 Feb;197(3):503-513. PMID 36463547
• Thill M, Wimberger P, Grafe A, Klare P, Luedtke-Heckenkamp K, Reichert D, Zaiss M, Ziegler-Lohr K, Eckl T, Schneeweiss A. Dual HER2 blockade with pertuzumab (P) and trastuzumab (T) in patients with HER2-positive metastatic breast cancer (mBC) relapsing after adjuvant treatment with T: results from a German non-interventional study (NIS) HELENA (NCT01777958). Breast Cancer Res Treat. 2022 Nov;196(2 PMID 36094611
• Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513. PMID 25693012
• Shi M, Gu A, Tu H, Huang C, Wang H, Yu Z, Wang X, Cao L, Shu Y, Wang H, Yang R, Li X, Chang J, Hu Y, Shen P, Hu Y, Guo Z, Tao M, Zhang Y, Liu X, Sun Q, Zhang X, Jiang Z, Zhao J, Chen F, Yu H, Zhang W, Sun J, Li D, Zhou J, Han B, Wu YL. Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, ran PMID 33130217

Идентификаторы

NCT: NCT07581795 · ZSCJSIITRX001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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