A Phase II Exploratory Study of Iparomlimab and Tuvonralimab Combined With Chemotherapy in Neoadjuvant Treatment of HR+/HER2- Breast Cancer Patients

A Phase II Exploratory Study of Iparomlimab and Tuvonralimab Combined With Chemotherapy in Neoadjuvant Treatment of HR+/HER2- Breast Cancer Patients

This study is a prospective, multicenter, single-arm, exploratory study. 30 patients with locally advanced HR+/HER2- breast cancer who have not received any treatment were recruited to receive apalutamide voraparib combined with chemotherapy for neoadjuvant therapy. This study adopts Simon's two-stage design: in the first stage, 12 patients need to be enrolled. If among these 12 patients, 1 or fewer patients achieve tpCR, the study will be prematurely terminated due to early failure. Otherwise, 18 patients will be enrolled in the second stage. If 7 or more patients achieve tpCR among the 30 patients, the study achieves the expected results, and the drug can be further studied; otherwise, the study fails, and the drug does not need further study. The aim of this study is to evaluate the efficacy and safety of apalutamide voraparib combined with chemotherapy for neoadjuvant therapy in patients with HR+/HER2- breast cancer.

Inclusion Criteria:

• The patient must meet all of the following criteria to be included in the study:

  1. Age ≥ 18 years and ≤ 75 years, regardless of gender;

  2. The primary lesion tissue pathology is confirmed as HR+/HER2- breast cancer, following the 2018 ASCO/CAP breast cancer HER2 testing guidelines and the 2010 ASCO/CAP breast cancer ER/PR testing guidelines for interpretation. HER2-negative is defined as confirmed by the pathology laboratory with an immunohistochemistry (IHC) score of HER2 0/1+ or 2+ and negative in in situ hybridization (ISH), and estrogen receptor positive (ER+) breast cancer with or without progesterone receptor (PgR) expression;

  3. Tumor histological grade 3, or histological grade 2 with the percentage of ER expression level between 1-10%;

  4. According to the American Joint Committee on Cancer (AJCC) 8th edition TNM classification, the clinical stage should be T1c-T2cN1-2 or T3-4cN0-2, M0 stage;

  5. At least one measurable lesion (in accordance with the RECIST 1.1 version standard);

  6. Expected survival time ≥ 12 weeks;

  7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1;

  8. The subject has no severe blood, heart, lung, liver, or kidney function abnormalities and immunodeficiency diseases. The functional level of important organs within one week before the first administration must meet the following requirements:

     1. Blood routine: HGB ≥ 90g/L; WBC ≥ 4.0×109/L; NEUT ≥ 2.0×109/L; PLT ≥ 100×109/L;
     2. Blood biochemistry: TBIL ≤ 1.5×ULN; ALT and AST ≤ 3×ULN (for those with liver metastasis, ALT and AST ≤ 5×ULN); BUN and Cr ≤ 1.5×ULN and creatinine clearance rate ≥ 50 mL/min;
     3. Cardiac color Doppler ultrasound before the first administration must meet: left ventricular ejection fraction (LVEF) > 50%;

  9. Thyroid stimulating hormone (TSH) ≤ upper limit of normal (ULN); if abnormal, T3 and T4 levels should be examined; if T3 and T4 levels are normal, the subject can be included;

  10. Pregnant patients should have a negative pregnancy test and voluntarily take effective and reliable contraceptive measures during the test period;

  11. The subject voluntarily joins this study, signs the informed consent, has good compliance and is willing to cooperate with follow-up.

Exclusion Criteria:

• If the patient meets any of the following conditions, they will not be eligible:

  1. Patients with stage IV metastatic breast cancer or other conditions deemed by the researchers as not achievable through neoadjuvant therapy for radical surgical resection;

  2. Bilateral invasive breast cancer;

  3. Breast cancer patients who have previously received anti-tumor treatments such as chemotherapy, endocrine therapy, or undergone breast surgery (except for the diagnostic biopsy of primary breast cancer);

  4. Patients who participated in other drug clinical trials within 4 weeks prior to enrollment, received major surgical treatment, incisional biopsy, or significant traumatic injury (except for the diagnostic biopsy of primary breast cancer);

  5. Within 4 weeks before the first administration or planned to receive attenuated live vaccines during the study;

  6. Patients with other malignant tumors within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or papillary thyroid carcinoma;

  7. Patients receiving any other anti-tumor treatment simultaneously;

  8. Patients with a known history of allergy to the components of this study drug;

  9. Patients with a clear history of neurological or mental disorders, including epilepsy or dementia, or a history of substance abuse or drug use for mental disorders;

  10. Patients with a known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;

  11. Pregnant or lactating female patients, or female patients with reproductive capacity and positive baseline pregnancy test results;

  12. Patients with active infectious diseases;

  13. Diagnosed with immunodeficiency or receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy;

  14. Patients with active or potentially recurrent autoimmune diseases, except for: vitiligo, alopecia, psoriasis or eczema that do not require systemic treatment; hypothyroidism caused by autoimmune thyroiditis, requiring only a stable dose of hormone replacement therapy; type 1 diabetes requiring only a stable dose of insulin replacement therapy;

  15. According to the investigator's judgment, there are serious diseases that endanger the patient's safety or affect the patient's ability to complete the study (including but not limited to drug-controlled interstitial lung disease, severe pulmonary dysfunction/disease, cerebrovascular accident, severe diabetes);

  16. Excluded patients with any of the following cardiovascular diseases:

      1. Within 6 months before the first administration, experienced myocardial infarction, unstable angina pectoris, pulmonary embolism, acute/ persistent myocardial ischemia, cerebrovascular accident, transient cerebral ischemic attack, or other clinically significant/ requiring drug treatment intervention thromboembolic or ischemic events;
      2. Had NYHA III-IV grade congestive heart failure in the past and/or currently;
      3. Had severe arrhythmias that require drug treatment in the past and/or currently;
      4. Within 12-lead ECG before the first administration showed a mean QT interval (QTcF) > 470 ms.

  17. The investigator determines that the patient is not suitable to participate in this study.