Clinical trial NCT04973319: Trastuzumab Combined With Pertuzumab for Adjuvant Treatment of Breast Cancer After Neoadjuvant Therapy
Official title: Trastuzumab Combined With Pertuzumab and Sequential Use of Pyrotinib vs. Trastuzumab Combined With Pertuzumab for Adjuvant Treatment of Breast Cancer After Neoadjuvant Therapy
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: breast cancer; pyrotinib; trastuzumab; pertuzumab
Lead sponsor: Shengjing Hospital
Sponsor class: OTHER
First posted: 2021-07-22
Enrollment: 450
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants are assigned to one of two or more groups in parallel for the duration of the study.
Primary purpose: TREATMENT

Brief summary: Patients with HER-2 positive breast cancer who have poor outcomes after endocrinotherapy and standard chemotherapy can be significantly improved by the use of anti-HER-2 monoclonal antibody trastuzumab. In the current clinical practice of neoadjuvant therapy, trastuzumab combined with chemotherapy can significantly increase the pCR and improve the outcomes in patients. However, there seems to be no available treatment for patients who have no pCR and still have residual tumors except for sequential trastuzumab treatment for 1 year. Compared with trastuzumab, a HER-2 macromolecule inhibitor, pyrotinib has a different site of action and an increased EGFR target. Compared with lapatinib, a small molecule inhibitor of EGFR and HER-2, pyrotinib is an irreversible inhibitor, with the ability to achieve a better curative effect at a lower human plasma exposure level. This trial is designed to evaluate the effectiveness and safety of trastuzumab combined with pertuzumab followed by sequential pyrotinib treatment in non-pCR patients after neoadjuvant therapy.

Detailed description: In recent years, the interest has greatly increased in how to proceed with postoperative intensive adjuvant therapy for early breast cancer patients who have not reached pCR and still have residual lesion after neoadjuvant therapy. Relevant efficacy and safety data have been continuously verified in clinical trials, and some treatments have been clinically approved. Moreover, new attempts and explorations are still going on in clinical practice. Based on the preliminary clinical findings, it is planned to design a randomized controlled, open-label, multi-center phase III clinical study that will explore the efficacy of trastuzumab combined with pertuzumab for 1 year followed by sequential pyrotinib vs. touzumab combined with pertuzumab for 1 year, aiming to verify that dual-target adjuvant therapy with sequential use of pyrotinib maleate tablets is superior to dual-target adjuvant therapy alone in HER-2 positive early breast cancer patients who have not reached pCR after neoadjuvant therapy. If this clinical trial achieves a positive result, the use of pyrotinib maleate tablets will be promoted for early breast cancer patients who have not reached pCR and still have residual tumor lesions after neoadjuvant therapy with an attempt to further achieve improved outcomes and prognosis.

Eligibility criteria: Inclusion Criteria:

* Female patients aged ≥ 18 but ≤ 75 years (The maximal age of the subjects enrolled in the Phase 3 study of pyrotinib is 75 years old, and there is no safety data for the use of the drug in older people);
* ECOG level 0-1;
* Primary infiltrating breast lesions and lymph nodes should follow these conditions at the same time: histologically confirmed invasive breast cancer; receiving neoadjuvant treatment and completing the operation, with postoperative pathological examination indicating residual invasive cancer in the breast or axillary lymph nodes; HER2-positive breast cancer is confirmed in the pathology test, with 3+ in immunohistochemistry (IHC) test and HER2 gene amplification (HER2/CEP17 ≥ 2.0 or average HER2 copy number/cell number ≥ 6); no recurrent and metastatic disease after surgery;
* HER-2 positive breast cancer patients who have non-pCR after trastuzumab+pertuzumab as neoadjuvant therapy, and have completed trastuzumab combined with pertuzumab as adjuvant treatment. During the neoadjuvant and/or adjuvant therapy phase, at least ≥24 weeks (8 drug delivery cycles) of trastuzumab + pertuzumab. And the time interval from the end of the last trastuzumab treatment to entering the trial must be ≤ 1 year;
* Hormone receptor status (ER and PR) that is known;
* The functional level of major organs must conform to the following requirements (no blood transfusion, no use of white blood cell- and platelet-increasing drugs within 2 weeks before screening): Neutrophils (ANC) ≥ 1.5×109/L; Platelet count (PLT) ≥ 90×109/L; Hemoglobin (Hb) ≥ 90 g/L; Total bilirubin (TBIL)≤ 1.5×upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5×ULN;
* Female patients who are not menopausal or not surgically sterilized agree to abstain from sex or use effective non-hormonal drugs for contraception during the treatment period and within 8 weeks after the last administration;
* Patients who participate in the trial voluntarily, sign an informed consent, have good compliance and are willing to comply with the follow-up visit.

Exclusion Criteria:

* With a history of recurrent local or regional breast disease;
* Stage IV (metastatic) breast cancer;
* Bilateral breast cancer;
* With a history of any malignancies other than breast cancer in the past 5 years, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or squamous cell carcinoma;
* Patients who have received pyrotinib, lapatinib, neratinib or other tyrosine kinase inhibitors, enmetrastuzumab (T-DM1), and other anti-tumor biological therapies or tumor immunotherapy;
* Patients who are receiving anti-tumor therapy in other clinical trials, including endocrine therapy, bisphosphonate therapy or immunotherapy;
* Severe heart disease or discomfort, including but not limited to the following diseases: a confirmed history of heart failure or systolic dysfunction (LVEF \< 50%); high-risk uncontrolled arrhythmia, such as atrial tachycardia, remarkable ventricular arrhythmia (such as ventricular tachycardia) or higher-grade atrioventricular block; angina pectoris requiring anti-angina medication; clinically significant valvular disease; transmural myocardial infarction shown by ECG; uncontrolled blood pressure in patients with hypertension who have been given antihypertensive drugs (systolic blood pressure \> 180 mmHg and/or diastolic blood pressure \> 100 mmHg);
* Inability to swallow, intestinal obstruction or other factors that affect drug taking and absorption;
* With a history of diagnosed neurological or mental disorders, including involuntary behavior or mental illness;
* With a history of gastrointestinal diseases with diarrhea as the main symptom;
* Patients who are known to have a history of allergies to the drug components in this trial; have a history of immunodeficiency, including HIV positive results, or other acquired or congenital immunodeficiency diseases; or have a history of organ transplantation;
* Female patients during pregnancy and lactation, or those who are fertile and positive for baseline pregnancy test;
* Serious concomitant diseases or other comorbid diseases that will interfere with the planned treatment, including infectious diseases with active infections (including but not limited to hepatitis B, active hepatitis C, active tuberculosis, active syphilis, etc.); or any other cases in which the investigator believes that the patient cannot participate in the trial.

Primary outcomes:
measure: Invasive Disease-Free Survival (IDFS)
timeFrame: at least 3 years from the beginning of randomization.
Secondary outcomes:
measure: Disease-Free Survival (DFS)
timeFrame: at least 3 years from the date of randomization
measure: overall survival (OS)
timeFrame: at least 3 years from the date of randomization
measure: Distant Disease-Free Survival (DDFS)
timeFrame: at least 3 years from the date of randomization
Other outcomes:
measure: Adverse event (AE)
timeFrame: from the date of randomization to no more than 28 days after the last drug withdrawal.
Locations:
city: Shenyang
country: China
facility: Shengjing Hospital affiliated to China Medical University
state: Liaoning
Study officials:
affiliation: Department of Breast Surgery, Shengjing Hospital affiliated to China Medical University
name: Cai-Gang Liu, MD
role: PRINCIPAL_INVESTIGATOR
References: