This is a Phase II, single-center, double-blind, placebo-controlled, randomized study of Pyrotinib in combination with Doxorubicin/Epirubicin and Cyclophosphamide followed by Docetaxel/nab-Paclitaxel as neoadjuvant therapy for women with hormone receptor positive HER2-negative stage II to III breast cancer. Patients randomized to the study arm/control arm will receive standard neoadjuvant chemotherapy in combination with pyrotinib/placebo, respectively. The primary endpoint of the study is the residual cancer burden 0/I (RCB 0/I) and total pathological complete response (tpCR) rate. Secondary endpoints include the breast pCR (bpCR) rate, objective response rate(ORR), event-free survival (EFS), overall survival (OS), rate of change in the Ki-67 proliferation index, correlations between potential biomarkers and treatment efficacy, and toxicity.
Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against epidermal growth factor receptor HER1(EGFR), HER2 and HER4. Improvement of the chemotherapy efficacy and good tolerability have been shown by several stage II and III clinical trials in both the neoadjuvant and metastasis setting in HER2-positive breast cancers. Yet, the anti-tumor effect of Pyrotinib by targeting HER4 has not been determined. Preclinical studies show that HER4 is relatively highly expressed in hormone receptor positive and HER2-negative(HR+/HER2-) breast cancers. In MCF7 cell lines, Pyrotinib effectively repressed phosphorylation of MAPK and Akt signal transduction pathways to inhibit tumor cell proliferation. In HR+/HER2- tumor xenografts, Pyrotinib has been observed to inhibit tumor growth in a dose-dependent manner (unpublished data). Taken together, the data support the rationale that Pyrotinib may be efficacious in HER4 high expressed HR+/HER2- breast cancer and in combination with chemotherapy may lead to a better RCB 0/I and pCR rate in the neoadjuvant setting. The study is a two-arm design with a 1:1 allocation ratio (equal numbers of patients randomized to Arms 1, 2). The sample size will be up to 140 patients with about 70 evaluable patients in each arm. Accrual is expected to occur over 48 months. Patients will be randomized to one of the two neoadjuvant therapy regimens: Patients in Arm 1 will be assigned to receive 400 mg Pyrotinib orally once per day with four cycles of epirubicin (100 mg/m2) (or doxorubicin hydrochloride liposome injection 30mg/m2) and cyclophosphamide (600 mg/m2) intravenously, once every 3 weeks, followed by four cycles of docetaxel (100 mg/m2) intravenously, once every 3 weeks(or nab-paclitaxel 260mg/m2 q3w, or 12 cycles of weekly nab-paclitaxel 120 mg/m2) . Dosage reduction of pyrotinib is permitted from 400 mg to 320 mg or 240 mg if Pyrotinib-related AEs are experienced. In Arm 2 (control), Pyrotinib will be replaced by 400mg placebo provided by the same pharmacy company. In all arms, clinical response will be evaluated by breast MRI. The primary endpoint will be assessed with the paraffin embedded pathological specimens collected from surgery. Submission of tumor samples for the correlative science studies will be optional for all patients. For patients who agree, pathological sections of core biopsy specimen before treatment (after the patient has signed the consent form and has been screened for eligibility) and pathological sections of surgery residual disease specimen after the completion of the treatment are collected. In addition, a blood sample collected after randomization (before the start of study therapy and after the completion of the neoadjuvant therapy) will also be required for the correlative studies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
140
400 mg orally once per day. Pyrotinib starts with a dose of 240 mg once daily for one week, followed by 320 mg once daily for the next week, before transitioning to 400 mg once daily as maintenance therapy.
100 mg/m2,q3W\*4
30mg/m2, q3w\*4
600 mg/m2, q3w\*4
100 mg/m2, q3w\*4
120mg/m2 qw\*12 or 260mg/m2 q3w\*4
400 mg orally once per day
Sun-Yat-Sen Memorial Hospital of Sun-Yat-Sen University
Guangzhou, Guangdong, China
RCB 0/I (Residual cancer burden 0/I) rate
defined as the proportion of patients whose surgical specimens after neoadjuvant therapy were pathologically assessed as RCB 0 or RCB I.
Time frame: At the time of surgery
tpCR (total pCR) rate
ypT0/isN0, number of participants with by no histologic evidence of invasive tumor cells in the surgical breast and axillary specimen.
Time frame: At the time of surgery.
bpCR (breast pCR)
ypT0/is, number of participants with by no histologic evidence of invasive tumor cells in the surgical breast specimen.
Time frame: At the time of surgery.
ORR (objective response) rate
the percentage of patients with a final overall response of CR or PR relative to the appropriate analysis set. Clinical response will be evaluated by breast MRI.
Time frame: At the time of surgery.
EFS (event-free survival) at 3 and 5 years
EFS is defined as the time from randomization to the date of progression(according to RECIST 1.1 ) of disease that precludes surgery, local relapse, regional relapse, distant relapse, second primary invasive breast cancer including contralateral breast cancer, or death due to any cause which ever occurred first.
Time frame: EFS will be determined at 3 and 5 years after randomization
OS (overall survival) at 3 and 5 years
OS is defined as the time from randomization to date of death.
Time frame: OS will be determined at 3 and 5 years after randomization
Rate of change in the Ki-67 proliferation index
defined as change of Ki-67 expression in the tumor tissue before and after neoadjuvant therapy
Time frame: Baseline and at the time of surgery
The correlation of potential biomarkers with the RCB 0/I, tpCR, bpCR and ORR rate.
We will used immunohistochemistry (IHC) method to assess the positive percentage of ER, PR, Ki67%, as well as the HER4 scores, and the status EGFR, HER3, and PD-L1 of the specimen from primary core biopsy at baseline. The IHC4 score will be calculated using our modified method (Jin et al. Oncologist. 2020 Aug;25(8):e1170-e1180.). The correlation between these biomarkers with treatment efficacy (RCB 0/I, tpCR, bpCR and ORR) will be explored.
Time frame: The correlation with RCB 0/I, tpCR, bpCR and ORR will be assessed when the surgery is performed on the last enrolled patients.
The correlation of potential biomarkers with EFS and OS.
We will used immunohistochemistry (IHC) method to assess the positive percentage of ER, PR, Ki67%, as well as the HER4 scores, and the status EGFR, HER3, and PD-L1 of the specimen from primary core biopsy at baseline, as well as the residual surgical specimen after neoadjuvant chemotherapy. The IHC4 score will be calculated using our modified method (Jin et al. Oncologist. 2020 Aug;25(8):e1170-e1180.). The correlation between these biomarkers with EFS and OS will be analyzed
Time frame: The correlation with EFS and OS will be performed at 5 years after the enrollment of the last patient.
AE (Adverse Event) and SAE (Serious Adverse Event) rate
Toxicities are graded according to NCI CTCAE v4.03.
Time frame: Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
The correlation between NGS sequencing and ctDNA data with clinical outcomes(Optional).
NGS sequencing will be performed with the pathological section of primary core biopsy and surgery residual specimen, and the ctDNA will be extracted from the patients' serum at baseline and the date of surgery, if with the agreement of participants. The correlation between these biomarkers with clinical outcomes (pCR and EFS) will be assessed when possible.
Time frame: The correlation with pCR will be assessed when the surgery is performed on the last enrolled patients. The correlation with EFS and OS will be performed at 5 years after the enrollment of the last patient.
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