Pyrotinib in Combination With Neoadjuvant Chemotherapy in HR+/HER2-, HER4 High Expression Breast Cancer Patients: A Phase II Trial

Breast Cancer Clinical Trial

Official title:

Efficacy and Safety of Pyrotinib in Combination With Neoadjuvant Chemotherapy in Stage II-III HR+/HER2-, HER4 High Expression Breast Cancer Patients: A Phase II, Single-center, Randomized, Double-Blinded, Placebo-Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04872985
• Other study ID #: MA-BC-II-018
• Status: Recruiting
• Phase: Phase 2
• Start date: April 20, 2021
• Est. completion date: December 31, 2028

Study information

• Verified date: April 2021
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Contact: Kai Chen, MD.,PhD.
• Phone: 15920164730
• Email: chenkai23[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 total pathological complete response (pCR) rate. Secondary endpoints include the pCR rate in breast only, objective response rate(ORR), event-free survival, overall survival, and toxicity. We will also explore potential prognostic and predictive biomarkers.

Description:

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 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 24 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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Presenting with histological(by core needle biopsy or by limited incisional biopsy) proven hormone receptor positive (ER=10% and/or PR =1%), HER2 negative(IHC =2+ and/or FISH-) , stage II/ III breast cancer.

• Have clinical indication for neoadjuvant therapy.

• HER4 IHC score = 4.

• Measurable disease (breast and/or lymph nodes).

• The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.

• Adequate bone marrow function (within 4 weeks prior to registration): WBC=3.0x109/l, neutrophils =1.5 x 109/l, platelets =100 x 109/l.

• Adequate liver function (within 4 weeks prior to registration): bilirubin =1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT =2.5 x UNL, Alkaline Phosphatase =5 x UNL.

• Adequate renal function (within 4 weeks prior to registration): the calculated creatinine clearance should be =50 ml/min.

• Patients must have the ability to swallow oral medication.

• Without history of any kind of treatment to known malignancy (solid tumor or hematologic).

• Written informed consent.

• Accessible for treatment and follow-up.

Exclusion Criteria:

• Evidence of stage IV breast cancer.

• Contralateral invasive breast cancer or Inflammatory breast cancer.

• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization.

• Known metastatic disease from any malignancy (solid tumor or hematologic).

• Serious other diseases as infections (hepatitis B, C and HIV), recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias or on screening, any of the following cardiac parameters: bradycardia (heart rate <50 at rest) or QTcF =450 msec.

• Known hypersensitivity reaction to any of the components of the treatment.

• Pregnancy or lactation at the time of randomization.

• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Hormone-receptor Positive Breast Cancer

Intervention

Drug:
• Pyrotinib
400 mg orally once per day
• Epirubicin
100 mg/m2,q3W*4
• Doxorubicin Hydrochloride Liposome Injection
30mg/m2, q3w*4
• Cyclophosphamide
600 mg/m2, q3w*4
• Docetaxel
100 mg/m2, q3w*4
• Nab paclitaxel
120mg/m2 qw*12
• Placebo
400 mg orally once per day

Locations

Country	Name	City	State
China	Sun-Yat-Sen Memorial Hospital of Sun-Yat-Sen University	Guangzhou	Guangdong

Sponsors (2)

Lead Sponsor	Collaborator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University	Jiangsu HengRui Medicine Co., Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	tpCR (total pCR)	ypT0/isN0, number of participants with by no histologic evidence of invasive tumor cells in the surgical breast and axillary specimen.	At the time of surgery.
Secondary	pCR of the breast	ypT0/is, number of participants with by no histologic evidence of invasive tumor cells in the surgical breast specimen.	At the time of surgery.
Secondary	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.	At the time of surgery.
Secondary	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.	EFS will be determined at 3 and 5 years after randomization
Secondary	OS (overall survival) at 3 and 5 years	OS is defined as the time from randomization to date of death.	OS will be determined at 3 and 5 years after randomization
Secondary	Exploring potential biomarkers as predictors of tpCR, pCR of the breast and ORR.	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 association between these biomarkers with tpCR, pCR of the breast and ORR will be explored. The association between these biomarkers with the benefit of adding pyrotinib to neoadjuvant chemotherapy (interaction/effect modification effects) will also be explored.	The correlation with pCR will be assessed when the surgery is performed on the last enrolled patients.
Secondary	Exploring potential biomarkers as predictors of 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 association between these biomarkers with EFS and OS will be explored. The association between these biomarkers with the benefit of adding pyrotinib to neoadjuvant chemotherapy (interaction/effect modification effects) will also be explored.	The association with EFS and OS will be performed at 5 years after the enrollment of the last patient.
Secondary	Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.	Toxicities are graded according to NCI CTCAE v4.03.	Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
Secondary	Exploring the association 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 association between these biomarkers with clinical outcomes (pCR and EFS) will be assessed when possible.	The correlation with pCR will be assessed when the surgery is performed on the last enrolled patients. The association with EFS and OS will be performed at 5 years after the enrollment of the last patient.