Clinical trial NCT04872985: Pyrotinib in Combination with Neoadjuvant Chemotherapy in HR+/HER2-, HER4 High Expression Breast Cancer Patients: a Phase II 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Hormone-receptor Positive Breast Cancer
Keywords: Pyrotinib
Pan-HER TKI
HER4
Lead sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Sponsor class: OTHER
Collaborators: name: Jiangsu HengRui Medicine Co., Ltd.
First posted: 2021-05-05
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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, RCB after surgery, objective response rate(ORR), event-free survival, overall survival, and toxicity. We will also explore potential prognostic and predictive biomarkers.

Detailed 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 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.

Eligibility criteria: 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 cervical cancers, basal cell carcinoma of the skin, squamous cell carcinomas of the skin or thyroid papillary carcinoma that had received curative treatment before enrollment) 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.

Primary outcomes:
measure: tpCR (total pCR)
timeFrame: At the time of surgery.
Secondary outcomes:
measure: pCR of the breast
timeFrame: At the time of surgery.
measure: RCB after neoadjuvant treatment
timeFrame: At the time of surgery.
measure: ORR (objective response rate)
timeFrame: At the time of surgery.
measure: EFS (event-free survival) at 3 and 5 years
timeFrame: EFS will be determined at 3 and 5 years after randomization
measure: OS (overall survival) at 3 and 5 years
timeFrame: OS will be determined at 3 and 5 years after randomization
measure: Exploring potential biomarkers as predictors of tpCR, pCR of the breast and ORR.
timeFrame: The correlation with pCR will be assessed when the surgery is performed on the last enrolled patients.
measure: Exploring potential biomarkers as predictors of EFS and OS.
timeFrame: The association with EFS and OS will be performed at 5 years after the enrollment of the last patient.
measure: Toxicity according to NCI CTCAE v4.03 all grades and grade III/IV.
timeFrame: Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.
measure: Exploring the association between NGS sequencing and ctDNA data with clinical outcomes(Optional).
timeFrame: 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.
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun-Yat-Sen Memorial Hospital of Sun-Yat-Sen University
state: Guangdong
Study officials:
affiliation: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
name: Erwei Song, MD.,Phd.
role: PRINCIPAL_INVESTIGATOR
References: