Pyrotinib Combined With Brain Radiotherapy in Breast Cancer Patients With Brain Metastases

Study Overview
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Brief Summary
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Brain metastases occur in 30-50% of patients with metastatic HER2-positive breast cancer. Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against epidermal growth factor receptor (EGFR)/HER1, HER2, and HER4. This study consists of two parts. In a phase Ib part, investigators will explore the safety and tolerance of Pyrotinib Plus Capecitabine combined with brain radiotherapy. After completing the phase Ib part, investigators will review the data and decide whether this patient is included in before the start of a phase II part. In the phase II part, investigators will evaluate the efficacy of Pyrotinib Plus Capecitabine combined with brain radiotherapy in patients with HER2 positive breast cancer patients with brain metastases.

Official Title
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A Phase Ib/II Pilot Study of Pyrotinib Plus Capecitabine Combined With Brain Radiotherapy in HER2 Positive Breast Cancer Patients With Brain Metastases

Conditions
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Breast Cancer, Brain Metastases, HER2-positive Breast Cancer

Intervention / Treatment
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* Other: Pyrotinib Plus Capecitabine combined with brain radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed HER2 positive advanced breast cancer Age>18 years. brain metastases confirmed by enhanced brain MRI KPS≥70 Life expectancy of more than 12 weeks Prior therapy of oral dexamethasone not exceeding 16mg/d Time interval from prior therapy was more than 2 weeks, and evaluation of adverse events is no more than grade 1. Maximum diameter of intracranial metastases is less than 3cm measured by enhanced brain MRI(2-3mm) Prior endocrine therapy were allowed Anti-Her2 targeted treatment were allowed Screening laboratory values must meet the following criteria( and should be obtained within 28 days prior to registration): Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, Platelets≥ 90 x 109/L, Hemoglobin ≥ 90 g/L Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 x ULN without liver metastasis,≤ 5 x ULN with liver metastases Serum BUN and creatinine ≤ 1.5 x Upper Limit of Normal (ULN) LVEF ≥ 50% QTcF < 480 ms INR≤1.5×ULN，APTT≤1.5×ULN Signed the informed consent form prior to patient entry Exclusion Criteria: Leptomeningeal or hemorrhagic metastases uncontrolled epilepsy Severe complication: cardiovascular disease, end-stage renal disease, severe hepatic disease, infection etc. Pregnancy or lactation period， women of child-bearing age who are unwilling to accept contraceptive measures. Inability to complete enhanced MRI Patients who are difficult or unable to be followed-up Not suitable for inclusion for specific reasons judged by sponsor Patients unable to swallow, with chronic diarrhea, intestinal obstruction, or multiple factors that affect drug use and absorption History of allergy to pyrotinib or capetabine History of immunodeficiency, including HIV positive, active HBV/HCV or other acquired, congenital immunodeficiency disease, or organ transplantation history Previous use of pyrotinib combined with capetabine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyrotinib Plus Capecitabine combined with brain radiotherapy<br>Fractionated stereotactic radiotherapy(FSRT) or whole brain radiation therapy (WBRT) Drug: Pyrotinib combined with capecitabine pyrotinib 400 mg once daily; Capecitabine 1000 mg/m2 per day on day 1 through 14, every 21 days. | Other: Pyrotinib Plus Capecitabine combined with brain radiotherapy<br>* Drug combined with radiation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess safety and tolerability of Pyrotinib Plus Capecitabine combined with brain radiotherapy(Phase Ib part) | AEs will be assessed according to CTCAE version 4.03. (1)Initially 3 patients will be accrued and treated with combined therapy as a lead-in safety phase. Enrollment of the study will not proceed if patients in the safety lead-in phase experience unacceptable toxicities including neurologic, hematologic and other dose limiting toxicities.(see protocol) (b)If one of initially 3 patients has experienced unacceptable toxicities, 3 more patients will be accrued . (3)If two or more patients are unable to complete radiation therapy (RT) due to toxicity related to Pyrotinib Plus Capecitabine combined with brain radiotherapy, accrual will be suspended and the study will be stopped. (4) If 3+3 patients are able to complete the treatment without unacceptable toxicities, 6 more patients will be accrued in Ib part. | 8 weeks | 
| Intracranial local tumor control rate （Phase II part) | All intracranial progression | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial local tumor control rate with FSRT or WBRT | Intracranial local tumor control rate | 2 years | 
| Intracranial Progression-Free Survival (PFS) | Time from the date of radiotherapy to the investigator-determined date of progression (determined by RANO) or death due to any cause, whichever occurs first | 2 years | 
| Extracranial Progression-Free Survival (PFS) |  | 2 years | 
| OS (overall survival) |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pyrotinib, brain radiotherapy