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

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

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.

Inclusion Criteria:

1. Pathologically confirmed HER2 positive advanced breast cancer

2. Age>18 years. brain metastases confirmed by enhanced brain MRI

3. KPS≥70

4. Life expectancy of more than 12 weeks

5. Prior therapy of oral dexamethasone not exceeding 16mg/d

6. Time interval from prior therapy was more than 2 weeks, and evaluation of adverse events is no more than grade 1.

7. Maximum diameter of intracranial metastases is less than 3cm measured by enhanced brain MRI(2-3mm)

8. Prior endocrine therapy were allowed

9. Anti-Her2 targeted treatment were allowed

10. Screening laboratory values must meet the following criteria( and should be obtained within 28 days prior to registration):

    1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, Platelets≥ 90 x 109/L, Hemoglobin ≥ 90 g/L
    2. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 x ULN without liver metastasis,≤ 5 x ULN with liver metastases
    3. Serum BUN and creatinine ≤ 1.5 x Upper Limit of Normal (ULN)
    4. LVEF ≥ 50%
    5. QTcF < 480 ms
    6. INR≤1.5×ULN，APTT≤1.5×ULN

11. Signed the informed consent form prior to patient entry

Exclusion Criteria:

1. Leptomeningeal or hemorrhagic metastases
2. uncontrolled epilepsy
3. Severe complication: cardiovascular disease, end-stage renal disease, severe hepatic disease, infection etc.
4. Pregnancy or lactation period， women of child-bearing age who are unwilling to accept contraceptive measures.
5. Inability to complete enhanced MRI
6. Patients who are difficult or unable to be followed-up
7. Not suitable for inclusion for specific reasons judged by sponsor
8. Patients unable to swallow, with chronic diarrhea, intestinal obstruction, or multiple factors that affect drug use and absorption
9. History of allergy to pyrotinib or capetabine
10. History of immunodeficiency, including HIV positive, active HBV/HCV or other acquired, congenital immunodeficiency disease, or organ transplantation history
11. Previous use of pyrotinib combined with capetabine