Study Evaluating Pyrotinib in Combination With Capecitabine In Patients With HER2 Positive Metastatic Breast Cancer

A Phase I Study of Pyrotinib In Combination With Capecitabine In Patients With HER2 Positive Metastatic Breast Cancer

Pyrotinib is an oral tyrosine kinase inhibitor targeting both EGFR and HER-2 receptors. This study is designed to evaluate the safety and tolerability of Pyrotinib in combination with capecitabine in patients with HER2 positive metastatic breast cancer:

To evaluate the safety and tolerability of pyrotinib, and the maximum tolerated dose (MTD) To determine the dose-limiting toxicity (DLT) To determine the pharmacokinetic profile of Pyrotinib To assess preliminary antitumor activity To determine preliminary regimen dose for phase II study

Inclusion Criteria:

• Aged ≥18 and ≤70 years.
• ECOG performance status of 0 to 1.
• Life expectancy of more than 12 weeks.
• At least one measurable lesion exists.(RECIST 1.1)
• Histologically or cytologic confirmed HER2 positive metastatic breast cancer which failed prior therapies.
• No previous treatment of capecitabin during the past 1 year.
• Required laboratory values including following parameters:

ANC: ≥ 1.5 x 109/L Platelet count: ≥ 100 x 109/L Hemoglobin: ≥ 9.0 g/dL Total bilirubin: ≤ 1.5 x upper limit of normal, ULN ALT and AST: ≤ 1.5 x ULN BUN and creatine clearance rate: ≥ 50 mL/min LVEF: ≥ 50% QTcF: < 470 ms

• Signed informed consent.

Exclusion Criteria:

• Subjects with third space fluid that can not be controled by drainage or other methods.
• Steroid treatment for more than 50 days, or in need of long-term use of steroids.
• Subjects that are unable to swallow tablets, or dysfunction of gastrointestinal absorption.
• Less than 4 weeks from the last radiotherapy,chemotherapy，surgery，hermone treatment,target therapy, or less than 6 weeks from the nitrosoureas or mitomycin chemotherapy.
• Subjects with no efficacy during the previous treatment of capecitabine.
• Subjects with uncontrolled hypokalemia and hypomagnesemia before study entry.
• Subjects who can not interrupt the using of the drugs that may cause QT prolongation during study.
• Subjects with intracranial lesions.
• Subjects with bone or skin as the only target lesion
• Treated or treating with HER2 tyrosine kinase inhibitors (TKIs) before study entry.
• Receiving any other antitumor therapy.
• Less than 4 weeks from the last clinical trial.
• Known history of hypersensitivity to pyrotinib、capecitabine or any of its components or metabolites.
• Ongoing infection (determined by investigator).
• History of immunodeficiency, including HIV-positive, suffering from other acquired, congenital immunodeficiency disease, or history of organ transplantation.
• Subjects had any heart disease, including: (1) angina; (2) requiring medication or clinically significant arrhythmia; (3) myocardial infarction; (4) heart failure; (5) Any heart diseases judged by investigator as unsuitable to participate in the trial.
• Female patients who are pregnancy, lactation or women who are of childbearing potential tested positive in baseline pregnancy test.
• Female patients of childbearing age that are reluctant to take effective contraceptive measures throughout the trial period.
• Evidence of significant medical illness that in the investigator's judgment will substantially increase the risk associated with the subject's participation in and completion of the study. Examples include, but are not limited to,hypertension, severe diabetes, or thyroid disease.
• Alcoholism, smoking (daily ≥ 5 roots) and other bad habits.
• Known history of neurological or psychiatric disease, including epilepsy or dementia.