study of shr-a1811 combined with pyrotinib and bevacizumab in advanced breast cancer with brain metastasis

Conditions: Breast Cancer Metastatic; Breast Cancer Brain Metastases

Summary: in phase ib, our study is aimed to evaluate the safety and tolerance of shr-a1811 combined with pyrotinib in breast cancer with brain metastasis, and confirm the recommended phase 2 dose combined with preliminary results of efficacy. in phase ii, our study is aimed to evaluate the efficacy and safety of shr-a1811 combined with pyrotinib and bevacizumab at rp2d in breast cancer with brain metastasis.


Eligibility criteria:
inclusion criteria: * more than 18 years old; * ecog ps score: 0\~2; * patients must have a life expectancy ≥ 3 months; * brian metastasis confirmed by mri, at least one measurable brain lesion based on rano-bm with no prior radiotherapy; * mannitol or hormone therapy is allowed to use for brain metastasis before enrolment, but treatment dosage should be stable for one week and not need to be increased; * adequate organ function and marrow function; * has recovered from any aes (≤ grade 1) related to prior anti-tumour treatments before first dose of study therapy, except: a. alopecia; b. hyperpigmentation; * willing to join in this study, able to provide written informed consent, good compliance and willing to cooperate with follow-up. exclusion criteria: * has leptomeningeal metastasis or cystic metastatic lesions confirmed by mri or lumbar puncture; * existence of third space fluid (e.g. massive ascites, pleural effusion, pericardial effusion) that is not well controlled by effective methods, e.g. drainage; * has cns complications with the need for emergency intervention, or brain metastasis with poorly controlled symptoms by hormone or dehydration therapy, such as uncontrollable intracranial hypertension, mental disorder or epilepsy; * prior bevacizumab or egfr-tki is allowed, but should meet the following requirements at the same time: 1. no disease progression during prior bevacizumab or egfr-tki; 2. more than 3 months from the interruption of bevacizumab or egfr-tki to disease progression; * has received whole brain radiotherapy, chemotherapy, surgery within 2 weeks before first dose of study therapy; has received trastuzumab-based therapy or endocrine therapy within one week before first dose of study therapy; has received palliative radiotherapy for bone metastasis within 2 weeks before first dose of study therapy; * has known clinically significant lung disease, that is, moderate-to-severe lung disease which severely affects respiratory function, including but not limited to: idiopathic pulmonary fibrosis, pneumonitis. prior ≥ grade 3 interstitial lung disease is not allowed to enrolment; * has received full-dose anticoagulants or thrombolytics within 10 days before enrolment, or non-steroid anti-inflammatory drugs with platelet inhibition (except low-dose aspirin (≤325mg qd) for preventive use); * existence of unhealed wound, active gastric ulcer, and other diseases which may cause haemorrhage risk (e.g., prior major operation within 4 weeks before enrolment, prior arterial or venous thrombotic event within one year before enrolment, prior cerebralvascular accident); * has known hereditary haemorrhagic tendency or coagulation disorder; * has joined in other clinical drug trials within 2 weeks before enrolment; * use of other antitumor systemic treatment during the study at the same time, except bisphosphonates for the treatment of bone metastasis or osteoporosis prevention; * other malignancy within prior 5 years unless curatively treated with no evidence of disease for at least recent 3 years, except: curatively treated in situ cancer of the cervix, skin basal cell carcinoma or skin squamous cell carcinoma; * cardiac insufficiency, including but not limited to: congestive heart failure, transmural myocardial infarction, angina which needs drug treatments, clinically significant valvulopathy and high-risk arrhythmia, or qtc abnormity with clinical significance in ecg examination during the screening period (corrected qtc \>450 msec \[male\] or qtc \>470 msec \[female\] under the resting state); * uncontrolled hypertension (under the resting state: systolic pressure \>160mmhg or diastolic pressure \>100mmhg); * other diseases which may affect study results, including but not limited to: 1) known history of immunodeficiency, including hiv-positive, other acquired or innate immunodeficient disease, or known history of organ transplantation; 2) hbsag-positive and hbv dna≥1000 iu/ml, or hcv antibody-positive, or treponema pallidum antibody-positive; 3) hypersensitivity to study therapy or any of its excipients; 4) severe infection requiring antibiotics, antiviral or antifungal treatment; * female patients during the gestation or suckling period, of childbearing potential and pregnancy test-positive, or unwilling to use an effective method of contraception during the whole study; * inability to swallow, intestinal obstruction or existence of other factors affecting medication and absorption; * any other conditions not appropriate for study enrolment in the opinion of the investigator.