DZD1516 in Combination With Trastuzumab and Capecitabine, or in Combination With T-DM1, in Patients With Metastatic HER2 Positive Breast Cancer

A Phase I, Open-Label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of DZD1516 in Combination With Trastuzumab and Capecitabine, or DZD1516 in Combination With T-DM1, in Patients With Metastatic HER2 Positive (HER2+) Breast Cancer

DZD1516 is an oral, blood brain barrier penetrable, selective HER2 tyrosine kinase inhibitor. This study is designed to evaluate the safety and tolerability of DZD1516 in patients with metastatic HER2 positive breast cancer who have progressed following prior therapy. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment. It will also measure the levels of drug in the body and assess its anti-cancer activity as monotherapy and in combination with trastuzumab and/or capecitabine, or in combination with T-DM1

Inclusion Criteria:

• Signed informed consent.
• Male or female patients aged ≥ 18 years
• histologically or cytologically confirmed HER2 positive advanced breast cancer which failed prior therapies
• Predicted life expectancy ≥ 12 weeks.
• ECOG performance status 0 to 1 for patients without LM, and 0 to 2 for patients with LM at the time of signing ICF
• Adequate bone marrow reserve and organ system functions
• For patients without CNS metastases, patients must have at least one measurable lesion according to RECIST (version 1.1)
• For patients with Brain metastasis: Patient must have at least one measurable intracranial lesion according to modified RECIST 1.1

Exclusion Criteria:

• Intervention with any of the following: Any investigational agents or study drugs from a previous clinical study within 4 weeks of the first dose of study treatment； Any cytotoxic chemotherapy or other anticancer drugs for the treatment of metastatic breast cancer from a previous treatment regimen within 4 weeks of the first dose of study treatment； Any intrathecal chemotherapy within 2 weeks of the first dose of study treatment；Major surgery procedure (excluding placement of vascular access), or significant traumatic injury within 4 weeks of the first dose of study treatment, or have an anticipated need for major surgery during the study； Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment;
• CNS complications that require urgent neurosurgical intervention
• Any evidence of severe or uncontrolled systemic diseases
• Another malignancy within 5 years prior to enrolment with the exception of adequately treated in-situ carcinoma of the cervix, uterus, basal or squamous cell carcinoma or non-melanomatous skin cancer.
• Live vaccines within 4 weeks prior to first dose.
• Active infections including:Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice)；Positive Hepatitis B surface antigen (HBsAg) or positive HCV antibodies or confirmed positive HIV test result.
• Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of DZD1516
• Involvement in the planning and conduct of the study (applies to Sponsor staff or staff at the study site).
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.