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

Study Overview
=================
Brief Summary
-----------------
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

Official Title
-----------------
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

Conditions
-----------------
Breast Cancer Metastatic

Intervention / Treatment
-----------------
* Drug: DZD1516 mono therapy in Part A, DZD1516 in combination with trastuzumab and/or capecitabine in Part B, DZD1516 in combination with T-DM1 in Part C


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: daily dose of DZD1516<br>daily dose of DZD1516 | Drug: DZD1516 mono therapy in Part A, DZD1516 in combination with trastuzumab and/or capecitabine in Part B, DZD1516 in combination with T-DM1 in Part C<br>* Part A is twice daily (except Cycle 0) oral dosing of DZD1516, starting from 50 mg. If tolerated, dose will be escalated in subsequent cohorts until MTD. Part B is twice daily oral dosing of DZD1516 in combination with capecitabine 1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle or with trastuzumab 8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of each 21-day cycle. Part C is twice daily oral dosing of DZD1516 in combination with T-DM1 3.6 mg/kg intravenously (IV) once every 21 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) and serious adverse events (SAEs) | To investigate the safety and tolerability of DZD1516 | up to approximately 1 year | 
| Incidence of dose limiting toxicities (DLTs) | To investigate the safety and tolerability of DZD1516 | 21 days after the first multiple dose | 
| To define maximum tolerated dose (MTD) of DZD1516 if possible (Part A only) | To investigate the safety and tolerability of DZD1516 | 21 days after the first multiple dose | 
| To define Recommended Phase II Combination Dose (RP2CD) of DZD1516 in combination with trastuzumab and capecitabine (Part B only) | To investigate the safety and tolerability of DZD1516 in combination with either trastuzumab, capecitabine, or both trastuzumab and capecitabine | 21 days after the first multiple dose | 
| To define Recommended Phase II Combination Dose (RP2CD) of DZD1516 in combination with T-DM1 (Part C only) | To investigate the safety and tolerability of DZD1516 in combination with T-DM1 | 21 days after the first multiple dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug concentrations of DZD1516 and its metabolite DZ2678 in plasma, urine and CSF | Pharmacokinetics endpoints | up to approximately 6 months | 
| Maximum plasma concentration (Cmax) of DZD1516 and its metabolite DZ2678 | Pharmacokinetics endpoints | up to approximately 6 months | 
| Area under the plasma concentration-time curve (AUC) of DZD1516 and its metabolite DZ2678 | Pharmacokinetics endpoints | up to approximately 6 months | 
| Plasma concentration of capecitabine and metabolites 5-FU (Part B only) | Pharmacokinetics endpoints | up to approximately 6 months | 
| Plasma Cmax of capecitabine and 5-FU (Part B only) | Pharmacokinetics endpoints | up to approximately 6 months | 
| Plasma AUC of capecitabine and 5-FU (Part B only) | Pharmacokinetics endpoints | up to approximately 6 months | 
| Plasma concentration of DM1 (Part C only) | Pharmacokinetics endpoints | up to approximately 6 months | 
| Objective Response Rate (ORR) | To assess preliminary anti-tumor efficacy of DZD1516 as monotherapy and as combination therapy | up to approximately 1 year | 
| Disease Control Rate (DCR) | To assess preliminary anti-tumor efficacy of DZD1516 as monotherapy and as combination therapy | up to approximately 1 year | 
| Duration of Response (DoR) | To assess preliminary anti-tumor efficacy of DZD1516 as monotherapy and as combination therapy | up to approximately 1 year | 
| Progression free survival (PFS) (Part B and Part C on) | To assess preliminary anti-tumor efficacy of DZD1516 as combination therapy | up to approximately 1 year | 
| Overall survival (for patients with leptomeningeal metastasis in Part B and Part C only) | To assess preliminary anti-tumor efficacy of DZD1516 as combination therapy | up to approximately 1 year |