Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer

Study Overview
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Brief Summary
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This first-in-human, Phase 1, open-label, multicenter, dose-escalation study will evaluate the safety, tolerability, and PK of DHES0815A as a single agent in participants with advanced and/or metastatic HER2-positive breast cancer for whom established treatment has proven ineffective or intolerable or is unavailable. The study may include a dose-expansion cohort (based on an ongoing assessment of the totality of data obtained in this study) to further assess safety, tolerability, PK, and preliminary anti-tumor activity.

Official Title
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A Phase I, Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Escalating Doses of DHES0815A in Patients With HER2-Positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: DHES0815A


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Measurable disease by RECIST v1.1 with at least one measurable target lesion Locally advanced or metastatic HER2-positive breast cancer that has relapsed or is refractory to established therapies Adequate hematologic and end-organ function For dose-expansion cohort only: no more than two prior systemic chemotherapy-containing regimens in the advanced/metastatic setting (excluding trastuzumab emtansine, which is considered a targeted cytotoxic agent) Key Exclusion Criteria: Treatment with chemotherapy, hormonal therapy (except hormone replacement therapy, oral contraceptives), immunotherapy, biologic therapy, radiation therapy (except palliative radiation to bony metastases), or herbal therapy as cancer therapy within 4 weeks prior to initiation of DHES0815A History of exposure to the protocol specified doses of anthracyclines Pregnancy, lactation, or breastfeeding Major surgical procedure within 4 weeks prior to Day 1 Evidence of a significant uncontrolled concomitant disease of the nervous system, pulmonary, autoimmune, renal, hepatic, endocrine, or gastrointestinal disorders; or a serious non-healing wound or fracture Known active bacterial, viral, fungal, mycobacterial, or other infection Clinically significant history of liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis Untreated or active central nervous system metastases Cardiopulmonary dysfunction, including inadequate left ventricular ejection function at baseline, less than 50% by either echocardiogram or multiple-gated acquisition scan QT interval corrected through use of Fridericia's formula (QTcF) > 470 milliseconds

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort: DHES0815A<br>Participants will receive DHES0815A in escalating doses in the dose-escalation cohort of the study. Participants will receive additional infusions of DHES0815A on Day 1 of subsequent cycles provided that they meet the protocol specified criteria for acceptable toxicity and ongoing clinical benefit. | Drug: DHES0815A<br>* DHES0815A will be administered via intravenous (IV) infusion on Day 1 of each 21-day cycle.<br>|
| Experimental: Dose Expansion Cohort: DHES0815A<br>Participants will be treated at or below the Maximum Tolerated Dose (MTD) of DHES0815A (based on the review of the totality of the data) to obtain additional safety, tolerability, PK, and anti-tumor activity data. | Drug: DHES0815A<br>* DHES0815A will be administered via intravenous (IV) infusion on Day 1 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events (AEs) and Serious AEs |  | From Day 1 to end of study (up to approximately 45 months) | 
| Percentage of Participants with DLT |  | From Day 1 up to Day 21 | 
| MTD of DHES0815A |  | From Day 1 up to Day 21 | 
| Recommended Phase 2 Dose (RP2D) of DHES0815A |  | From Day 1 up to Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of DHES0815A |  | Cycle 1 Day 1 up to 42 days after last dose (up to approximately 45 months) (Cycle length = 21 days) | 
| Area Under the Concentration-Time Curve (AUC) of DHES0815A |  | Cycle 1 Day 1 up to 42 days after last dose (up to approximately 45 months) (Cycle length = 21 days) | 
| Maximum Observed blood Concentration (Cmax) of DHES0815A |  | Cycle 1 Day 1 up to 42 days after last dose (up to approximately 45 months) (Cycle length = 21 days) | 
| Minimum Observed blood Concentration (Cmin) of DHES0815A |  | Cycle 1 Day 1 up to 42 days after last dose (up to approximately 45 months) (Cycle length = 21 days) | 
| Clearance of DHES0815A |  | Cycle 1 Day 1 up to 42 days after last dose (up to approximately 45 months) (Cycle length = 21 days) | 
| Volume of Distribution at Steady State (Vss) of DHES0815A |  | Cycle 1 Day 1 up to 42 days after last dose (up to approximately 45 months) (Cycle length = 21 days) | 
| Percentage of Participants with Objective Response Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |  | From start of treatment until confirmation of complete response (CR) or partial response (PR) (up to approximately 45 months) | 
| Duration of Response (DoR) Assessed According to RECIST v1.1 |  | From the initial CR or PR to the time of disease progression (PD) or death, whichever occurs first (up to approximately 45 months) | 
| Percentage of Participants with Anti-Drug Antibody (ADA) to DHES0815A |  | Pre-dose (0 hours) on Day 1 up to 42 days after last infusion (up to approximately 45 months) |