Anti-HER2 Bispecific Antibody ZW25 Activity in Combination With Chemotherapy With/Without Tislelizumab

Study Overview
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Brief Summary
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The purpose of the study is to assess the safety, tolerability and preliminary antitumor activity of ZW25 in combination with docetaxel in participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and ZW25 in combination with tislelizumab and chemotherapy in participants with HER2-positive gastric/gastroesophageal Junction (GEJ) adenocarcinoma

Official Title
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Phase 1b/2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Anti-HER2 Bispecific Antibody ZW25 in Combination With Chemotherapy With/Without Tislelizumab in Patients With Advanced HER2-positive Breast Cancer or Gastric/Gastroesophageal Junction Adenocarcinoma

Conditions
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Breast Cancer, Gastric Cancer, Gastroesophageal Junction Cancer

Intervention / Treatment
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* Biological: ZW25
* Drug: Docetaxel
* Biological: Tislelizumab
* Drug: Capecitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Disease diagnosis and prior treatment: Cohort 1 (the first-line breast cancer treatment cohort): Female participants with histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic adenocarcinoma of the breast and candidate for chemotherapy. Locally recurrent disease must not be amenable to resection with curative intent. Human epidermal growth factor receptor 2 (HER2) IHC 3+ or in situ hybridization positive on the archival tumor tissue or fresh biopsy sample. Have not received previous systemic anticancer therapy for locally advanced unresectable or metastatic disease. Cohort 2 (the first-line gastric/gastroesophageal junction adenocarcinoma treatment cohort): Histologically or cytologically confirmed unresectable, locally advanced, recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction HER2 IHC 3+ or HER2 IHC 2+ together with in situ hybridization positive on the archival tumor tissue or fresh biopsy sample. Have not received previous systemic anticancer therapy for locally advanced unresectable or metastatic disease, including any approved or investigational estimated glomerular filtration rate (EGFR) or anti-HER2 agents or vaccines, cytotoxic chemotherapy or checkpoint inhibitors At least 1 measurable lesion as defined per RECIST Version 1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 Adequate organ function as indicated by the following laboratory values during screening: Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram or multigated acquisition scan (MUGA) (echocardiogram is the preferred method) within 28 days before the first dose of study drug Key Exclusion Criteria: Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways History of approved or investigative tyrosine kinase/HER inhibitors in any treatment setting a. except trastuzumab with or without pertuzumab used in neoadjuvant or adjuvant setting for Cohort 1 Active leptomeningeal disease, untreated or uncontrolled brain metastasis Any active malignancy ≤ 2 years before the first dose of study drug, except for the specific cancer under investigation in this trial and any localized cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast) Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study drug Note: Participants who are currently or have previously been on any of the following steroid regimens are not excluded: Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen) NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1- ZW25 + Docetaxel<br>ZW25 intravenous (IV) infusion followed by docetaxel IV infusion first-line therapy once every three weeks (Q3W) in female participants with metastatic breast cancer | Biological: ZW25<br>* Administered as specified in the treatment arm<br>Drug: Docetaxel<br>* Administered as specified in the treatment arm<br>|
| Experimental: Cohort 2- ZW25 + Tiselizumab + Chemotherapy<br>ZW25 intravenous (IV) infusion followed by tiselizumab IV infusion and CAPOX chemotherapy (oral capecitabine + IV oxaliplatin) first-line therapy once every three weeks (Q3W) in participants with metastatic gastric / GEJ adenocarcinoma | Biological: ZW25<br>* Administered as specified in the treatment arm<br>Biological: Tislelizumab<br>* Administered as specified in the treatment arm<br>* Other names: BGB-A317;Drug: Capecitabine<br>* Administered as specified in the treatment arm<br>Drug: Oxaliplatin<br>* Administered as specified in the treatment arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants experiencing Adverse Events (AEs) |  | Up to 12 months after the last dose of study drug. | 
| Number of Participants experiencing Severe Adverse Events (SAEs) as assessed by the investigator. |  | Up to 12 months after the last dose of study drug. | 
| Objective response rate (ORR) | Defined as the proportion of participants who had a best overall response of complete response or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. | Up to 12 months after the last dose of study drug or before the initiation of a new anticancer treatment, whichever occurs first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) |  | Up to 36 Months | 
| Time to response (TRR) | Time from the start date of study drug to the first determination of an objective response by investigator per RECIST Version 1.1 | Up to 36 Months | 
| Progression-free survival (PFS) | Proportion of participants with best overall response of complete response, partial response, and stable disease by investigator per RECIST Version 1.1 | Up to 36 Months | 
| Overall survival (OS) | Time from the start date of study drug to the date of death due to any cause | Up to 60 Months | 
| Serum concentration of ZW25 as a function of time |  | Predose and immediately postdose | 
| Observed maximum plasma concentration during a sample interval (Cmax (ng/mL) |  | Predose and immediately postdose | 
| Observed time to maximum plasma concentration during a sampling interval (tmax(hour)) |  | Predose and immediately postdose | 
| Terminal elimination half-life (t1/2(hour)) |  | Predose and immediately postdose | 
| Area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUC(0-t) (ng*h/mL)) |  | Predose and immediately postdose | 
| Apparent clearance after oral administration (CL/F(L/hr)) |  | Predose and immediately postdose | 
| Presence of anti-ZW25-antibodies |  | Predose and immediately postdose | 
| Presence of ZW25 neutralizing antibodies |  | Predose and immediately postdose |