A Study of Zanidatamab (ZW25) With Evorpacept (ALX148) in Patients With Advanced HER2-expressing Cancer

Study Overview
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Brief Summary
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This study is being done to find out if zanidatamab when given with evorpacept (ALX148) is safe and can treat patients with advanced (locally advanced [inoperable] and/or metastatic) human epidermal growth factor receptor 2 (HER2)-expressing cancer.

Detailed Description
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Part 1 of the study will first evaluate the safety and tolerability and establish the recommended doses (RDs) of zanidatamab in combination with evorpacept (ALX148). Part 2 of the study will evaluate the anti-tumor activity of the combination of zanidatamab plus evorpacept (ALX148) at the RD levels in indication-specific expansion cohorts.

Official Title
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A Phase 1b/2, 2-part Open-label Study to Assess the Safety and Antitumor Activity of Zanidatamab in Combination With ALX148 in Advanced HER2-expressing Cancer

Conditions
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HER2-expressing Cancers

Intervention / Treatment
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* Drug: Zanidatamab
* Drug: Evorpacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced (inoperable) and/or metastatic HER2-expressing cancer based on local or central laboratory test results as follows: Parts 1 and 2: HER2-positive breast cancer as defined per American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) guidelines Parts 1 and 2: HER2-low breast cancer (defined as immunohistochemistry [IHC] 1+ or IHC 2+; AND is currently not and has never been HER2-positive per the ASCO/CAP guidelines) Part 2: HER2-positive gastroesophageal adenocarcinoma as defined per the ASCO/CAP gastric cancer-specific guidelines; or other HER2-overexpressing non-breast cancers (defined as IHC 3+; or IHC 2+ and in situ hybridization [ISH]+) per the ASCO/CAP guidelines for breast cancer Progression after or during the most recent systemic regimen of treatment for advanced cancer. For both Part 1 and Part 2, prior therapies must have included approved agents known to confer clinical benefit. Subjects with HER2-positive breast cancer who did not receive trastuzumab or pertuzumab due to medical contraindications will not be eligible for this study Subjects with HER2-low breast cancer who have received prior HER2-targeted therapy (other than trastuzumab deruxtecan, which is allowed but not required) will not be eligible for this study Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) Willingness to undergo a new biopsy to provide a tumor tissue for central laboratory testing of HER2 protein expression and gene amplification by IHC and ISH assays, respectively Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ functions Adequate cardiac left ventricular function, as defined by a left ventricular ejection fraction (LVEF) ≥ 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA) obtained within 4 weeks prior to first dose of study treatment Exclusion Criteria: Previous allogeneic stem cell transplant Prior treatment with any anti-CD47 or anti-signal regulatory protein alpha (SIRPα) agent Prior or concurrent invasive malignancy whose natural history or treatment has, in the opinion of the investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of the investigational regimen Received systemic anticancer therapy within 4 weeks of starting study treatment (6 weeks for mitomycin C or nitrosoureas). Received radiotherapy within 2 weeks of the first dose of zanidatamab/evorpacept (ALX148) Untreated brain metastases, symptomatic brain metastases; or radiation treatment (stereotactic radiosurgery and whole brain radiation) for brain metastases within 2 weeks of start of study treatment Known leptomeningeal disease Active hepatitis Infection with human immunodeficiency virus (HIV)-1 or HIV-2. (Exception: Subjects with well controlled HIV [e.g., CD4 > 350/mm3 and undetectable viral load] are eligible.) QTc Fridericia (QTcF) > 470 ms History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease

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: Single Group Assignment
Interventional Model Description: single-arm, open-label, multi-cohort, multi-center study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanidatamab plus evorpacept (ALX148)<br> | Drug: Zanidatamab<br>* Administered intravenously (IV)<br>* Other names: JZP598;Drug: Evorpacept<br>* Administered IV<br>* Other names: ALX148;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs; Part 1) | Number of patients who experienced a DLT. DLTs include specifically defined adverse events (AEs) considered to be related to zanidatamab or evorpacept (ALX148), including combination of zanidatamab with evorpacept (ALX148) | Up to 4 weeks | 
| Incidence of AEs (Part 1) | Number of patients who experienced AEs, serious adverse events (SAEs), or adverse events of special interest (AESIs) | Up to 7 months | 
| Incidence of clinical laboratory abnormalities (Part 1) | Number of patients who experienced a Grade 3 or higher post-baseline laboratory abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0 | Up to 7 months | 
| Confirmed objective response rate (ORR)(Part 2) | Number of patients who achieved a confirmed best overall response (BOR) of either complete response (CR) or partial response (PR) during treatment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR)(Part 2) | Number of patients who achieved a best response of CR, PR, or stable disease (SD) during treatment per RECIST 1.1 | Up to 2 years | 
| Clinical benefit rate (CBR)(Part 2) | Number of patients who achieved a SD for ≥ 24 weeks or a confirmed BOR of CR or PR during treatment per RECIST 1.1 | Up to 2 years | 
| Duration of response (DOR)(Part 2) | The time from the first objective response (CR or PR) to documented progressive disease per RECIST 1.1, clinical progression, or death within 30 days of last dose of study drug (zanidatamab and/or evorpacept [ALX148]) from any cause | Up to 2 years | 
| Progression-free survival (PFS)(Part 2) | The time from the first dose of study treatment to the date of documented disease progression (per RECIST 1.1), clinical progression, or death from any cause | Up to 2 years | 
| Progression-free survival 6 (PFS6)(Part 2) | Number of patients with a PFS time ≥ 24 weeks | Up to 6 months | 
| Overall survival (OS)(Part 2) | The time from first dose of study treatment until death from any cause | Up to 2 years | 
| Incidence of AEs (Part 2) | Number of patients who experienced AEs, SAEs, or AESIs | Up to 7 months | 
| Incidence of clinical laboratory abnormalities (Part 2) | Number of patients who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology or chemistry. Grades are defined using NCI-CTCAE, version 5.0 | Up to 7 months | 
| Maximum serum concentration of zanidatamab and evorpacept (ALX148) (Part 2) |  | Up to 7 months | 
| Trough concentration of zanidatamab and evorpacept (ALX148) (Part 2) | Minimum observed serum concentration (trough) | Up to 7 months | 
| Incidence of anti-drug antibodies (ADAs)(Part 2) | Number of patients who develop ADAs | Up to 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JZP598