A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer

Study Overview
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Brief Summary
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This is a multicenter, Phase 2a, open-label, 2-part study to investigate the safety, tolerability, and anti-tumor activity of ZW25 (zanidatamab) in combination with palbociclib plus fulvestrant. Eligible patients include those with locally advanced (unresectable) and/or metastatic human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer.

Detailed Description
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Part 1 of the study will first evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant and will confirm the recommended doses (RDs) of ZW25 and palbociclib in this combination. Part 2 of the study will evaluate the anti-tumor activity of the combination of ZW25 with palbociclib plus fulvestrant at the RD level in patients with HER2-positive, HR-positive advanced breast cancer.

Official Title
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Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant

Conditions
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HER2+/HR+ Breast Cancer

Intervention / Treatment
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* Drug: ZW25 (Zanidatamab)
* Drug: Palbociclib
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically-confirmed diagnosis of breast cancer with evidence of locally advanced (unresectable) and/or metastatic disease. All patients in both Parts 1 and 2 must have HER2-positive and HR-positive disease. Received prior treatment with trastuzumab, pertuzumab, AND ado-trastuzumab emtansine (T-DM1); disease progression during or after the most recent prior therapy. Patients in any part of the study who did not receive pertuzumab or T-DM1 because of lack of access (e.g., due to insurance coverage or because they were treated prior to regulatory agency approval of the agent in a relevant indication) or due to medical ineligibility for treatment with T-DM1 (e.g., history of severe infusion reactions to trastuzumab, >/= Grade 2 peripheral neuropathy, or platelet count < 100 x 10^9/L) may be eligible for the study. Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, and/or metastatic setting is permitted. Sites of disease assessible per RECIST version 1.1 (both measurable and non-measurable disease allowed) An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 Adequate organ function Adequate cardiac left ventricular function, as defined by left ventricular ejection fraction (LVEF) >/= institutional standard of normal Exclusion Criteria: Prior treatment with trastuzumab, pertuzumab, lapatinib, T-DM1, or other anti-HER2-targeted therapy </= 3 weeks before the first dose of ZW25 Prior treatment with chemotherapy, other anti-cancer therapy not otherwise specified, or hormonal cancer therapy </= 3 weeks before the first dose of ZW25 Prior treatment with palbociclib or any other CDK4/6 inhibitor, including experimental agents 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 (CHF) QTc Fridericia (QTcF) > 470 ms Grade 2 or greater pneumonitis and/or interstitial lung disease, including pulmonary fibrosis, or other clinically significant infiltrative pulmonary disease not related to lung metastases Active hepatitis B or hepatitis C infection Acute or chronic uncontrolled renal disease, pancreatitis, or severe liver disease (Child-Pugh Class C) Known infection with Human Immunodeficiency Virus (HIV)-1 or HIV-2 (Exception: patients with well controlled-HIV [e.g., cluster of differentiation 4 (CD4)-positive T-cell count > 350 mm3 and undetectable viral load] are eligible.) Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen Brain metastases: Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as patients who are off steroids and anticonvulsants and are neurologically stable for at least 1 month at the time of screening). History of or ongoing leptomeningeal disease Grade 3 or greater peripheral neuropathy

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZW25 (zanidatamab) + palbociclib + fulvestrant<br>ZW25 (zanidatamab) plus palbociclib, fulvestrant | Drug: ZW25 (Zanidatamab)<br>* Administered intravenously<br>Drug: Palbociclib<br>* Administered orally<br>Drug: Fulvestrant<br>* Administered as an intramuscular injection<br>|

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 participants who experienced a DLT. DLTs include specifically defined adverse events (AEs) considered to be related to ZW25, including combination of ZW25 with palbociclib and/or fulvestrant | Up to 4 weeks | 
| Incidence of AEs (Part 1) | Number of participants who experienced AEs, serious adverse events (SAEs), or adverse events of special interest (AESIs) | Up to 3.5 years | 
| Incidence of lab abnormalities (Part 1) | Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline lab abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. | Up to 3.5 years | 
| Progression-free survival 6 (PFS6; Part 2) | Percent of modified intent to treat patients with PFS greater than or equal to 24 weeks | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration of ZW25 (Parts 1 and 2) |  | Up to 9 months | 
| Trough concentration of ZW25 (Parts 1 and 2) | Minimum observed serum concentration (trough) | Up to 9 months | 
| Incidence of anti-drug antibodies (ADAs) (Parts 1 and 2) | Number of participants who develop ADAs | Up to 10 months | 
| Objective response rate (Part 2) | Number of participants who achieved a best response of either complete response (CR) or partial response (PR) during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and as assessed by the investigator | Up to 3.5 years | 
| Duration of response (Part 2) | Time from the first objective response (CR or PR) to documented progressive disease per RECIST 1.1 or death within 30 days of last dose of study drug (ZW25, palbociclib, and/or fulvestrant) from any cause | Up to 3.5 years | 
| Disease control rate (Part 2) | Number of participants who achieved a best response of CR, PR, or stable disease during treatment according to the RECIST version 1.1 and as assessed by the investigator | Up to 3.5 years | 
| Progression-free survival (PFS; Part 2) | Time from the first dose of ZW25, palbociclib, and/or fulvestrant to the date of documented disease progression (per RECIST 1.1), clinical progression, or death from any cause | Up to 3.5 years | 
| Overall survival (Part 2) | Time from the first dose of ZW25, palbociclib, and/or fulvestrant until death from any cause | Up to 3.5 years | 
| Incidence of AEs (Part 2) | Number of participants who experienced AEs, SAEs, or AESIs | Up to 3.5 years | 
| Incidence of lab abnormalities (Part 2) | Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline lab abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's CTCAE, version 5.0. | Up to 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, HR, Bispecific antibody, Biparatopic antibody, Immunotherapy, Breast cancer, Chemotherapy, Palbociclib, Fulvestrant