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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: HER2+/HR+ Breast Cancer
• Intervention / Treatment: Drug: ZW25 (Zanidatamab); Drug: Palbociclib; Drug: Fulvestrant

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N4N2
      • Tom Baker Cancer Centre
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital Cancer Centre
    • Toronto, Ontario, Canada, M4N3M5
      • Sunnybrook Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • Jewish General Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
• United States
  • California
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology Parkside
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Investigators: Study Director: Elaina Gartner, MD, Zymeworks Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2020
• Primary Completion (Actual): April 28, 2023
• Study Completion (Estimated): October 26, 2025

Study Registration Dates

• First Submitted: January 7, 2020
• First Submitted That Met QC Criteria: January 8, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): December 6, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: HER2; Immunotherapy; Breast cancer; Chemotherapy; Fulvestrant; Bispecific antibody; Biparatopic antibody; Palbociclib; HR
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant; Palbociclib
• Other Study ID Numbers: ZWI-ZW25-202; 2019-002956-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No