A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer
- Conditions
- HER2+/HR+ Breast Cancer
- Interventions
- Registration Number
- NCT04224272
- Lead Sponsor
- Jazz Pharmaceuticals
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 51
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description ZW25 (zanidatamab) + palbociclib + fulvestrant ZW25 (Zanidatamab) ZW25 (zanidatamab) plus palbociclib, fulvestrant ZW25 (zanidatamab) + palbociclib + fulvestrant Fulvestrant ZW25 (zanidatamab) plus palbociclib, fulvestrant ZW25 (zanidatamab) + palbociclib + fulvestrant Palbociclib ZW25 (zanidatamab) plus palbociclib, fulvestrant
- Primary Outcome Measures
Name Time Method Progression-free Survival 6 6 months from first dose of any study drug to the date of documented disease progression or death The progression-free survival at 6 months (PFS6) is a binary endpoint variable based on the progression-free survival (PFS) time, defined as the proportion of participants having PFS time greater than or equal to 24 weeks (168 days).
Number of Participants With Dose-Limiting Toxicities Cycle 1 Day 1 to Day 28 (each cycle is 28 days) Dose-limiting toxicities, defined using NCI CTCAE version 5.0, are events that 1) occur following administration of ZW25, palbociclib, and fulvestrant, or any combination of ZW25 and 1 or more of these drugs; and 2) meet the criteria as specified in the protocol.
Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events Baseline from the start of dosing of any study drug up until 30 days after last study dose, up to approximately 2 years 10 months. A treatment-emergent adverse event occurs after the start of study treatment and is defined as any unfavorable or unintended symptom, sign, or disease (including abnormal lab) temporally associated with the use of treatment that may or may not be considered related to treatment. TEAEs were coded using MedDRA v24.0.
- Secondary Outcome Measures
Name Time Method Disease Control Rate Baseline up to end of study, approximately 5 years 4 months Overall Survival Baseline up to end of study, approximately 5 years 4 months Incidence of Lab Abnormalities Baseline up to end of study, approximately 5 years 4 months Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 2 years 10 months A treatment-emergent adverse events (TEAEs) was defined as an adverse event (AE) with onset on or after 1st dose of study treatment through 30 days after final dose of study treatment inclusive. An AE is classified as a serious adverse event (SAE) if fatal, life threatening, requires hospitalization, is disabling/incapacitating, causes congenital anomaly or birth defect, and medically significant. Adverse events of special interest (AESI) include absolute decreases in LVEF greater than or equal to 10 percentage points from baseline, symptomatic heart failure, infusion-related reactions, and all greater than or equal to Grade 2 events of pneumonitis and/or interstitial lung disease, including pulmonary fibrosis.
Trough Concentration of ZW25 Cycle 1, Days 1, 2, 5, 15; Cycle 2, Days 1 and 15; Day 1 of all subsequent cycles (each cycle is 28 days); and end of treatment, up to approximately 5 years 4 months Duration of Response Baseline up to end of study, approximately 5 years 4 months Objective Response Rate Baseline up to end of study, approximately 5 years 4 months Maximum Serum Concentration of ZW25 Cycle 1, Days 1, 2, 5, 15; Cycle 2, Days 1 and 15; Day 1 of all subsequent cycles (each cycle is 28 days); and end of treatment, up to approximately 5 years 4 months Incidence of Anti-drug Antibodies (ADAs) Cycles 1 and 2, Day 15; Day 1 of all subsequent cycles (each cycle is 28 days); end of treatment, 30 days post-last dose (safety follow up), and every 8 weeks (efficacy follow up), up to approximately 5 years 4 months Progression-free Survival Baseline up to end of study, approximately 5 years 4 months
Trial Locations
- Locations (13)
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
UCLA Hematology/Oncology Parkside
🇺🇸Santa Monica, California, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Hospital General Universitario de Elche
🇪🇸Elche, Alicante, Spain
Hospital Universitario Vall d'Hebrón
🇪🇸Barcelona, Spain
Hospital Ruber Internacional
🇪🇸Madrid, Spain
Hospital Universitario Virgen del RocÃo
🇪🇸Sevilla, Spain
Hospital Universitario Virgen de la Victoria
🇪🇸Málaga, Spain
Hospital ClÃnico Universitario de Valencia
🇪🇸Valencia, Spain
Sunnybrook Research Institute
🇨🇦Toronto, Ontario, Canada
The Ottawa Hospital Cancer Centre
🇨🇦Ottawa, Ontario, Canada