Clinical trial NCT04224272: A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer
Official title: Phase 2a Study of ZW25 in Combination With Palbociclib Plus Fulvestrant
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: HER2+/HR+ Breast Cancer
Keywords: HER2
HR
Bispecific antibody
Biparatopic antibody
Immunotherapy
Breast cancer
Chemotherapy
Palbociclib
Fulvestrant
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2020-01-13
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities
timeFrame: Cycle 1 Day 1 to Day 28 (each cycle is 28 days)
measure: Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events
timeFrame: 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.
measure: Progression-free Survival 6
timeFrame: 6 months from first dose of any study drug to the date of documented disease progression or death
Secondary outcomes:
measure: Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest
timeFrame: From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 2 years 10 months
measure: Maximum Serum Concentration of ZW25
timeFrame: 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
measure: Trough Concentration of ZW25
timeFrame: 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
measure: Incidence of Anti-drug Antibodies (ADAs)
timeFrame: 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
measure: Objective Response Rate
timeFrame: Baseline up to end of study, approximately 5 years 4 months
measure: Duration of Response
timeFrame: Baseline up to end of study, approximately 5 years 4 months
measure: Disease Control Rate
timeFrame: Baseline up to end of study, approximately 5 years 4 months
measure: Progression-free Survival
timeFrame: Baseline up to end of study, approximately 5 years 4 months
measure: Overall Survival
timeFrame: Baseline up to end of study, approximately 5 years 4 months
measure: Incidence of Lab Abnormalities
timeFrame: Baseline up to end of study, approximately 5 years 4 months
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology Parkside
state: California
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
Study officials:
References: