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

Jazz Pharmaceuticals51 enrolled

Overview

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.

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

HER2+/HR+ Breast Cancer

Interventions

ZW25 (Zanidatamab)DRUG

Administered intravenously

PalbociclibDRUG

Administered orally

FulvestrantDRUG

Administered as an intramuscular injection

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (13)

UCLA Hematology/Oncology Parkside

Santa Monica, California, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

Outcomes

Primary Outcomes

Number of Participants With Dose-Limiting Toxicities

Dose-limiting toxicities, defined using NCI CTCAE version 5.0, are events that 1) occur following administration of ZW25, palbociclib, and fulvestrant; and 2) meet the criteria as specified in the protocol.

Time frame: Cycle 1 Day 1 to Day 28 (each cycle is 28 days)

Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events

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.

Time frame: From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 5 years 20 days.

Progression-free Survival 6

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).

Time frame: 6 months from first dose of all study drugs to the date of documented disease progression or death

Secondary Outcomes

Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest

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 decrease in LVEF greater than or equal to 10 percentage points from baseline and LVEF value less than 50% post-baseline or LVEF value greater than or equal to 20% to less than or equal to 39% post 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.

Data from ClinicalTrials.gov

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