HER2+/HR+ Breast Cancer
Conditions
Keywords
HER2, HR, Bispecific antibody, Biparatopic antibody, Immunotherapy, Breast cancer, Chemotherapy, Palbociclib, Fulvestrant
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.
Interventions
Administered intravenously
DRUGPalbociclib
Administered orally
DRUGFulvestrant
Administered as an intramuscular injection
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Objective Response Rate | Baseline up to end of study, approximately 5 years 4 months | — |
| Duration of Response | 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. |
| Progression-free Survival | 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 | — |
| Disease Control 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 | — |
| 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 | — |
Countries
Canada, Spain, United States
Participant flow
Recruitment details
A total of 51 participants who met all eligibility criteria were enrolled and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant Participants who received intravenous dose of 20 mg/kg ZW25 (zanidatamab) every 2 weeks (Q2W) in combination with an oral administration of 125 mg palbociclib once daily from Days 1 to 21, and an intramuscular injection of 500 mg fulvestrant Q2W for 3 doses (Cycle 1 Days 1 and 15 and Cycle 2 Day 1), and every 4 weeks (Q4W) thereafter. | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part 1 - Dose Finding | Death | 4 |
| Part 1 - Dose Finding | Lost to Follow-up | 1 |
| Part 1 - Dose Finding | Withdrawal by Subject | 2 |
| Part 2 - Dose Expansion | Death | 10 |
| Part 2 - Dose Expansion | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | ZW25 (Zanidatamab) + Palbociclib + Fulvestrant |
|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 10.9 |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants |
| Race/Ethnicity, Customized White | 42 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 51 |
| other Total, other adverse events | 51 / 51 |
| serious Total, serious adverse events | 8 / 51 |
Outcome results
Primary
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: 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.
Population: Treatment-emergent adverse events were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Blood and Lymphatic System Disorders AE | 20 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Neutropenia | 16 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Anaemia | 6 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Thrombocytopenia | 3 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Gastrointestinal Disorder AE | 13 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Diarrhoea | 8 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Abdominal pain | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Duodenal ulcer | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Gastric ulcer | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Nausea | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Small intestinal obstruction | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Stomatitis | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Vomiting | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Investigation AE | 12 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Neutrophil count decreased | 11 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Ejection fraction decreased | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Transaminases increased | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | White blood cell count decreased | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Metabolism and Nutrition Disorder AE | 8 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Hypokalaemia | 4 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Hypomagnesaemia | 3 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Hypercalcaemia | 2 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any General Disorders and Administration Site Conditions AE | 2 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Fatigue | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Pyrexia | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Infections and Infestations AE | 2 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | COVID-19 pneumonia | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Psoas abscess | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Staphylococcal bacteraemia | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Respiratory, Thoracic and Mediastinal Disorder AE | 2 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Pleural effusion | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Pneumothorax | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Renal and Urinary Disorder AE | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Acute kidney injury | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Any Skin and Subcutaneous Tissue Disorder AE | 1 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Grade 3 or Higher Treatment-emergent Adverse Events | Rash maculo-papular | 1 Participants |
Primary
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, or any combination of ZW25 and 1 or more of these drugs; and 2) meet the criteria as specified in the protocol.
Time frame: Cycle 1 Day 1 to Day 28 (each cycle is 28 days)
Population: Dose-limiting toxicities were assessed in participants with available data in the Safety Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants With Dose-Limiting Toxicities | 1 Participants |
Primary
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 any study drug to the date of documented disease progression or death
Population: Progression-free survival 6 will be assessed in the Safety Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Progression-free Survival 6 | 34 Participants |
Secondary
Disease Control Rate
Time frame: Baseline up to end of study, approximately 5 years 4 months
Secondary
Duration of Response
Time frame: Baseline up to end of study, approximately 5 years 4 months
Secondary
Incidence of Anti-drug Antibodies (ADAs)
Time frame: 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
Secondary
Incidence of Lab Abnormalities
Time frame: Baseline up to end of study, approximately 5 years 4 months
Secondary
Maximum Serum Concentration of ZW25
Time frame: 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
Secondary
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 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.
Time frame: From the start of dosing of any study drug up until 30 days after last study dose, up to approximately 2 years 10 months
Population: Safety data were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest | TEAE | 51 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest | SAE | 8 Participants |
| ZW25 (Zanidatamab) + Palbociclib + Fulvestrant | Number of Participants Reporting Any Treatment-emergent Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest | AESI | 10 Participants |
Secondary
Objective Response Rate
Time frame: Baseline up to end of study, approximately 5 years 4 months
Secondary
Overall Survival
Time frame: Baseline up to end of study, approximately 5 years 4 months
Secondary
Progression-free Survival
Time frame: Baseline up to end of study, approximately 5 years 4 months
Secondary
Trough Concentration of ZW25
Time frame: 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