Anti-HER2 Therapy + Fulvestrant/Capecitabine in Women With HR+, HER2+, Non-visceral Metastases Stage IV Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of anti-HER2 therapy plus Fulvestrant or Capecitabine in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), non-visceral metastases, stage IV breast cancer.

Detailed Description
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This is a prospective, randomized, 2-arm, multicenter study to compare the safety and efficiency of anti-HER2 therapy (Trastuzumab ± Pertuzumab) plus fulvestrant versus anti-HER2 therapy (Trastuzumab ± Pertuzumab) plus capecitabine in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), non-visceral metastases, stage IV breast cancer. Subjects will be randomized into one of two treatment arms. Arm A subjects will receive the anti-HER2 therapy plus fulvestrant. Arm B subjects will receive the anti-HER2 therapy plus capecitabine. The use of Pertuzumab depends on patients' choices.

Official Title
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A Phase 3, Randomized, Multicenter, Open-Label Study to Compare the Efficacy and Safety of Anti-HER2 Therapy Plus Fulvestrant or Capecitabine in First-line Treatment of Women With HR+, HER2+, Non-visceral Metastases, Stage IV Breast Cancer

Conditions
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HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Pertuzumab
* Drug: Trastuzumab
* Drug: Fulvestrant
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients provided written informed consent Postmenopausal or premenopausal or perimenopausal women aged 18-75 years: ≥60 years, or bilateral ovariectomy was previously performed, or <60 years, natural postmenopausal status (defined as a continuous period of at least 12 months following spontaneous cessation without other pathological or physiological causes), estrogen (E2) and follicle-stimulating hormone (FSH) are present at postmenopausal levels Premenopausal or perimenopausal women, willing to receive luteinizing hormone (LHRH) stimulation during the study Histologically or cytologically confirmed HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+) breast cancer At least one measurable non-visceral metastatic lesion (liver, lung, pleura, pericardium, peritoneum, kidney, adrenal, brain or leptomeningeal metastases are excluded), HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+), (≥10 mm on T1-weighted, gadolinium-enhanced MRI) (RECIST v1.1) Previous treatment with HER2 inhibitors to be discontinued prior to first study treatment administration (at least 14 days for trastuzumab and other antibodies, at least 7 days for lapatinib) Previous chemotherapy, biological or target therapy to recurrent or metastatic disease are not allowed; Previous radiotherapy allowed, but radiotherapy must have been discontinued at least 14 days prior to first study treatment administration. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 Life expectancy > 24 weeks left ventricular ejection fraction (LVEF) of 50% or higher at baseline (within 42 days before randomization) Previous adjuvant chemotherapy treatment is allowed Previous adjuvant trastuzumab treatment is allowed Hormone therapy must have been discontinued at least 1 month prior to recruitment Patients with good compliance Patients must have recovered to baseline condition or to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade = 1 from any acute CTCAE v. 5.0 grade =2 side effects of previous treatments Without infection of human immunodeficiency virus (HIV) on central laboratory assay results prior to randomization Alanine aminotransferase (ALT) </= 2.5 × the upper limit of normal (ULN), Aspartate aminotransferase (AST) </= 2.5 × ULN prior to randomization Total bilirubin (TBIL) </= 1.25 × ULN Alkaline phosphatase (ALK) </= 2.5 × ULN Gamma glutamyl transpeptidase (GGT) </= 2.5 × ULN Serum total bilirubin (TBil) </= 1.5 × ULN Serum creatinine (Scr) </= 1.5 × ULN WBC >/= 3×109/L, Blood neutrophil count >/= 1×109/L, Platelet count >/= 100×109/L, HB >/= 9 g/dL Albumin >/= 30g/L Women of child-bearing age who had a negative serum pregnancy test (within 14 days before randomization) should take effective contraceptive measures Exclusion Criteria: Primary and metastatic lesion lack of histological or cytological confirmation of HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+) Breast cancer with visceral metastases (liver, lung, pleura, pericardium, peritoneum, kidney, adrenal, brain or leptomeningeal metastases) Inflammatory breast cancer Having a life-threatening metastatic visceral disease, defined as extensive liver damage or brain or leptomeninges damage (past or present) or symptomatic pulmonary lymphatic diffusion. Patients with discrete pulmonary parenchyma metastasis were eligible if the investigators determined that their respiratory function was not significantly impaired by the disease. Disease progression or recurrence within 12 months after neo/adjuvant endocrine therapy Unable to tolerate endocrine therapy, including those who with symptoms, who have spread to the viscera, and who are at risk for short-term life-threatening complications (including uncontrolled thorax, pericardium, or abdominal cavity exudation, pulmonary lymphangitis, and more than 50% liver damage). CT or MRI confirmed the presence of brain or leptomeningeal metastases. Any other current malignancy or malignancy diagnosed within the past five years (other than breast cancer, carcinoma in situ of the cervix, skin basal cell carcinoma or squamous cell carcinoma), unless radical treatment is performed and there is no evidence of recurrence or metastasis within the last 5 years. Non- visceral metastatic lesions cannot be evaluated by RECIST v1.1 Active infection with human immunodeficiency virus (HIV) prior to first study treatment administration. History of participating any other clinical trials within 30 days prior to randomization Known hypersensitivity (Grade 3 or 4) to Pertuzumab, Trastuzumab, Fulvestrant or Capecitabine or the excipients of any of the trial drugs Pregnancy or lactation Uncontrolled illnesses including symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia requiring therapy, myocardial infarction within the past 6 months, or active infection severe pulmonary and renal disease Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis) Legal incompetence or limitation. Considered unable to complete the study or sign the informed consent due to a medical or mental disorder by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab± Pertuzumab+ Fulvestrant<br>Pertuzumab(Perjeta): Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. It depends on the patient's choice. Trastuzumab(Herceptin): Participants will receive trastuzumab (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) administered by IV infusion every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. Fulvestrant(Faslodex): 500mg intramuscular injections at day 1, 15, 28 and every 4 weeks thereafter | Drug: Pertuzumab<br>* Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.<br>* Other names: Perjeta;Drug: Trastuzumab<br>* Participants will receive trastuzumab (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) administered by IV infusion every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.<br>* Other names: Herceptin;Drug: Fulvestrant<br>* 500mg intramuscular injections at day 1, 15, 28 and 4 weeks thereafter<br>* Other names: Faslodex;|
| Active Comparator: Trastuzumab± Pertuzumab+ Capecitabine<br>Pertuzumab(Perjeta): Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. It depends on the patient's choice. Trastuzumab(Herceptin): Participants will receive trastuzumab (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) administered by IV infusion every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. Capecitabine: 1000mg/m2 orally Bid on day 1 to day 14 every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. | Drug: Pertuzumab<br>* Participants will receive 840 milligrams (mg) loading dose of pertuzumab, followed every 3 weeks thereafter by a dose of 420 mg via intravenous (IV) infusion until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.<br>* Other names: Perjeta;Drug: Trastuzumab<br>* Participants will receive trastuzumab (8 mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) administered by IV infusion every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.<br>* Other names: Herceptin;Drug: Capecitabine<br>* 1000mg/m2 orally Bid on day 1 to day 14 every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first. | up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) was defined as the time from randomization to death from any cause. | up to approximately 2 years | 
| Clinical Benefit Rate (CBR) | Clinical Benefit Rate (CBR) is estimated by dividing the number of patients with CR, PR, or SD (for patients with measurable disease) ≥ 24 weeks from randomization. | up to approximately 2 years | 
| Duration of Clinical Benefit (DOCB) | DOCB was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first (only for patients of CB) | up to approximately 2 years | 
| Safety:Type incidence and severity (as graded by NCI CTCAE v 5.0) | Seriousness and attribution to the study medications of AEs | up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, hormone receptor positive, human epidermal growth factor receptor 2 positive, non-visceral metastases, fulvestrant, capecitabine, trastuzumab, pertuzumab