A Study to Compare Pertuzumab + Trastuzumab + Vinorelbine vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, two-arm, phase III trial in Germany to investigate whether vinorelbine-based triple combination presents a less toxic treatment option than docetaxel-based triple combination in patients with HER2-positive advanced breast cancer who have not previously received any systemic treatment in the metastatic setting. The primary objective of the study is to compare patient-reported quality of life in the two treatment arms. Patients will be followed-up for survival until death or end of study after at least 79 deaths occured in each arm, whatever comes first.

Official Title
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Phase III Study to Compare Trastuzumab-biosimilar (Kanjinti®) Plus Pertuzumab Plus Vinorelbine With Trastuzumab-biosimilar (Kanjinti®) Plus Pertuzumab Plus Docetaxel as First-line Treatment for HER2-positive Advanced Breast Cancer

Conditions
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Advanced Breast Cancer, HER2-positive Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Vinorelbine
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent prior to beginning of protocol-specific procedures. Histologically or cytologically confirmed adenocarcinoma of the breast. Locally advanced and inoperable or metastatic disease. HER2-positive disease, defined as IHC status HER2+++ or CISH/FISH status positive. Female patients aged ≥ 18 years. In case of adjuvant treatment, disease-free interval of at least 12 months after completion of adjuvant treatment (excluding hormonal therapy). Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Left Ventricular Ejection Fraction (LVEF) ≥ 50%. For women with childbearing potential, defined as physiologically capable of becoming pregnant: Negative pregnancy test. Agreement to use an effective form of contraception during study treatment and for 7 months after the last dose of study treatment. Life expectancy of at least 12 weeks. Adequate organ and bone marrow function Fluent in spoken and written German and willing to answer the questionnaires Exclusion Criteria: Previous systemic treatment in palliative intention (chemotherapy, hormonal therapy and / or biological therapy) Persistent peripheral sensory or motor neuropathy grade 2 or higher (NCI CTCAE v5.0) Evidence of central nervous system metastases. CT or MRI of the brain is only mandatory in case of clinical suspicion of brain metastases Current uncontrolled hypertension (systolic > 150 mmHg and / or diastolic > 100 mmHg) or clinically significant cardiovascular disease History of LVEF < 50% during or after prior (neo)adjuvant therapy with trastuzumab Current severe, uncontrolled systemic disease (e.g. cardiovascular, pulmonary, or metabolic disease, wound healing disorder, ulcers, or bone fractures, or severe fungal, bacterial or viral infection) Major surgery within 28 days prior to start of study medication, or anticipation of the need for major surgery during the course of study treatment Current known infection with HIV, HBV, or HCV (testing not required) Dyspnea at rest due to complications of advanced malignancy, or other diseases requiring continuous oxygen therapy. Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies. Participation in investigational studies within 30 days or five half-lives of the respective IMP, whichever is longer, prior randomization. Pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kanjinti/Pertuzumab plus Vinorelbine<br>Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus vinorelbine. | Drug: Trastuzumab<br>* administered as combined therapy with pertuzumab and vinorelbine or docetaxel. Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) on day 1 of cycle 1 (1 cycle length = 21 days), and 6 mg/kg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.<br>* Other names: ABP 980;Drug: Pertuzumab<br>* administered as combined therapy with Kanjinti® and vinorelbine or docetaxel. Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) on day 1 of cycle 1 (1 cycle length = 21 days), and 420 mg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.<br>* Other names: Perjeta®;Drug: Vinorelbine<br>* administered as combined therapy with Kanjinti® and pertuzumab. Vinorelbine will be administered as an IV dose of 25 milligrams per kilogram (mg/kg) on days 1 and 8 of cycle 1 (1 cycle length = 21 days), and 25mg/kg up to 30 mg/kg (as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.<br>|
| Active Comparator: Kanjinti/Pertuzumab plus Docetaxel<br>Patients will receive Kanjinti® (trastuzumab-biosimilar) plus pertuzumab plus docetaxel. | Drug: Trastuzumab<br>* administered as combined therapy with pertuzumab and vinorelbine or docetaxel. Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) on day 1 of cycle 1 (1 cycle length = 21 days), and 6 mg/kg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.<br>* Other names: ABP 980;Drug: Pertuzumab<br>* administered as combined therapy with Kanjinti® and vinorelbine or docetaxel. Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) on day 1 of cycle 1 (1 cycle length = 21 days), and 420 mg Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.<br>* Other names: Perjeta®;Drug: Docetaxel<br>* administered as combined therapy with Kanjinti® and pertuzumab. Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) on day 1 of cycle 1 (1 cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on day 1 of subsequent cycles until progressive disease, intolerable toxicity, or death.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported health-related quality of life (QoL): FACT-B | Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 18 weeks (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life. To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life. | Baseline to week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) assessed by the investigator | PFS is defined as time from randomization to date of progressive disease or death, whichever comes first. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive without progressive disease at database lock. If subsequent treatment was started prior to progressive disease, then data will be censored at the onset of this treatment. | Baseline, every 12 weeks after randomization (maximum up to 76 months) | 
| Overall survival (OS) | OS is defined as time from randomization to date of death. It will be analyzed using Kaplan-Meier method. Data will be censored at date of last contact for patients alive at database cut/lock. | Time from randomization to date of death (maximum up to approximately 76 months) | 
| Overall response rate (ORR) | Overall response rate is defined as the proportion of patients achieving a complete or partial remission as best response. | Baseline, every 12 weeks after randomization (maximum up to 76 months) | 
| Clinical benefit rate (CBR) | CBR is defined as proportion of patients achieving a complete or partial remission or a stable disease lasting at least 24 weeks. | Baseline, every 12 weeks after randomization (maximum up to 76 months) | 
| Time to treatment failure (TTF) | TTF is defined as time from randomization to discontinuation of all study medications. Date of discontinuation is the earliest end of last cycle (= 20 days after first administration of a study drug in the last cycle) OR progressive disease after last administration of any study drug OR death OR start of a subsequent treatment. | Baseline, every 12 weeks after randomization (maximum up to 56 months) | 
| Incidence of (Serious) Adverse events ((S)AEs) | Type, frequency and severity of adverse events (including those from the pre- and post-treatment periods) will be listed according to Common Toxicity Criteria for Adverse Events (CTCAE). | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Blood count: Hemoglobin | The amount of hemoglobin in the blood will be measured in g/dL as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Blood count: Platelet Count | The number of platelets in the blood will be counted as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Blood count: Leukocytes | The number of leukocytes in the blood will be counted as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Blood count: Absolute Neutrophil Count | The absolute neutrophil count will be determined as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Safety monitoring (coagulation): Coagulation (INR) | Coagulation (INR) as per clinical routine will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Clinical chemistry: Alkaline Phosphatase | Alkaline phosphatase will be measured in U/L as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Clinical chemistry: Alanine transaminase (ALT) | ALT will be measured in U/L as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Clinical chemistry: Aspartate transaminase (AST) | AST will be measured in U/L as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Clinical chemistry: Bilirubin total | Total bilirubin will be measured in mg/dL as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Clinical chemistry: Creatinine (Serum) | Serum creatinine will be measured in µmol/L as per clinical routine and will be displayed using by-patient listings. | From date of informed consent to +30 days from last application of study medication (maximum up to 57 months) | 
| Left Ventricular Ejection Fraction (LVEF) monitoring | Incidence of clinically relevant LVEF levels. Change from baseline at each assessment time point, worst-on-treatment will be displayed using descriptive statistics. | LVEF at baseline, every three months thereafter until end of treatment, then every six months for 24 months thereafter (maximum up to 76 months) | 
| Patient-reported health-related quality of life (QoL): Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) | AUC in TOI-PFB at 12, 18, 24 and 36 months. Area under the curve (AUC) in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) after 12, 18, 24 and 36 months (irrespective of disease or treatment situation at that time point). Higher AUC indicates better quality of life. To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; higher values indicate better quality of life. | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B TOI-PFB | Time to decline by 5 points in the Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire subscale Trial Outcome Index-Physical/Functional/Breast (TOI-PFB). To calculate the TOI-PFB the three subscales Physical well-being (PWB - 7 statements), Functional well-being (FWB - 7 statements) and breast cancer subscale (BCS - 10 statements) are summed up. In all subscales each statement will be rated by the patient from 0 (not at all) - 4 (very much). Therefore ranges of subscales are: PWB 0 - 28; FWB 0 - 28; BCS 0 - 40; TOI-PFB 0 - 96; decline of scale indicates worsening quality of life. | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B total score | Change from baseline in the FACT-B total score for all questionnaire timepoints. To calculate FACT-B total score patient ratings from 0 (not at all) - 4 (very much) to each of the 37 questionnaire statement are summed up. Total score range: 0 - 148. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B subscale physical well-being (PWB) | Change from baseline in the FACT-B subscale PWB for all questionnaire timepoints. PWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B subscale social/family well-being (SWB) | Change from baseline in the FACT-B subscale SWB for all questionnaire timepoints. SWB subscale consists of 8 statements leading to a scale range of 0-32. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B subscale emotional well-being (EWB) | Change from baseline in the FACT-B subscale EWB for all questionnaire timepoints. EWB subscale consists of 6 statements leading to a scale range of 0-24. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B subscale functional well-being (FWB) | Change from baseline in the FACT-B subscale FWB for all questionnaire timepoints. FWB subscale consists of 7 statements leading to a scale range of 0-28. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS) | Change from baseline in the FACT-B BCS score for all questionnaire timepoints. BCS consists of 10 statements leading to a score range of 0-40. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT-B breast cancer subscale (BCS) score decline | Time to decline by 2 points in the FACT-B BCS score. BCS consists of 10 statements leading to a score range of 0-40. BCS score decline indicates worsening quality of life. | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Patient-reported health-related quality of life (QoL): FACT/GOG-Ntx4 subscale | Change from baseline in the FACT/GOG-Ntx4 subscale for all questionnaire timepoints. FACT/GOG-Ntx4 subscale consists of 11 statements leading to a scale range of 0-44. Higher values indicate better quality of life | Baseline, every three weeks for the first 24 weeks, every three months thereafter (maximum up to 36 months). | 
| Exploratory endpoint: Treatment costs | Treatment costs (drug costs) | From randomization until end of treatment (maximum up to 56 months). | 
| Exploratory endpoints: Duration of hospitalizations | Total duration of hospitalizations (per patients) | From randomization until end of treatment (maximum up to 57 months). | 
| Exploratory endpoints: Number of hospitalizations | Number of hospitalizations (in-patient stays) | From randomization until end of treatment (maximum up to 57 months). | 
| Exploratory endpoints: Reasons for hospitalizations | Reasons for hospitalizations | From randomization until end of treatment (maximum up to 57 months). | 
| Exploratory endpoints: Febrile infections | Incidence of febrile infections | From randomization until end of treatment (maximum up to 57 months). | 
| Exploratory endpoints: Employment status | Employment status (kind and duration of sick leaves) | From randomization until end of treatment (maximum up to 56 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced breast cancer, HER2-positive, metastatic, inoperable, female, quality of life