Study to Compare Neoadjuvant Combination of Trastuzumab and Pertuzumab With Concurrent Taxane Chemotherapy or Endocrine Therapy and Quality of Life Assessment Under Adjuvant Therapy in Operable HER2+/HR+ Breast Cancer Patients

Study Overview
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Brief Summary
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This is a prospective, phase IIa, multicenter, randomized, open-label study comparing a pre-surgical combination of trastuzumab and pertuzumab with concurrent weekly paclitaxel chemotherapy or endocrine therapy given for 12 weeks with a quality of life assessment for 40 additional weeks in patients with operable HER2+/HR+ breast cancer.

Official Title
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A Prospective, Randomized, Multicenter, Open-label Comparison of Pre-surgical Combination of Trastuzumab and Pertuzumab With Concurrent Taxane Chemotherapy or Endocrine Therapy Given for Twelve Weeks With a Quality of Life Assessment of Trastuzumab, Pertuzumab in Combination With Standard (Neo)Adjuvant Treatment in Patients With Operable HER2+/HR+ Breast Cancer.

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Perjeta Injectable Product
* Drug: Herceptin
* Drug: Tamoxifen
* Drug: Paclitaxel
* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Anastrozole
* Drug: Letrozole
* Drug: Exemestane
* Drug: Leuprorelin acetate
* Drug: Goserelin
* Drug: Anastrozole
* Drug: Letrozole
* Drug: Exemestane
* Drug: Paclitaxel
* Drug: Tamoxifen
* Drug: Leuporelin acetate
* Drug: Goserelin
* Diagnostic Test: Biopsy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients, age at diagnosis 18 years and older Histologically confirmed unilateral primary invasive carcinoma of the breast Patients must qualify for neoadjuvant treatment as follows: No clinical evidence for distant metastasis (M0) Clinical cT1c-T4a-c (participation of patients with tumors > cT2 is strongly recommended) and no evidence for distant metastases (M0) All clinical N (participation of patients with cN+, also in case of cT1c, is strongly recommended) Known positive HR-status and centrally confirmed HER2+-status by IHC/FISH Patients need to fulfill adequate blood count and organ function to receive chemotherapy (see exclusion criteria). Tumor block available for central pathology review Performance Status ECOG ≤ 1 or KI ≥ 80% Negative pregnancy test (urine or serum) within 7 days prior to registration in premenopausal patients Patients of childbearing potential must accept to implement a highly effective (less than 1% failure rate according to Pearl index) non-hormonal contraceptive measures during the study treatment and for 6 months following the last dose of study treatment (trastuzumab and pertuzumab) such as: Intrauterine device (IUD) bilateral tubal occlusion vasectomised partner sexual abstinence Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements The patient must be accessible for treatment and follow-up LVEF > 55%; LVEF within normal limits of each institution measured by echocardiography (within 42 days prior to randomization) Normal ECG (within 42 days prior to randomization) Exclusion Criteria: Known hypersensitivity reaction to the compounds or incorporated substances Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri Non-operable breast cancer including inflammatory breast cancer Previous or concurrent treatment with cytotoxic agents for any reason Concurrent treatment with other experimental drugs and participation in another clinical trial or clinical research project within 30 days prior to study entry is excluded Male breast cancer Concurrent pregnancy Breastfeeding Sequential breast cancer Reasons indicating risk of poor compliance Known polyneuropathy ≥ grade 2 Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including but not confined to: Uncompensated chronic heart failure or systolic dysfunction (LVEF < 55%, CHF NYHA classes II-IV), unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block, Angina pectoris within the last 6 months requiring anti-anginal medication, Clinically significant valvular heart disease, Evidence of myocardial infarction on electrocardiogram (ECG), Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic > 100 mm Hg). Inadequate organ function including but not confined to: hepatic impairment (Child Pugh Class C) pulmonary disease (severe dyspnea at rest requiring oxygen therapy) Abnormal blood values: Thrombocytopenia > CTCAE grade 1 Increases in ALT/AST > CTCAE grade 1 Hypokalaemia > CTCAE grade 1 Neutropenia > CTCAE grade 1 Anaemia > CTCAE grade 1

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Paclitaxel+Trastuzumab+Pertuzumab<br>Neoadjuvant therapy: Trastuzumab and Pertuzumab in a 3-weekly schedule in combination with standard Taxane chemotherapy. Adjuvant Therapy: Standard of care | Drug: Perjeta Injectable Product<br>* Single dose of 840mg (loading dose) day1 cycle 1, 420mg at day1 of each subsequent cycle, every 3 weeks. (The latter cycle is called cycle of treatment and is to be given 4 times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)<br>* Other names: Pertuzumab;Drug: Herceptin<br>* Single dose of 8mg/kg (loading dose) day1 cycle 1; 6mg/kg at day1 of each subsequent cycle body weight every 3 weeks. (This is called cycle of treatment and is to be given four times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)<br>* Other names: Trastuzumab;Drug: Tamoxifen<br>* 20 mg per day for a total of 40 weeks in the adjuvant therapy phase.<br>Drug: Paclitaxel<br>* 80mg/sqm, day one of each cycle, every week. This is called a cycle of treatment and is to be given for 12 weeks in neoadjuvant therapy phase.<br>Drug: Epirubicin<br>* 12 weeks (4cycles) of max. 90mg/sqm in adjuvant therapy phase<br>Drug: Cyclophosphamide<br>* 12 weeks (4cycles) of 600 mg/sqm i.v. on day 1+8 or 12 weeks (4cycles) of 500 mg/sqm i.v. on day 1 in adjuvant therapy phase<br>Drug: Anastrozole<br>* 1mg per day for a total of 40 weeks in adjuvant therapy phase<br>Drug: Letrozole<br>* 2,5 mg/day for a total of 40 weeks in adjuvant therapy phase<br>Drug: Exemestane<br>* 25mg/day for a total of 40 weeks in adjuvant therapy phase<br>Drug: Leuprorelin acetate<br>* One injection of 3,75mg every month or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane, for a total of 40 weeks in the adjuvant therapy phase.<br>Drug: Goserelin<br>* 3,6mg every 28 days or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane, for a total of 40 weeks in the adjuvant therapy phase.<br>Diagnostic Test: Biopsy<br>* Core biopsy at screening (outside of protocol), at week 4 after randomization, (at week 14 in addition if neoadjuvant phase is prolonged)<br>Procedure: Surgery<br>* Surgery at week 14 after randomization (or later, if neoadjuvant phase is prolonged)<br>|
| Experimental: Endocrine+Trastuzumab+Pertuzumab<br>Neoadjuvant therapy: Trastuzumab and Pertuzumab in a 3-weekly schedule in combination with endocrine therapy. Adjuvant Therapy: Standard of care | Drug: Perjeta Injectable Product<br>* Single dose of 840mg (loading dose) day1 cycle 1, 420mg at day1 of each subsequent cycle, every 3 weeks. (The latter cycle is called cycle of treatment and is to be given 4 times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)<br>* Other names: Pertuzumab;Drug: Herceptin<br>* Single dose of 8mg/kg (loading dose) day1 cycle 1; 6mg/kg at day1 of each subsequent cycle body weight every 3 weeks. (This is called cycle of treatment and is to be given four times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)<br>* Other names: Trastuzumab;Drug: Epirubicin<br>* 12 weeks (4cycles) of max. 90mg/sqm in adjuvant therapy phase<br>Drug: Cyclophosphamide<br>* 12 weeks (4cycles) of 600 mg/sqm i.v. on day 1+8 or 12 weeks (4cycles) of 500 mg/sqm i.v. on day 1 in adjuvant therapy phase<br>Drug: Anastrozole<br>* 1mg per day for 12 weeks in neoadjuvant therapy phase; 1mg per day for a total of 40 weeks max. in adjuvant therapy phase<br>Drug: Letrozole<br>* 2,5 mg per day for 12 weeks in neoadjuvant therapy phase; 2,5 mg perday for a total of 40 weeks max. in adjuvant therapy phase<br>Drug: Exemestane<br>* 25mg/day for 12 weeks in neoadjuvant therapy phase; 25mg/day for a total of 40 weeks max. in adjuvant therapy phase<br>Drug: Paclitaxel<br>* 80mg/sqm, day one of each cycle, every week. This is called a cycle of treatment an is to be given for 12 weeks in the adjuvant phase<br>Drug: Tamoxifen<br>* 20mg per day (given over 12 weeks in the neoadjuvant therapy phase and over 40 weeks max. in the adjuvant therapy phase.<br>Drug: Leuporelin acetate<br>* One injection of 3,75mg every month or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane (given over 12 weeks in the neoadjuvant therapy phase and over 40 weeks max. in the adjuvant therapy phase).<br>Drug: Goserelin<br>* 3,5mg every 28 days or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane (given over 12 weeks in the neoadjuvant therapy phase and over 40 weeks max. in the adjuvant therapy phase).<br>Diagnostic Test: Biopsy<br>* Core biopsy at screening (outside of protocol), at week 4 after randomization, (at week 14 in addition if neoadjuvant phase is prolonged)<br>Procedure: Surgery<br>* Surgery at week 14 after randomization (or later, if neoadjuvant phase is prolonged)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) | 14 weeks after start of therapy treatment, tumor and lymph node biopsy is performed to reach the primary endpoint of pathological complete response (pCR) which is defined as the absence of residual invasive cancer of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/is ypN0 in the current AJCC staging system). As secondary endpoint, also other response states will be taken into account: no invasive tumor in the complete resected breast specimen irrespective of the lymph node state following completion of neoadjuvant systemic therapy (ypT0/is, any ypN). | 14 weeks after start of therapy treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health-related quality of life using EORTC QBL-BR-23 scale | Assessment of quality of life questions during the past week or during the past 4 weeks (depending on the questions) are measured on a 4 level-scale: 1 (not at all); 2 (a little); 3 (quite a bit); 4 (very much) | During the neoadjuvant treatment phase at baseline (week 1) and at week 13. In the adjuvant therapy phase, every 3 month, up to 12 months (from date of randomization) or date of drop out, whatever comes first | 
| Health-related quality of life using EQ5D-5L scale | questions about self care, usual activities, pain /discomfort, anxiety/depression are assessed on a 5 level-scale using tick boxes : I have no problem; I have slight problems; I have moderate problems; I have severe problems I am unable assessment of the patient health (good or bad) is measured on a scale numbered from 0 to 100 (100 means the best heath and 0 means the worst) | During the neoadjuvant treatment phase at baseline (week 1) and at week 13. In the adjuvant therapy phase, every 3 month, up to 12 months (from date of randomization) or date of drop out, whatever comes first | 
| Health-related quality of life using EORTC QLQ-C30 scale | Assessment of quality of life questions (activities, breath, pain, sleep, appetite, vomiting, constipation, others..) are measured on a 4 level-scale: 1 (not at all); 2 (a little); 3 (quite a bit); 4 (very much) Assessment of Overall health and overall quality of life during the past week is measured on a 7 level-scale going from 1 (very poor) to 7 (excellent) | During the neoadjuvant treatment phase at baseline (week 1) and at week 13. In the adjuvant therapy phase, every 3 month, up to 12 months (from date of randomization) or date of drop out, whatever comes first | 
| Tumor size reduction by mammography | The diameters of the tumors in the breast will be measured in millimeter by mammography as part of clinical response measure. The tumor size measurement 13 weeks after start of therapy is also used to reach a secondary endpoint: near pCR, defined as tumor sized ypT1a/is, any ypN with tumor size. | at screening visit and 12 weeks after start of therapy treatment | 
| Tumor size reduction by palpation and ultrasound | The diameters of the tumors in the breast will be measured in millimeter by palpation and ultrasound as part of clinical response measure. The tumor size measurement 13 weeks after start of therapy is also used to reach a secondary endpoint: near pCR, defined as tumor sized ypT1a/is, any ypN with tumor size. | at screening visit and 4, 7 and 13 weeks after start of therapy treatment | 
| Overall survival | The overall survival is defined as time (days) between study treatment allocation and death of patient due to any cause. | From date of randomization until the date of death from any cause, assessed up to 60 months | 
| Duration of invasive disease-free survival | Duration of invasive disease-free survival is defined as time (days) between study treatment allocation and relapse, secondary tumor event or death. | From date of treatment allocation until the date of first documented progression or secondary tumor or date of death from any cause, whichever came first, assessed up to 60 months (study duration including follow up) | 
| Number of mastectomies | The number of mastectomies will be determined at time of surgery (week 14 and week 18) | 14 weeks after start of therapy treatment | 
| Ki67 level | The level of Ki67 in biopsie material will be measured at week 4 of neoadjuvant therapy | 4 weeks after start of therapy treatment | 
| cDNA composition | The composition of cDNA in blood samples will be measured | at baseline, 3 weeks, 4 weeks and 6, 18, 24, 36 48 and 60 months after start of therapy treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hormone receptor positive, human epidermal growth factor receptor 2 positive, Early breast cancer, HR+/HER2+