A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer

Study Overview
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Brief Summary
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This 3 arm study will assess the tolerability, safety and efficacy of 3 neoadjuvant treatment regimens in participants with locally advanced, inflammatory or early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Before surgery, participants will be randomized to receive either A) 6 cycles of pertuzumab plus trastuzumab (Herceptin), with 5-fluorouracil/epirubicin/cyclophosphamide (FEC) for cycles 1-3 and docetaxel for cycles 4-6, or B) FEC for cycles 1-3 followed by pertuzumab plus trastuzumab with docetaxel for cycles 4-6, or C) 6 cycles of pertuzumab plus trastuzumab with docetaxel and carboplatin. Pertuzumab will be administered at a loading dose of 840 mg intravenously (iv), then 420 mg iv 3-weekly, trastuzumab at a loading dose of 8 mg/kg iv, then 6 mg/kg iv 3-weekly, docetaxel at 75 mg/m^2 iv, increased to 100 mg/m^2 iv 3-weekly, and FEC and carboplatin iv 3-weekly at standard doses. Following surgery participants will receive trastuzumab 6 mg/kg iv 3-weekly for a total of 1 year, as well as adequate chemo-, radio- and hormone therapy. Anticipated time on study treatment is 4-12 months, and target sample size is 200-300.

Official Title
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A Randomised, Multicentre, Multinational Phase II Study to Evaluate Pertuzumab in Combination With Trastuzumab, Given Either Concomitantly or Sequentially With Standard Anthracycline-based Chemotherapy or Concomitantly With a Non-anthracycline-based Chemotherapy Regimen, as Neoadjuvant Therapy for Patients With Locally Advanced, Inflammatory or Early Stage HER2-positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Pertuzumab
* Drug: Trastuzumab
* Drug: FEC
* Drug: Docetaxel
* Drug: TCH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: female participants, age >/=18 years advanced, inflammatory or early stage unilateral invasive breast cancer HER2-positive breast cancer baseline left ventricular ejection fraction (LVEF) >/=55% Exclusion Criteria: metastatic disease (Stage IV) or bilateral breast cancer previous anticancer therapy or radiotherapy for any malignancy other malignancy, except for carcinoma in situ of the cervix, or basal cell carcinoma clinically relevant cardiovascular disease current chronic treatment with corticosteroids of >10mg methylprednisolone or equivalent

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 |
| --- | --- |
| Experimental: T+P Concomitant Anthracycline-based chemotherapy<br>5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab (T) and pertuzumab (P) every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery. | Drug: Pertuzumab<br>* 840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.<br>* Other names: Perjeta;Drug: Trastuzumab<br>* 8 mg/kg loading dose IV, then 6 mg/kg every 3 weeks.<br>* Other names: Herceptin;Drug: FEC<br>* 5-fluorouracil 500 mg/m^2, epirubicin 100 mg/m^2 and cyclophosphamide 600 mg/m^2.<br>Drug: Docetaxel<br>* 75 mg/m^2 for the first dose; 100 mg/m^2 if no dose limiting toxicity occurs.<br>|
| Experimental: T+P Sequential Anthracycline-based chemotherapy<br>FEC every three weeks for three cycles, followed by docetaxel, trastuzumab (T) and pertuzumab (P) every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery. | Drug: Pertuzumab<br>* 840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.<br>* Other names: Perjeta;Drug: Trastuzumab<br>* 8 mg/kg loading dose IV, then 6 mg/kg every 3 weeks.<br>* Other names: Herceptin;Drug: FEC<br>* 5-fluorouracil 500 mg/m^2, epirubicin 100 mg/m^2 and cyclophosphamide 600 mg/m^2.<br>Drug: Docetaxel<br>* 75 mg/m^2 for the first dose; 100 mg/m^2 if no dose limiting toxicity occurs.<br>|
| Experimental: T+P Concomitant Non-Anthracycline chemotherapy<br>Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab (P) every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery. | Drug: Pertuzumab<br>* 840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.<br>* Other names: Perjeta;Drug: TCH<br>* Trastuzumab followed by carboplatin at target area under the plasma concentration-time curve (AUC) 6 and docetaxel at a starting dose of 75 mg/m^2. All treatments were given every three weeks by the IV route.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Percentage of Participants With Symptomatic Cardiac Events as Assessed by the Investigator | Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events. | From baseline up to approximately 3.5 years | 
| Safety: Percentage of Participants With Left Ventricular Ejection Fraction (LVEF) Decline During Pre-operative (Neoadjuvant) Period | Percentage of participants with LVEF measures decline of ≥ 10% from baseline and to a value of <50% during the pre-operative (neoadjuvant) period. | From baseline up to approximately 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Percentage of Participants With Complete Pathological Response (pCR) | pCR is defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. pCR is evaluated after 6 cycles of treatment and surgery or following withdrawal from the study whichever occurs sooner. | At surgery, after 18 weeks (6 cycles) of treatment | 
| Efficacy: Clinical Response Rate | Tumor response is defined as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) and is identified as per local practice. Clinical response rate is defined as the percentage of participants who achieve a response of CR or PR at any time pre-surgery. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by mammogram or magnetic resonance imaging (MRI) and clinical breast examination (CBE), CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions. | During each 3-week cycle of 6 total cycles: up to 18 weeks | 
| Efficacy: Time to Clinical Response | Time to clinical response is defined as the time from the date of first dose received to the first date of assessment of clinical response. Clinical response is defined as a response of CR or PR at any time pre-surgery. Per RECIST v1.0 for target lesions and assessed by mammogram or MRI and CBE, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions. | Up to 18 weeks | 
| Efficacy: Percentage of Participants Achieving Breast Conserving Surgery | This is the percentage of participants who achieved breast conserving surgery out of the intent-to-treat population without inflammatory breast cancer, as these participants received mastectomy irrespective of their response to neoadjuvant (pre-operative) treatment. | At approximately 18 weeks | 
| Efficacy: Percentage of Participants Without an Overall Survival (OS) Event | Overall survival (OS) was defined as the time from randomization to the date of death from any cause. Participants who were alive or lost to follow-up were censored at the last known alive date. Participants with no post-baseline information were censored at the date of randomization plus one day. | From baseline to end of study up to 5 years | 
| Efficacy: Percentage of Participants Without a Disease-Free Survival (DFS) Event | The DFS was defined as the time from the first date of no disease (i.e., date of surgery) to the first documentation of progressive disease (PD) or death. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Any evidence of contralateral disease in situ was not considered as PD. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be disease-free. | From baseline to end of study up to 5 years | 
| Efficacy: Percentage of Participants Without a Progression-Free Survival (PFS) Event | Progression-free survival was defined as the time from the date of randomization to the first documentation of PD or death from any cause, whichever occurred first. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be free from PD. Participants without post-baseline assessments but known to be alive were censored at the time of randomization plus one day. | From baseline to end of study up to 5 years | 
| Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD) | Percentage of participants with signs or symptoms of cardiac events. | From Baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years) | 
| Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events | Percentage of participants with LVEF events without signs or symptoms of cardiac events. | From baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years) | 
| Safety: Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures | Maximum decrease in LVEF measures is the change from baseline at worst treatment value. LVEF is measured as percentage. | From baseline up to approximately 3.5 years |