Impact of Pegfilgrastim on Trastuzumab Anti-tumor Effect and ADCC in Operable HER2+ Breast Cancer Breast Cancer

Study Overview
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Brief Summary
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First preclinical data suggest that pegfilgrastim could constitute a potent adjuvant for immunotherapy with mAb possessing ADCC/ADCP properties as trastuzumab. Combined treatment of pegfilgrastim and trastuzumab should translate into an increased rate of pathological clinical response. Therefore the investigators' proposal is to evaluate the clinical and biological impact of pegfilgrastim in combination with trastuzumab + paclitaxel in HER2-positive early stage breast cancer patients. Breastimmune02 is a multicenter, randomized, open-label, Phase II trial. Operable HER2+ breast cancer patients previously treated with 4 cycles of standard adriamycine/cyclophosphamide (AC) chemotherapy will be randomized (1:1) to receive in the neoadjuvant setting:Arm A: weekly paclitaxel + trastuzumab (every 3 weeks, Q3W) + pegfilgrastim (Q3W) versus Arm B: weekly paclitaxel + trastuzumab (Q3W).Stratification criteria will be: cN0 versus cN1.

Detailed Description
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The duration of the neoadjuvant treatment period is planned to be 12 weeks (4 cycles of 3 weeks), except in case of Inacceptable toxicity, or Patient decision, or Withdrawal of consent, or Clinical/radiological signs of disease progression.This neoadjuvant treatment period will be ended with a short term safety visit (STSVNeo) to be scheduled 28 days after the last dose of study treatments (considering the latest study treatments administered). Following the STSVNeo, patients will undergo surgery as per usual practice and pathological response will be centrally assessed by a referent pathologist blinded for the treatment arms.Following surgery, all patients will be treated in the adjuvant setting with trastuzumab administered every 3 weeks for up to 12 months in both arms with clinical assessments every 3 months (cf. Réseau régional de Cancérologie, http://espacecancer.sante-ra.fr/Pages/Accueil.aspx). In case of RH+ disease, endocrine therapy may be initiated as per standard treatment guidelines.This adjuvant treatment period is planned for a maximum of 12 months; except in case of Inacceptable toxicity, or Patient decision, or Withdrawal of consent, or Clinical/radiological signs of disease progression. All randomized and treated patients will be followed-up for relapse and survival for at least 15 months post-randomization (i.e. 1 year post-surgery). A total of 90 patients will be randomized in the study. (45 per arm). All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study serious adverse event (SAE) reporting will be also paper-based by e-mail and/or Fax. The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements

Official Title
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A Multicenter, Randomized, Open-label, Phase II Trial Aiming to Evaluate the Impact of Pegfilgrastim on Trastuzumab Anti-tumor Effect and ADCC in Operable HER2 Positive Breast Cancer Patients

Conditions
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HER2-positive Breast Cancer, Operable Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab + Paclitaxel
* Drug: Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients aged ≥ 18 years at time of inform consent signature. Histologically proven HER2 positive breast cancer defined as 3+ staining intensity by immunohistochemistry (IHC) or a 2+ IHC staining intensity and HER2 gene amplification by FISH.Note: HER2 status will be determined as per institutional practice. Operable breast tumor with tumor size and staging: > 20 mm, cN0 or cN1, M0 before any AC or FEC chemotherapy, and at least one measurable lesion ≥10 mm in longest diameter at inclusion according to RECIST 1.1. No radiological sign of disease progression at time of randomisation. Patient previously treated by 4 cycles of AC or 3 to 4 cycles of FEC without febrile neutropenia and without prior pegfilgrastim treatment. Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumor specimen from initial diagnosis (i.e. an archival paraffin block is preferred; or at least 20 unstained slides) with its histological report. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Adequate organ function as defined by the following lab tests (to be carried out within 7 days prior C1D1):Bone marrow (Absolute neutrophil count ≥ 1.5 x 109/L, Platelet count > 100 x 109/L, (without transfusion within 21 days prior to C1D1), Hemoglobin value ≥ 9 g/dL), Renal function (Calculated creatinine clearance by MDRD or CKD-EPI >50 mL/min/1.73m2 or serum creatinine < 1.5ULN), Liver function (Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3ULN, Total serum bilirubin ≤ 1.5 ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤3 ULN is acceptable), Coagulation (INR and aPTT≤ 1.5 ULN) Adequate cardiac function with Mean resting corrected QT interval (QTc), calculated using Fridericia's formula, ≤470ms obtained from 3 electrocardiograms (ECGs) and Systolic blood pressure <160mmHg and Diastolic blood pressure <100mmHg (hypertension controlled by standard medical treatment is allowed) Women of childbearing potential (entering the study after a confirmed menstrual period and who have a negative pregnancy test within 7 days before C1D1) must agree to use two methods of medically acceptable forms of contraception from the date of negative pregnancy test to 3 months after the last study drug intake Patients should be able and willing to comply with study visits and procedures as per protocol Patients should understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed. Patients must be covered by a medical insurance. Exclusion Criteria: Patients with inflammatory breast cancer. Previous exposure to pegfilgrastim or trastuzumab. Note: the use of filgrastim (non pegylated form only) is authorized prior to the randomisation. Patients requiring the concomitant use of any forbidden treatment including: Any other anti-cancer treatments not listed in the protocol, including chemotherapy, radiotherapy, immunotherapy, targeted therapy or biologic therapy for cancer treatment, Any investigational treatment. Any contra-indication to trastuzumab, paclitaxel, and pegfilgrastim respective SPCs including:Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in trastuzumab SPC, Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy, Hypersensitivity to pegfilgrastim or filgrastim, or to any of the excipients listed in SPC, Hereditary problems of fructose intolerance, Hypersensitivity to paclitaxel or to any excipient, particularly macrogolglycerol ricinoleate, Patients with history of or active cardiac disease including myocardial infarction (MI), angina pectoris requiring medical treatment, congestive heart failure NYHA (New York Heart Association) Class ≥II, other cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant cardiac valvular disease, and hemodynamic effective pericardial effusion. Active secondary malignancy unless this malignancy is not expected to interfere with the evaluation of study endpoints and is approved by the sponsor. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix. Patients with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible. Pregnant or breast-feeding female patients.

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: Paclitaxel+Trastuzumab+Pegfilgrastim<br>NEOADJUVANT TREATMENT PERIOD (up to 12 weeks) :Paclitaxel (80 mg/m2, weekly (D1, D8, D15), IV) + Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, IV OR 600mg, Q3W SC) + Pegfilgrastim (6 mg, Q3W, subcutaneously, the day after the trastuzumab + paclitaxel infusion (i.e. Day 2 of each cycle)). ADJUVANT TREATMENT PERIOD (up to 12 months) : Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, (IV) OR 600mg, Q3W SC) | Drug: Trastuzumab + Paclitaxel<br>* During neoadjuvant period, weekly paclitaxel + trastuzumab (every 3 weeks, Q3W) During adjuvant period, weekly trastuzumab (every 3 weeks, Q3W)<br>Drug: Pegfilgrastim<br>* During neoadjuvant period, weekly pegfilgrastim (every 3 weeks, Q3W)<br>* Other names: Neulasta;|
| Active Comparator: Paclitaxel+Trastuzumab<br>NEOADJUVANT TREATMENT PERIOD (up to 12 weeks) :Paclitaxel (80 mg/m2, weekly (D1, D8, D15), IV) + Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, IV OR 600mg, Q3W SC). ADJUVANT TREATMENT PERIOD (up to 12 months) : Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, (IV) OR 600mg, Q3W SC) | Drug: Trastuzumab + Paclitaxel<br>* During neoadjuvant period, weekly paclitaxel + trastuzumab (every 3 weeks, Q3W) During adjuvant period, weekly trastuzumab (every 3 weeks, Q3W)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate (pCR) | Defined as ypT0 ypN0 or ypT0/is ypN0 after 12 weeks of treatment by trastuzumab + paclitaxel ± pegfilgrastim with ypT0/Tis ypN0 defined as absence of invasive cancer in the breast and axillary nodes in all surgically excised specimens. | 16 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free survival | From the date of randomisation until the date of event defined as the first documented relapse after surgery or death from any cause. | At least 15 months following randomisation | 
| Time to relapse | From the time of treatment start until the first documented relapse | At least 15 months following randomisation | 
| Overall survival | From the date of randomisation to the date of death from any cause | At least 15 months following randomisation | 
| Adverse events reporting | Based mainly on the frequency of AE graded according to the common toxicity criteria grading system (CTCAE-V4.03). | At least 15 months following randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pegfilgrastim, Trastuzumab/Paclitaxel, Antibody-dependent cell-mediated cytotoxicity