Protocol for Herceptin as Adjuvant Therapy With Reduced Exposure to Chemotherapy (PHARE-C)

Study Overview
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Brief Summary
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RATIONALE: According to previous results from PHARE study, a subgroup of patients with low-risk cancer (< 3 cm) without axillary lymph node involvement or small (< 2 cm) with minimal lymph node involvement (1 positive node) presented low risk of recurrence. Maintaining chemotherapy in this subgroup could cause toxicity and it is not yet known whether giving trastuzumab as monotherapy in neoadjuvant setting is as effective as giving trastuzumab combined with paclitaxel in patients with low risk early breast cancer. PURPOSE: This randomized phase III trial is studying trastuzumab as monotherapy in neoadjuvant setting to see if this treatment regimen is as efficient compared to trastuzumab combination with paclitaxel chemotherapy in treating women with low risk (tumor size< 3 cm, N0) early breast cancer.

Detailed Description
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PHARE-C is an open-label, randomized, phase III, non-inferiority trial, that will recruit patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer to allow for comparison of neoadjuvant treatment with paclitaxel plus trastuzumab versus trastuzumab as monotherapy. Non-inferiority between the two treatment arms will be evaluated in terms of time to progression as primary objective. Treatment tolerance and cardiac toxicity will be assessed as secondary objectives. In case of non pCR, a rescue by Trastuzumab emtansine (T-DM1) is planned to control the survival outcome.

Official Title
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Protocol for Herceptin as Adjuvant Therapy With Reduced Exposure to Chemotherapy, a Randomised Comparison of Trastuzumab vs Trastuzumab+Paclitaxel in Women With HER2-positive Early Breast Cancer Receiving Neoadjuvant Treatment

Conditions
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HER2-positive Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the breast, nonmetastatic disease and non operated tumor Without suspicious axillary nodes Tumor size < 30 mm Eligibility to receive a weekly paclitaxel based chemotherapy for this cancer Left Ventricular Ejection Fraction (LVEF) obtained and > 50% as measured by echocardiography (Simpson method) or multigated acquisition scan (MUGA) at 3 months (-/+ 1 month) Overexpression of HER-2 in the invasive component of the primary tumor as indicated by one of the following: 3+ by immunohistochemistry (IHC) 2+ by IHC and confirmation by fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) With signed Informed consent Exclusion Criteria: Previous anti-HER2 treatment (except for HERCEPTIN) Cardiac disease or other medical conditions preventing trastuzumab administration Known allergy to trastuzumab, murine proteins or other excipients Pregnant or breastfeeding women Patients that are not able to comply to the protocol assessments for geographic, social or psychological reasons

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: Group A (Paclitaxel + Trastuzumab)<br> | Drug: Paclitaxel + Trastuzumab<br>* Regarding neoadjuvant treatment : - 9 to 12 weeks of neoadjuvant treatment Trastuzumab IV (8mg/kg loading dose followed by 6 mg/kg maintenance dose) or SubCutaneous (SC) (600mg fixed dose) every 3 weeks + weekly Paclitaxel IV : 80 to 90 mg/m2 Regarding adjuvant treatment patients will receive one of the following anti-HER2 therapy following the current standard to complete 1 year of anti-HER2 therapy in total : in case of pCR : patient will receive trastuzumab in case of non pCR : patients will receive trastuzumab emtansine (T-DM1)<br>|
| Experimental: Group B (Trastuzumab)<br> | Drug: Trastuzumab<br>* Regarding neoadjuvant treatment : - 9 to 12 weeks of neoadjuvant treatment Trastuzumab IV (8mg/kg loading dose followed by 6 mg/kg maintenance dose) or SC (600mg fixed dose) every 3 weeks Regarding adjuvant treatment patients will receive one of the following anti-HER2 therapy following the current standard to complete 1 year of anti-HER2 therapy in total : in case of pCR : patient will receive trastuzumab in case of non pCR : patients will receive trastuzumab emtansine (T-DM1)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression | Time from the date of randomization to the date of progression | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac toxicity | defined by Ventricular Ejection Fraction measure according to the technique used, clinical examination or any other appropriate exams | up to 5 years | 
| Treatment toxicity | Adverse Event and Serious Adverse Event due to trastuzumab or paclitaxel graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | up to 5 years | 
| Total pathological Complete Response (tpCR) | Defined by complete absence of cancerous cells in breast, axillary lymph node chain and/or axillary sentinel lymph node (ypT0/is) in excised tissues | through surgery completion, an average of 12 weeks | 
| Breast pathological Complete Response (bpCR) | Defined by complete absence of cancerous cells in breast (ypT0/is, ypN0) in excised tissues | through surgery completion, an average of 12 weeks | 
| Distant metastasis Free Survival | Time from the date of randomization to the date of 1st metastasis | up to 5 years | 
| Overall Survival |  | up to 5 years |