Neoadjuvant Phase II Trial in Patients With T1c Operable, HER2-positive Breast Cancer According to TOP2A Status

Study Overview
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Brief Summary
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The main objective of this multicenter study will therefore be to evaluate pathologic complete response rates of an anthracycline-based regimen [FEC 100 - TAXOTERE® - HERCEPTIN® - PERTUZUMAB] and a non anthracycline-based regimen [TAXOTERE® - CARBOPLATINE - HERCEPTIN® - PERTUZUMAB] according to the presence or not of TOP2A gene amplification in a population of breast cancer patients with HER2 overexpression. A very important objective of the study will be the evaluation of biomarkers that predict response to treatment.

Detailed Description
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In this phase II study, we propose a treatment strategy that not only takes advantage of the complementary action of trastuzumab and pertuzumab but also the relevance of an anthracycline-based regimen. Indeed, besides the cardiac toxicity that can be induced by these three agents, anthracycline chemotherapy may not confer benefit to all patients. The underlying scientific hypothesis is based on data from the NEOSPHERE neoadjuvant trial showing that addition of pertuzumab to trastuzumab plus docetaxel improved the pCR rate (46% versus 29% without pertuzumab) in T2-T3 tumors. Therefore, we hypothesize that for smaller tumors (T1c), the pCR rate should be higher, on the order of 60% in patients with the coamplification (with anthracycline therapy) and 55% for the group without coamplification (without anthracycline therapy). The sample size of 90 patients (45 per group) planned for the phase II study will allow 15% precision with the expected pCR rates of 60% (95%CI: 45%-75%) for patients with coamplification and 55% (95%CI: 40%-70%) for those without coamplification. In addition, exploratory analyses will aim to identify predictive markers of pCR in order to target biologically defined subpopulations in which pCR rates might even be higher.

Official Title
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Neoadjuvant Phase II Trial Combining [3 FEC 100 Followed by 3 Docetaxel Associated With Trastuzumab Plus Pertuzumab] or [6 Docetaxel, Carboplatin Associated With Trastuzumab Plus Pertuzumab] According to TOP2A Status in Patients With T1c Operable, HER2-positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: FEC100
* Drug: Docetaxel
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged ≥ 18; Patient has histologically confirmed breast cancer, with a clinical tumour diameter of > 1 cm (cT1c, cT2-3 or T4a)- Any N status No clinically or radiologically detectable metastases (M0); HR negative (both ER and PR < 10% by IHC); for T1c status, otherwise HR negative or positive Her-2 positive (i.e. IHC score 3+ or FISH/SISH/CISH positive); Performance status ≤ 1 (according to WHO criteria); Patients not previously treated by surgery, radiotherapy, hormone therapy or chemotherapy; Hæmatology: Absolute neutrophil count (ANC) ≥1,500/mm³; Platelets ≥100,000/mm³; Total white blood cell count (WBC) ≥3.000/mm³; Hb> 9g/dl; Hepatic Function: Total bilirubin ≤1.5 time the upper normal limit (UNL); ASAT ≤ 1.5xUNL; ALAT ≤ 1.5xUNL; Alkaline phosphatase ≤ 2.5xUNL; Renal Function: Serum creatinine ≤1.5xUNL (and if Serum creatinine >1.5xUNL, Creatinine clearance ≥50 mL/min (MDRD formula); Metabolic Function: Magnesium ≥ lower limit of normal; Calcium ≥ lower limit of normal; Patient with not controlled heart disease and for whom anthracyclines are not contraindicated. Cardiac ejection fraction ≥50% measured by MUGA or ECHO done within 4 weeks before inclusion; Patient agreeing to use effective contraception during and for ≥ 7 months after completion of study treatment; Patient able to comply with the protocol; Patient must have signed a written informed consent form prior to any study specific procedures; Patient must be affiliated to a Social Health Insurance. Exclusion Criteria: Bilateral or multifocal breast cancer; Non-measurable tumour; Any form of breast cancer other than those described in the inclusion criteria, particularly inflammatory and/or overlooked forms (T4b or T4d); HER2 negative status (i.e. IHC score 0 or 1+, or IHC score 2+ and FISH/SISH/CISH negative); RH positive (ER or PR ≥ 10% by IHC) ; Patient has a history of second cancer, with exception of in situ cervical cancer or basocellular skin cancer which is regarded as cured; Patient has already been treated for new breast cancer; Patients have already undergone surgery for their disease or have had primary axillary dissection; Prior docetaxel administration or anti-HER2 antibody therapy (e.g.: trastuzumab or pertuzumab); Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, such as, but not limited to: Heart or kidney failure, medullary, respiratory or liver failure, dyspnea Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, poorly controlled hypertension) ≤ 1 year before enrollment Uncontrolled diabetes Significant neurological or psychiatric abnormalities Symptomatic or progressive disorder of the central nervous system (CNS) or metastasis at the initial check-up. Peripheral neuropathy > grade 2 Acute urinary infection, ongoing hemorrhagic cystitis; Patients with a known history of HIV seropositivity; Sensitivity to any of the study medications or any of the ingredients or excipients of these medications; Patients receiving of the concomitant medications with phenytoin; Patients who received any other investigational drugs within 30 days of initiation of treatment and/or during the study; Must not have had a major surgical procedure within 30 days of initiation of treatment; Pregnant women, women who are likely to become pregnant or are breast-feeding; Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial; Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol; Individual deprived of liberty or placed under the authority of a tutor.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TOP2A amplified<br>If TOP2A amplified: FEC x 3 then THP x 3 3 cycles of FEC 100 administered IV q3w 5-Fluorouracil (5-FU) 500 mg/m² Epirubicin 100 mg/m² Cyclophosphamide 500 mg/m² Followed by 3 cycles of Trastuzumab-Pertuzumab-Docetaxel: Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles. Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles. DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w | Drug: FEC100<br>* 3 cycles of FEC 100 administered IV q3w 5-Fluorouracil (5-FU) 500 mg/m² Epirubicin 100 mg/m² Cyclophosphamide 500 mg/m²<br>Drug: Docetaxel<br>* TOP2A amplified : DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w TOP2A not amplified : DOCETAXEL 75 mg/m² IV<br>Drug: Trastuzumab<br>* Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.<br>Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.<br>|
| Experimental: TOP2A not amplified<br>If TOP2A not amplified: TCHP x 6 TCHP administered IV q3w for 6 cycles Trastuzumab 8 mg/kg loading dose administered IV followed by 6 mg/kg IV q3w in subsequent cycles. Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles. DOCETAXEL 75 mg/m² IV q3w CARBOPLATIN AUC 6 IV q3w The Calvert formula will be used to calculate the dose of carboplatin: Dose (mg) = target AUC (mg/mL x min) x [GFR mL/min + 25] Dose (mg) = 6 x [GFR mL/min + 25] NOTE: the Calvert formula gives the dose in mg, not mg/m². GFR, glomerular filtration rate The maximum dose of CARBOPLATIN must not exceed 900 mg. | Drug: Docetaxel<br>* TOP2A amplified : DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w TOP2A not amplified : DOCETAXEL 75 mg/m² IV<br>Drug: Trastuzumab<br>* Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.<br>Drug: Pertuzumab<br>* Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.<br>Drug: Carboplatin<br>* CARBOPLATIN AUC 6 IV q3w<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response according to Chevallier classification | on surgical specimen and lymph nodes at the time of the surgery | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictive factors of response to both treatment regimens (anthracycline-based and non anthracycline-based regimens) | on surgical specimen and lymph nodes at the time of the surgery | 20 weeks | 
| Pathological complete response (pCR), according to Sataloff's classification | on surgical specimen and lymph nodes at the time of the surgery | 20 weeks | 
| Clinical and radiological response according to the WHO criteria | on mammography and breast echography | after two cycles of treatment and after the end of treatment | 
| Toxicity according to NCI CTC-AE v4.0 criteria | according the occurrence of adverse events and toxicities assessed every week | during on-treatment period (defined as the period from the first dose of study medication up to 30 days of the last dose | 
| Progression-free survival | The PFS is defined as the time from the first administration of treatment to progression or death of any cause, if progression has not been documented. | up to 60 months | 
| Overall survival | The OS is defined as the time from the first administration of treatment to death from any cause. | up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive, non-metastatic, TOP2A