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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: FEC100; Drug: Docetaxel; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Carboplatin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France
    • Institut de Cancérologie de l'Ouest - Site Paul Papin
  • Brest, France
    • Centre Hospitalier Regional Universitaire de Brest - Hopital Morvan
  • Caen, France
    • Centre Francois Baclesse
  • Clermont Ferrand, France
    • Centre Jean Perrin
  • Grenoble, France
    • CHU de Grenoble - Hôpital Michallon
  • Limoges, France
    • Chu de Limoges - Hopital Dupuytren
  • Lyon, France
    • Centre Léon Bérard
  • Montpellier, France
    • Institut Régional du Cancer Montpellier Val d'Aurelle
  • Saint Herblain, France
    • Institut de Cancérologie de l'Ouest - Site René Gauducheau
  • Saint-Mande, France
    • Hopital D'Instructions Des Armees
  • Strasbourg, France
    • Centre Paul Strauss
  • Vandoeuvre-les-Nancy, France
    • Institut de Cancérologie de Lorraine Alexis Vautrin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TOP2A amplified; 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; 3 cycles of FEC 100 administered IV q3w; 5-Fluorouracil (5-FU) 500 mg/m²; Epirubicin 100 mg/m²; Cyclophosphamide 500 mg/m²; Drug: Docetaxel; TOP2A amplified : DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w TOP2A not amplified : DOCETAXEL 75 mg/m² IV; Drug: Trastuzumab; Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.; Drug: Pertuzumab; Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.
Experimental: TOP2A not amplified; 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; TOP2A amplified : DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w TOP2A not amplified : DOCETAXEL 75 mg/m² IV; Drug: Trastuzumab; Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.; Drug: Pertuzumab; Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.; Drug: Carboplatin; CARBOPLATIN AUC 6 IV q3w

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Marie-Ange MOURET REYNIER, Centre Jean Perrin

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): October 7, 2019
• Study Completion (Actual): July 8, 2024

Study Registration Dates

• First Submitted: December 14, 2014
• First Submitted That Met QC Criteria: January 14, 2015
• First Posted (Estimated): January 15, 2015

Study Record Updates

• Last Update Posted (Actual): November 8, 2024
• Last Update Submitted That Met QC Criteria: November 6, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: HER2-positive; non-metastatic; TOP2A
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel; Trastuzumab; Carboplatin; Pertuzumab
• Other Study ID Numbers: GEP13

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No