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

NCT ID: NCT02339532

Last Updated: 2024-11-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 86 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2024-07-08

Brief Summary

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

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

FEC100

Intervention Type: DRUG

3 cycles of FEC 100 administered IV q3w

• 5-Fluorouracil (5-FU) 500 mg/m²
• Epirubicin 100 mg/m²
• Cyclophosphamide 500 mg/m²

Docetaxel

Intervention Type: DRUG

TOP2A amplified : DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w TOP2A not amplified : DOCETAXEL 75 mg/m² IV

Trastuzumab

Intervention Type: DRUG

Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.

Pertuzumab

Intervention Type: DRUG

Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.

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.

Group Type: EXPERIMENTAL

Docetaxel

Intervention Type: DRUG

TOP2A amplified : DOCETAXEL 75 mg/m² IV escalating at 100 mg/m² IV as tolerated q3w TOP2A not amplified : DOCETAXEL 75 mg/m² IV

Trastuzumab

Intervention Type: DRUG

Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.

Pertuzumab

Intervention Type: DRUG

Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.

Carboplatin

Intervention Type: DRUG

CARBOPLATIN AUC 6 IV q3w

Interventions

FEC100

3 cycles of FEC 100 administered IV q3w

• 5-Fluorouracil (5-FU) 500 mg/m²
• Epirubicin 100 mg/m²
• Cyclophosphamide 500 mg/m²

Intervention Type: 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

Intervention Type: DRUG

Trastuzumab

Trastuzumab 8 mg/kg loading dose administered intravenously (IV) followed by 6 mg/kg IV q3w in subsequent cycles.

Intervention Type: DRUG

Pertuzumab

Pertuzumab 840 mg loading dose administered IV followed by 420 mg IV q3w in subsequent cycles.

Intervention Type: DRUG

Carboplatin

CARBOPLATIN AUC 6 IV q3w

Intervention Type: DRUG

Eligibility Criteria

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.

• 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.

Exclusion Criteria

• Bilateral or multifocal breast cancer;
• Non-measurable tumour;

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

UNICANCER

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marie-Ange MOURET REYNIER

Role: PRINCIPAL_INVESTIGATOR

Centre Jean Perrin

Locations

Institut de Cancerologie de L'Ouest - Site Paul Papin

Angers, , France

Centre Hospitalier Regional Universitaire de Brest - Hôpital Morvan

Brest, , France

Centre Francois Baclesse

Caen, , France

Centre Jean Perrin

Clermont-Ferrand, , France

Chu de Grenoble - Hopital Michallon

Grenoble, , France

Chu de Limoges - Hôpital Dupuytren

Limoges, , France

Centre Leon Berard

Lyon, , France

Institut Regional Du Cancer Montpellier Val D'Aurelle

Montpellier, , France

Institut de Cancerologie de L'Ouest - Site Rene Gauducheau

Saint-Herblain, , France

Hopital D'Instructions Des Armees

Saint-Mandé, , France

Centre Paul Strauss

Strasbourg, , France

Institut de Cancerologie de Lorraine Alexis Vautrin

Vandœuvre-lès-Nancy, , France

Countries

France

References

Ginzac A, Molnar I, Durando X, Motte Rouge T, Petit T, D'hondt V, Campone M, Bonichon-Lamichhane N, Venat Bouvet L, Levy C, Augereau P, Pistilli B, Arsene O, Jouannaud C, Nguyen S, Cayre A, Tixier L, Mahier Ait Oukhatar C, Nabholtz JM, Penault-Llorca F, Mouret-Reynier MA. Neoadjuvant anthracycline-based (5-FEC) or anthracycline-free (docetaxel/carboplatin) chemotherapy plus trastuzumab and pertuzmab in HER2 + BC patients according to their TOP2A: a multicentre, open-label, non-randomized phase II trial. Breast Cancer Res Treat. 2024 Jun;205(2):267-279. doi: 10.1007/s10549-024-07285-y. Epub 2024 Mar 7.

Reference Type: DERIVED

PMID: 38453781 (View on PubMed)

Other Identifiers

GEP13

Identifier Type: -

Identifier Source: org_study_id