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

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ClinicalTrials.gov Identifier: NCT02339532
Recruitment Status : Recruiting
First Posted : January 15, 2015
Last Update Posted : November 7, 2017
Sponsor:
Information provided by (Responsible Party):
UNICANCER

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.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: FEC100 Drug: Docetaxel Drug: Trastuzumab Drug: Pertuzumab Drug: Carboplatin Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 2015
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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 escalading 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 escalading 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 escalading 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




Primary Outcome Measures :
  1. Pathological complete response according to Chevallier classification [ Time Frame: 20 weeks ]
    on surgical specimen and lymph nodes at the time of the surgery


Secondary Outcome Measures :
  1. Predictive factors of response to both treatment regimens (anthracycline-based and non anthracycline-based regimens) [ Time Frame: 20 weeks ]
    on surgical specimen and lymph nodes at the time of the surgery

  2. Pathological complete response (pCR), according to Sataloff's classification [ Time Frame: 20 weeks ]
    on surgical specimen and lymph nodes at the time of the surgery

  3. Clinical and radiological response according to the WHO criteria [ Time Frame: after two cycles of treatment and after the end of treatment ]
    on mammography and breast echography

  4. Toxicity according to NCI CTC-AE v4.0 criteria [ Time Frame: during on-treatment period (defined as the period from the first dose of study medication up to 30 days of the last dose ]
    accordiang the occurrence of adverse events and toxicities assessed every week

  5. Progression-free survival [ Time Frame: up to 60 months ]
    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.

  6. Overall survival [ Time Frame: up to 60 months ]
    The OS is defined as the time from the first administration of treatment to death from any cause.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02339532


Contacts
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Contact: Christine Orsini, PhD +33 (0)1 71 93 67 07 c-orsini@unicancer.fr

Locations
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France
Institut de Cancerologie de L'Ouest - Site Paul Papin Recruiting
Angers, France
Principal Investigator: Paule AUGEREAU         
Centre Hospitalier Regional Universitaire de Brest - Hôpital Morvan Recruiting
Brest, France
Principal Investigator: Pierre-François DUPRE         
Centre Francois Baclesse Recruiting
Caen, France
Principal Investigator: Christelle LEVY         
Centre Jean Perrin Recruiting
Clermont Ferrand, France
Principal Investigator: Marie-Ange MOURET REYNIER         
Centre Georges-Francois Leclerc Withdrawn
Dijon, France
Chu de Grenoble - Hopital Michallon Recruiting
Grenoble, France
Principal Investigator: Mireille MOUSSEAU         
Centre Jean Bernard - Clinique Victor Hugo Withdrawn
Le Mans, France
Centre Oscar Lambret Withdrawn
Lille, France
Chu de Limoges - Hôpital Dupuytren Recruiting
Limoges, France
Principal Investigator: Laurence VENAT BOUVET         
Centre Leon Berard Not yet recruiting
Lyon, France
Principal Investigator: Pierre-Etienne HEUDEL         
Institut Regional Du Cancer Montpellier Val D'Aurelle Recruiting
Montpellier, France
Principal Investigator: Véronique D'HONDT         
Institut de Cancerologie de L'Ouest - Site Rene Gauducheau Recruiting
Nantes-Saint Herblain, France
Principal Investigator: Mario CAMPONE         
Groupe Hospitalier Les Diaconesses - Croix Saint Simon Withdrawn
Paris, France
Hôpital Tenon Withdrawn
Paris, France
Hopital D'Instructions Des Armees Not yet recruiting
Saint-Mande, France
Principal Investigator: Serge CREMADES         
Institut de Cancerologie Lucien Neuwirth Withdrawn
Saint-priest-en-jarez, France
Centre Paul Strauss Recruiting
Strasbourg, France
Principal Investigator: Thierry PETIT         
Institut de Cancerologie de Lorraine Alexis Vautrin Recruiting
Vandoeuvre-les-Nancy, France
Principal Investigator: Elisabeth LUPORSI         
Sponsors and Collaborators
UNICANCER
Investigators
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Principal Investigator: Marie-Ange MOURET REYNIER Centre Jean Perrin

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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT02339532     History of Changes
Other Study ID Numbers: GEP13
First Posted: January 15, 2015    Key Record Dates
Last Update Posted: November 7, 2017
Last Verified: November 2017

Keywords provided by UNICANCER:
HER2-positive
non-metastatic
TOP2A

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carboplatin
Docetaxel
Trastuzumab
Pertuzumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological