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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

Tracking Information
First Submitted Date  ICMJE December 14, 2014
First Posted Date  ICMJE January 15, 2015
Last Update Posted Date November 7, 2017
Actual Study Start Date  ICMJE January 2015
Estimated Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 31, 2015)
Pathological complete response according to Chevallier classification [ Time Frame: 20 weeks ]
on surgical specimen and lymph nodes at the time of the surgery
Original Primary Outcome Measures  ICMJE
 (submitted: January 14, 2015)
Pathological complete response according to Chevallier classification [ Time Frame: 11 months ]
on surgical specimen and lymph nodes at the time of the surgery
Change History Complete list of historical versions of study NCT02339532 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2017)
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2015)
  • 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
  • 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
  • Clinical and radiological response according to the WHO criteria [ Time Frame: 6 weeks and 18 weeks ]
  • 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 ]
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Phase II Trial in Patients With T1c Operable, HER2-positive Breast Cancer According to TOP2A Status
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • 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.
  • Drug: Carboplatin
    CARBOPLATIN AUC 6 IV q3w
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: FEC100
    • Drug: Docetaxel
    • Drug: Trastuzumab
    • Drug: Pertuzumab
  • 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.

    Interventions:
    • Drug: Docetaxel
    • Drug: Trastuzumab
    • Drug: Pertuzumab
    • Drug: Carboplatin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 14, 2015)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Christine Orsini, PhD +33 (0)1 71 93 67 07 c-orsini@unicancer.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02339532
Other Study ID Numbers  ICMJE GEP13
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party UNICANCER
Study Sponsor  ICMJE UNICANCER
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marie-Ange MOURET REYNIER Centre Jean Perrin
PRS Account UNICANCER
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP