Clinical Trials /

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

NCT02339532

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: GEP13
  • NCT ID: NCT02339532

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
FEC100TOP2A amplified
DocetaxelTOP2A amplified
TrastuzumabTOP2A amplified
PertuzumabTOP2A amplified
CarboplatinTOP2A not amplified

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
TOP2A amplifiedExperimentalIf 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
  • FEC100
  • Docetaxel
  • Trastuzumab
  • Pertuzumab
TOP2A not amplifiedExperimentalIf 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.
  • Docetaxel
  • Trastuzumab
  • Pertuzumab
  • Carboplatin

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.

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Predictive factors of response to both treatment regimens (anthracycline-based and non anthracycline-based regimens)
Time Frame:20 weeks
Safety Issue:
Description:on surgical specimen and lymph nodes at the time of the surgery
Measure:Pathological complete response (pCR), according to Sataloff's classification
Time Frame:20 weeks
Safety Issue:
Description:on surgical specimen and lymph nodes at the time of the surgery
Measure:Clinical and radiological response according to the WHO criteria
Time Frame:after two cycles of treatment and after the end of treatment
Safety Issue:
Description:on mammography and breast echography
Measure: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
Safety Issue:
Description:accordiang the occurrence of adverse events and toxicities assessed every week
Measure:Progression-free survival
Time Frame:up to 60 months
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:up to 60 months
Safety Issue:
Description:The OS is defined as the time from the first administration of treatment to death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNICANCER

Trial Keywords

  • HER2-positive
  • non-metastatic
  • TOP2A

Last Updated

November 6, 2017