Clinical Trials /

Impact of Pegfilgrastim on Trastuzumab Anti-tumor Effect and ADCC in Operable HER2+ Breast Cancer Breast Cancer

NCT03571633

Description:

First preclinical data suggest that pegfilgrastim could constitute a potent adjuvant for immunotherapy with mAb possessing ADCC/ADCP properties as trastuzumab. Combined treatment of pegfilgrastim and trastuzumab should translate into an increased rate of pathological clinical response. Therefore the investigators' proposal is to evaluate the clinical and biological impact of pegfilgrastim in combination with trastuzumab + paclitaxel in HER2-positive early stage breast cancer patients. Breastimmune02 is a multicenter, randomized, open-label, Phase II trial. Operable HER2+ breast cancer patients previously treated with 4 cycles of standard adriamycine/cyclophosphamide (AC) chemotherapy will be randomized (1:1) to receive in the neoadjuvant setting:Arm A: weekly paclitaxel + trastuzumab (every 3 weeks, Q3W) + pegfilgrastim (Q3W) versus Arm B: weekly paclitaxel + trastuzumab (Q3W).Stratification criteria will be: cN0 versus cN1.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Impact of Pegfilgrastim on Trastuzumab Anti-tumor Effect and ADCC in Operable HER2+ Breast Cancer Breast Cancer
  • Official Title: A Multicenter, Randomized, Open-label, Phase II Trial Aiming to Evaluate the Impact of Pegfilgrastim on Trastuzumab Anti-tumor Effect and ADCC in Operable HER2 Positive Breast Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: ET17-057
  • SECONDARY ID: 2017-002069-22
  • NCT ID: NCT03571633

Conditions

  • HER2-positive Breast Cancer
  • Operable Breast Cancer

Interventions

DrugSynonymsArms
Trastuzumab + PaclitaxelPaclitaxel+Trastuzumab+Pegfilgrastim
PegfilgrastimNeulastaPaclitaxel+Trastuzumab+Pegfilgrastim

Purpose

First preclinical data suggest that pegfilgrastim could constitute a potent adjuvant for immunotherapy with mAb possessing ADCC/ADCP properties as trastuzumab. Combined treatment of pegfilgrastim and trastuzumab should translate into an increased rate of pathological clinical response. Therefore the investigators' proposal is to evaluate the clinical and biological impact of pegfilgrastim in combination with trastuzumab + paclitaxel in HER2-positive early stage breast cancer patients. Breastimmune02 is a multicenter, randomized, open-label, Phase II trial. Operable HER2+ breast cancer patients previously treated with 4 cycles of standard adriamycine/cyclophosphamide (AC) chemotherapy will be randomized (1:1) to receive in the neoadjuvant setting:Arm A: weekly paclitaxel + trastuzumab (every 3 weeks, Q3W) + pegfilgrastim (Q3W) versus Arm B: weekly paclitaxel + trastuzumab (Q3W).Stratification criteria will be: cN0 versus cN1.

Detailed Description

      The duration of the neoadjuvant treatment period is planned to be 12 weeks (4 cycles of 3
      weeks), except in case of Inacceptable toxicity, or Patient decision, or Withdrawal of
      consent, or Clinical/radiological signs of disease progression.This neoadjuvant treatment
      period will be ended with a short term safety visit (STSVNeo) to be scheduled 28 days after
      the last dose of study treatments (considering the latest study treatments administered).
      Following the STSVNeo, patients will undergo surgery as per usual practice and pathological
      response will be centrally assessed by a referent pathologist blinded for the treatment
      arms.Following surgery, all patients will be treated in the adjuvant setting with trastuzumab
      administered every 3 weeks for up to 12 months in both arms with clinical assessments every 3
      months (cf. Réseau régional de Cancérologie,
      http://espacecancer.sante-ra.fr/Pages/Accueil.aspx). In case of RH+ disease, endocrine
      therapy may be initiated as per standard treatment guidelines.This adjuvant treatment period
      is planned for a maximum of 12 months; except in case of Inacceptable toxicity, or Patient
      decision, or Withdrawal of consent, or Clinical/radiological signs of disease progression.
      All randomized and treated patients will be followed-up for relapse and survival for at least
      15 months post-randomization (i.e. 1 year post-surgery).

      A total of 90 patients will be randomized in the study. (45 per arm). All the data concerning
      the patients will be recorded in the electronic case report form (eCRF) throughout the study
      serious adverse event (SAE) reporting will be also paper-based by e-mail and/or Fax. The
      sponsor will perform the study monitoring and will help the investigators to conduct the
      study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local
      law requirements
    

Trial Arms

NameTypeDescriptionInterventions
Paclitaxel+Trastuzumab+PegfilgrastimExperimentalNEOADJUVANT TREATMENT PERIOD (up to 12 weeks) :Paclitaxel (80 mg/m2, weekly (D1, D8, D15), IV) + Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, IV OR 600mg, Q3W SC) + Pegfilgrastim (6 mg, Q3W, subcutaneously, the day after the trastuzumab + paclitaxel infusion (i.e. Day 2 of each cycle)). ADJUVANT TREATMENT PERIOD (up to 12 months) : Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, (IV) OR 600mg, Q3W SC)
  • Trastuzumab + Paclitaxel
  • Pegfilgrastim
Paclitaxel+TrastuzumabActive ComparatorNEOADJUVANT TREATMENT PERIOD (up to 12 weeks) :Paclitaxel (80 mg/m2, weekly (D1, D8, D15), IV) + Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, IV OR 600mg, Q3W SC). ADJUVANT TREATMENT PERIOD (up to 12 months) : Trastuzumab (a loading dose 8 mg/kg at C1D1 followed by 6 mg/kg Q3W, (IV) OR 600mg, Q3W SC)
  • Trastuzumab + Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Female patients aged ≥ 18 years at time of inform consent signature.

          -  Histologically proven HER2 positive breast cancer defined as 3+ staining intensity by
             immunohistochemistry (IHC) or a 2+ IHC staining intensity and HER2 gene amplification
             by FISH.Note: HER2 status will be determined as per institutional practice.

          -  Operable breast tumor with tumor size and staging: > 20 mm, cN0 or cN1, M0.

          -  No radiological sign of disease progression at time of randomisation.

          -  Patient previously treated by 4 cycles of AC or 3 to 4 cycles of FEC without febrile
             neutropenia and without prior pegfilgrastim treatment.

          -  Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumor
             specimen from initial diagnosis (i.e. an archival paraffin block is preferred; or at
             least 20 unstained slides) with its histological report.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Adequate organ function as defined by the following lab tests (to be carried out
             within 7 days prior C1D1):Bone marrow (Absolute neutrophil count ≥ 1.5 x 109/L,
             Platelet count > 100 x 109/L, (without transfusion within 21 days prior to C1D1),
             Hemoglobin value ≥ 9 g/dL), Renal function (Calculated creatinine clearance by MDRD or
             CKD-EPI >50 mL/min/1.73m2 or serum creatinine < 1.5ULN), Liver function (Alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3ULN, Total serum
             bilirubin ≤ 1.5 ULN (except for patients with Gilbert disease for whom a total serum
             bilirubin ≤3 ULN is acceptable), Coagulation (INR and aPTT≤ 1.5 ULN)

          -  Adequate cardiac function with Mean resting corrected QT interval (QTc), calculated
             using Fridericia's formula, ≤470ms obtained from 3 electrocardiograms (ECGs) and
             Systolic blood pressure <160mmHg and Diastolic blood pressure <100mmHg (hypertension
             controlled by standard medical treatment is allowed)

          -  Women of childbearing potential (entering the study after a confirmed menstrual period
             and who have a negative pregnancy test within 7 days before C1D1) must agree to use
             two methods of medically acceptable forms of contraception from the date of negative
             pregnancy test to 3 months after the last study drug intake

          -  Patients should be able and willing to comply with study visits and procedures as per
             protocol

          -  Patients should understand, sign, and date the written voluntary informed consent form
             at the screening visit prior to any protocol-specific procedures performed.

          -  Patients must be covered by a medical insurance.

        Exclusion Criteria:

          -  Patients with inflammatory breast cancer.

          -  Previous exposure to pegfilgrastim or trastuzumab. Note: the use of filgrastim (non
             pegylated form only) is authorized prior to the randomisation.

          -  Patients requiring the concomitant use of any forbidden treatment including: Any other
             anti-cancer treatments not listed in the protocol, including chemotherapy,
             radiotherapy, immunotherapy, targeted therapy or biologic therapy for cancer
             treatment, Any investigational treatment.

          -  Any contra-indication to trastuzumab, paclitaxel, and pegfilgrastim respective SPCs
             including:Hypersensitivity to trastuzumab, murine proteins, or to any of the
             excipients listed in trastuzumab SPC, Severe dyspnea at rest due to complications of
             advanced malignancy or requiring supplementary oxygen therapy, Hypersensitivity to
             pegfilgrastim or filgrastim, or to any of the excipients listed in SPC, Hereditary
             problems of fructose intolerance, Hypersensitivity to paclitaxel or to any excipient,
             particularly macrogolglycerol ricinoleate, Patients with history of or active cardiac
             disease including myocardial infarction (MI), angina pectoris requiring medical
             treatment, congestive heart failure NYHA (New York Heart Association) Class ≥II, other
             cardiomyopathy, cardiac arrhythmia requiring medical treatment, clinically significant
             cardiac valvular disease, and hemodynamic effective pericardial effusion.

          -  Active secondary malignancy unless this malignancy is not expected to interfere with
             the evaluation of study endpoints and is approved by the sponsor. Examples of the
             latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the
             cervix. Patients with a completely treated prior malignancy and no evidence of disease
             for ≥ 2 years are eligible.

          -  Pregnant or breast-feeding female patients.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response rate (pCR)
Time Frame:16 weeks after start of treatment
Safety Issue:
Description:Defined as ypT0 ypN0 or ypT0/is ypN0 after 12 weeks of treatment by trastuzumab + paclitaxel ± pegfilgrastim with ypT0/Tis ypN0 defined as absence of invasive cancer in the breast and axillary nodes in all surgically excised specimens.

Secondary Outcome Measures

Measure:Disease Free survival
Time Frame:At least 15 months following randomisation
Safety Issue:
Description:From the date of randomisation until the date of event defined as the first documented relapse after surgery or death from any cause.
Measure:Time to relapse
Time Frame:At least 15 months following randomisation
Safety Issue:
Description:From the time of treatment start until the first documented relapse
Measure:Overall survival
Time Frame:At least 15 months following randomisation
Safety Issue:
Description:From the date of randomisation to the date of death from any cause
Measure:Adverse events reporting
Time Frame:At least 15 months following randomisation
Safety Issue:
Description:Based mainly on the frequency of AE graded according to the common toxicity criteria grading system (CTCAE-V4.03).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Pegfilgrastim
  • Trastuzumab/Paclitaxel
  • Antibody-dependent cell-mediated cytotoxicity

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