Clinical Trials /

Trastuzumab or Lapatinib Ditosylate in Treating Women With Early Breast Cancer

NCT01104571

Description:

RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trastuzumab or lapatinib ditosylate is more effective in treating women with early breast cancer. Update June 2013: Since the initial development of EPHOS-B in 2007 more evidence in relation to safety and efficacy of anti-HER2 therapies are now available, and in particular, a growing body of evidence that combinations of two anti-HER2 therapies are more effective than monotherapies. Therefore this study has been amended (PART 2) to a 1:1:2 ratio to control, perioperative trastuzumab or the combination of lapatinib and trastuzumab. PURPOSE: This randomized phase III trial is studying trastuzumab to see how well it works compared with lapatinib ditosylate (and in since June 2013 - compared with a combination of lapatinib and trastuzumab) in treating women with early breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Trastuzumab or Lapatinib Ditosylate in Treating Women With Early Breast Cancer
  • Official Title: Effect of Perioperative AntiHER-2 Therapy on Early Breast Cancer Study - Biological Phase (EPHOS-B)

Clinical Trial IDs

  • ORG STUDY ID: CDR0000669882
  • SECONDARY ID: ICR-CTSU-2008-10017
  • SECONDARY ID: UM-EPHOS-B
  • SECONDARY ID: CRUK-08-002
  • SECONDARY ID: MREC-09-H1208-52
  • SECONDARY ID: ISRCTN-15004993
  • SECONDARY ID: EUDRACT-2008-005466-30
  • SECONDARY ID: EU-21029
  • SECONDARY ID: GSK-ICR-CTSU-2008-10017
  • NCT ID: NCT01104571

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
trastuzumabPart 1: Trastuzumab
lapatinib ditosylatePart 1: lapatinib

Purpose

RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trastuzumab or lapatinib ditosylate is more effective in treating women with early breast cancer. Update June 2013: Since the initial development of EPHOS-B in 2007 more evidence in relation to safety and efficacy of anti-HER2 therapies are now available, and in particular, a growing body of evidence that combinations of two anti-HER2 therapies are more effective than monotherapies. Therefore this study has been amended (PART 2) to a 1:1:2 ratio to control, perioperative trastuzumab or the combination of lapatinib and trastuzumab. PURPOSE: This randomized phase III trial is studying trastuzumab to see how well it works compared with lapatinib ditosylate (and in since June 2013 - Part 2 - compared with a combination of lapatinib and trastuzumab) in treating women with early breast cancer.

Detailed Description

      OBJECTIVES:

      Primary

        -  To determine whether pre-operative treatment of HER-2 positive breast cancer patients
           with anti-HER2 therapy consisting of trastuzumab (Herceptin®) vs lapatinib ditosylate
           inhibits proliferation or increases apoptosis.

        -  To compare the effects of trastuzumab (Herceptin®), lapatinib ditosylate and the
           combination of lapatinib ditosylate and trastuzumab (Herceptin®) on the inhibition of
           proliferation or increase of apoptosis

      Secondary

        -  To determine whether pre-operative anti-HER2 treatment reduces serum angiogenic factors.

        -  To identify molecular predictors of biological response to anti-HER2 therapy

      OUTLINE:

      This is a multicenter study.Patients are stratified according to center. Patients are
      randomized to 1 of 3 treatment arms.

      PART 1: From Protocol versions 1 to 4:

        -  Arm I (control): Patients receive no neoadjuvant or adjuvant therapy. Approximately 14
           days after randomization, patients undergo either breast-conservation surgery or
           mastectomy.

        -  Arm II (trastuzumab [Herceptin®]): Patients receive neoadjuvant trastuzumab IV over 90
           minutes on days 1 and 8. Approximately 11 days after beginning of neoadjuvant therapy,
           patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant
           trastuzumab on day 15.

        -  Arm III (lapatinib ditosylate): Patients receive neoadjuvant oral lapatinib ditosylate
           once daily on days 1-11. Within 24 hours after completion of neoadjuvant therapy,
           patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant
           lapatinib ditosylate once daily on days 12-28.

      Patients also receive standard adjuvant systemic therapy, including endocrine therapy (for
      hormone-sensitive disease) and/or chemotherapy and radiotherapy.

      PART 2: From Protocol Version 5 (June 2013)

        -  Arm I (control): Patients receive no neoadjuvant or adjuvant therapy. Approximately 14
           days after randomization, patients undergo either breast-conservation surgery or
           mastectomy.

        -  Arm II (trastuzumab [Herceptin®]): Patients receive neoadjuvant trastuzumab IV over 90
           minutes on days 1 and 8. Approximately 11 days after beginning of neoadjuvant therapy,
           patients undergo either breast-conservation surgery or mastectomy, and receive adjuvant
           trastuzumab on day 15.

        -  Arm III (lapatinib ditosylate and (trastuzumab [Herceptin®] combination): Patients
           receive oral lapatinib ditosylate once daily on days 1-11. Within 24 hours after
           completion of neoadjuvant therapy, patients undergo either breast-conservation surgery
           or mastectomy, and receive adjuvant lapatinib ditosylate once daily on days 12-28.
           Patients also receive neoadjuvant trastuzumab IV over 90 minutes on days 1 and 8 and
           receive adjuvant trastuzumab on day 15.

      PART 1 and 2:

      Patients also receive standard adjuvant systemic therapy, including endocrine therapy (for
      hormone-sensitive disease) and/or chemotherapy and radiotherapy.

      All patients undergo blood and tissue sample collection periodically for biomarker research
      studies comprising biomarkers of proliferation, apoptosis, and angiogenesis.

      After completion of study treatment, patients are followed up every 6 months for 2 years and
      then annually for 10 years.

      Peer Reviewed and Funded or Endorsed by Cancer Research UK
    

Trial Arms

NameTypeDescriptionInterventions
Part 1: ControlOtherNo peri-operative therapy given
    Part 1: TrastuzumabExperimentalTrastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery.
      Part 1: lapatinibExperimentalLapatinib 1500mg/day p.o. continuously for 28 days. Should start 11 days (+2 or -1 day) before the scheduled surgery
      • lapatinib ditosylate
      Part 2: ControlOtherNo peri-operative therapy
        Part 2: TrastuzumabExperimentalTrastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery.
          Part 2: lapatinib- trastuzumab combinationExperimentalLapatinib 1000mg/day p.o. continuously for 28 days, in combination with trastuzumab 6mg/kg iv given on days 1 & 8 pre-surgery & one dose of 2mg/kg iv between days 15-19 post surgery. Both drugs should start 11 days (+2 or -1 day) before the scheduled surgery.
          • lapatinib ditosylate

          Eligibility Criteria

                  DISEASE CHARACTERISTICS:
          
                    -  Histologically confirmed (by core biopsy) invasive breast cancer
          
                         -  Newly diagnosed disease
          
                         -  Resectable disease
          
                    -  HER2-positive disease, defined as 3+ measured by IHC or gene amplification by
                       fluorescent in situ hybridization (FISH)
          
                    -  No evidence of metastatic disease (T4 category) or suspicion of distant metastases
          
                    -  No inflammatory breast cancer
          
                    -  Planned surgery within 1 month of diagnosis, and willing to undergo adjuvant
                       chemotherapy and trastuzumab post-surgery
          
                    -  Must consent to donation of tissue and blood samples
          
                    -  Hormone receptor status known
          
                         -  Estrogen receptor-positive patients on hormone replacement therapy (HRT) must
                            either continue HRT or must not have taken HRT within the past 3 weeks
          
                         -  Estrogen receptor-negative patients may enter the trial whether or not they have
                            taken HRT within the past 3 weeks
          
                  PATIENT CHARACTERISTICS:
          
                    -  Menopausal status not specified
          
                    -  ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
          
                    -  Serum creatinine < 2 times upper limit of normal (ULN) OR creatinine clearance > 30
                       mg/dL
          
                    -  Bilirubin < 2 times ULN
          
                    -  Not pregnant or nursing
          
                    -  Negative pregnancy test
          
                    -  Fertile patients must use effective non-hormonal contraception
          
                    -  LVEF ≥ 55% by echocardiography or MUGA
          
                    -  No clinically significant cardiac abnormalities or uncontrolled hypertension
          
                    -  No prior myocardial infarction, heart failure, or significant angina
          
                    -  No prior cancer at any other site that has been treated within the past 6 months
                       (except basal cell carcinoma or cervical carcinoma in situ)
          
                    -  No current active hepatic or biliary disease (except Gilbert syndrome, asymptomatic
                       gallstones, liver metastases, or stable chronic liver disease, per investigator
                       assessment)
          
                    -  No impaired gastrointestinal function that would sufficiently reduce lapatinib
                       ditosylate absorption
          
                    -  No known immediate or delayed hypersensitivity or reaction to drugs chemically related
                       to trastuzumab or lapatinib ditosylate
          
                    -  No altered mental state that would preclude obtaining written informed consent
          
                  PRIOR CONCURRENT THERAPY:
          
                    -  See Disease Characteristics
          
                    -  No prior trastuzumab (Herceptin®) therapy within the past 3 months
          
                    -  No prior local cancer treatment (e.g., radiotherapy)
          
                    -  No other concurrent investigational agent or anticancer therapy
          
                    -  No use of herbal (alternative) therapies within 1 day of study entry (vitamin and/or
                       mineral supplements allowed)
          
                    -  No regular use of systemic steroids or other agents that could influence study
                       endpoints (inhaled steroids allowed)
          
                    -  No grapefruit and grapefruit juice for the duration of the study
          
                    -  At least 14 days since prior and no concurrent CYP3A4 inducers
          
                    -  At least 7 days since prior and no concurrent CYP3A4 inhibitors
          
                    -  At least 6 months since prior and no concurrent amiodarone
                
          Maximum Eligible Age:N/A
          Minimum Eligible Age:18 Years
          Eligible Gender:Female
          Healthy Volunteers:No

          Primary Outcome Measures

          Measure:Increase in apoptosis, by change in the tumor (morphological apoptosis and activated caspase 3) measured at diagnosis and at surgery (biological phase)
          Time Frame:10-13 days
          Safety Issue:
          Description:

          Secondary Outcome Measures

          Measure:Changes in the angiogenic serum markers VEGF-A, VEGF R1, and CD105, measured at diagnosis, surgery (plus also tumor CD31) and 28-30 days post surgery (biological phase)
          Time Frame:TBC
          Safety Issue:
          Description:
          Measure:Pre-treatment and/or surgical expression of molecular markers (EGFR, Her-3, IGF1R, c-myc, AKT, p-ERK, pS6 inase, activated src, or truncated p95HER-2 expression)
          Time Frame:TBC
          Safety Issue:
          Description:
          Measure:Time to local recurrence (clinical phase)
          Time Frame:TBC
          Safety Issue:
          Description:
          Measure:Time to distant recurrence (clinical phase)
          Time Frame:TBC
          Safety Issue:
          Description:
          Measure:Overall survival (clinical phase)
          Time Frame:TBC
          Safety Issue:
          Description:

          Details

          Phase:Phase 3
          Primary Purpose:Interventional
          Overall Status:Unknown status
          Lead Sponsor:Institute of Cancer Research, United Kingdom

          Trial Keywords

          • HER2-positive breast cancer
          • stage IA breast cancer
          • stage IB breast cancer
          • stage II breast cancer
          • stage IIIA breast cancer
          • estrogen receptor-negative breast cancer
          • estrogen receptor-positive breast cancer

          Last Updated

          May 27, 2014