Overview

Background Information and Rationale:

Trastuzumab is a humanized monoclonal antibody that acts extracellularly on the erbB-2 receptor.Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2/erbB-2),which has shown in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress erbB-2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on erbB-2 overexpressing cancer cells compared with cancer cells that do not overexpress erbB-2. Trastuzumab has emerged as a widely accepted standard of care for erbB-2-positive disease. (Metastatic/ adjuvant/neoadjuvant.

Our current hypothesis suggests that the cells which are disseminated at the time of surgery will encounter an inhospitable environment which will be anti-HER in nature. Therefore combining the above mentioned streams of thought, we would like to assess the effect of a short pre-operative course of Trastuzumab on breast cancer relapse. The study is proposed in HER2 positive patients with operable breast cancer.

Objectives :

Primary

The primary objective of the study is to see the effect of short duration of peri-operative Trastuzumab on disease-free survival in comparison in all patients

Secondary

The safety of the pre-operative therapies including the early post operative morbidity

1. Overall survival (OS) in all patients and in pathologically node positive patients.
2. The level of circulating tumor cells (CTCs) in the peripheral blood assessed before starting pre-operative therapy and at the same time point in the control arm, level of CTCs 10 minutes prior to start of surgery, during surgery and 10 days after surgery on 40 consecutive consenting patients (20 in each arm). The levels of circulating chromatin will also be estimated at the same time points as CTC for these 40 patients.
3. Evaluation of the paraffin blocks for pTEN loss6-8 and p95ErbB2 truncated form of HER2 on 100 consecutive consenting patients (50 in each arm).9-11

Study Design :

This is phase 3, randomized Double blinded parallel group study of Trastuzumab in pre operative setting in operable breast cancer patients.

Approximately 1000 patients with Women with HER2neu positive, T1/T2/T3 and N0/N1. clinical T4 and/or N2 disease who are considered operable by the treating surgeon with histopathological diagnosis on core biopsies, will be included in the study. Patients with T4 or N2 (locally advanced and large operable for neo-adjuvant chemotherapy) will not be included. All node positive patients will receive single injection of Depot Inj. Progesterone 500 mg deep IM 4 -14 days prior to surgery

Patients will be stratified, before randomization for Tumor size, menopausal status, and affordability for Trastuzumab and centre of the study. These patients will then be randomized 1:1 to receive the following

Intervention arm: .A single dose of Trastuzumab (Herceptin, Hoffman La Roche) at 8 mg/Kg as a 90 minute intravenous infusion in 250 ml of normal saline, in the window period of 10-15 4 to 14 days (both days inclusive) prior to the planned date of surgery.

Control arm: A 90 minute intravenous infusion of saline as placebo

All patients will thereafter receive standard post-operative adjuvant therapy as per local institutional practice including hormonal therapy, chemotherapy and radiation therapy.

Eligibility

Inclusion Criteria:a.

1. Female subjects aged 18 years or older.
2. Histologically and/or cytologically confirmed diagnosis of breast cancer. Clinical stages breast cancer: HER2 positive, T1 or T2 or T3, N0 or N1, resectable T4, or resectable N2, (all M0)
3. Documentation of erbB-2 gene amplification by FISH (as defined by a ratio >2.2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer's kit instruction) or documentation of erbB-2-overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory.
4. LVEF within institutional range of normal as measured by MUGA or ECHO.
5. Screening laboratory values within the following parameters:
   1. Absolute neutrophil count (ANC) ≥1.5 x 109 /L (1500/mm3)
   2. Platelet count ≥100 x 109/L (100,000/mm3)
   3. Hemoglobin ≥9.0 g/dL (90 g/L)
   4. Serum creatinine ≤1.5 x upper limit of normal (ULN)
   5. Total bilirubin ≤1.5 x ULN (<3 ULN if Gilbert's disease) 6Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
      • 2.5 x ULN

Exclusion Criteria:

1. Bilateral breast cancer
2. Active uncontrolled cardiac disease, including cardiomyopathy, CHF (New York Heart Association [NYHA] functional classification of ≥3), unstable angina, and myocardial infarction (within 12 months of study entry).
3. Inadequately controlled hypertension (ie, systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg).
4. Family history of congenital long or short QT syndrome, Brugada syndrome or QT/QTc interval > 0.45 second or known history of QT/QTc prolongation or torsade de pointe (TdP).
5. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or grade ≥2 diarrhea of any etiology at baseline).
6. Women who are pregnant, breast-feeding.