6 Weeks Treatment of Locally Advanced Breast Cancer With BIBW 2992 (Afatinib) or Lapatinib or Trastuzumab

Study Overview
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Brief Summary
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An open-label, randomized three-arm Phase II trial to explore the efficacy of BIBW 2992 as a single agent versus lapatinib versus trastuzumab in patients with HER2-positive treatment-naïve Stage IIIa locally advanced breast cancer. Additional information will be obtained on the safety profile and pharmacokinetics of BIBW 2992.

Official Title
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Randomised Phase II Study of Neoadjuvant BIBW 2992 Versus Herceptin Versus Lapatinib in Her2 Positive Breast Cancer Patients

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: lapatinib
* Drug: BIBW 2992
* Drug: trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Female, age 18 years or older. Histologically proven breast cancer who have not received any prior therapy. Locally advanced disease Stage IIIa with no evidence of distant metastatic disease other than anatomical site lymph nodes. HER2-positive. Exclusion criteria: Absolute neutrophil count (ANC) less than 1500/mm3. Platelet count less than 100 000/ mm3. Hemoglobin level less than 9.0 g/dl. Bilirubin greater than 1.5 mg/dI. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than twice the upper limit of normal. Serum creatinine greater than 1.5 times of the upper normal limit. Significant or recent acute gastrointestinal disorders with diarrhea Pregnancy or breast-feeding. Organ system dysfunction including cardiac (LVEF < 50%). Prior chemotherapy, radiotherapy or hormone therapy. Previous treatment with trastuzumab, EGFR, or EGFR/HER2-inhibitors. Other malignancies diagnosed within the past five years. Serious active infection. HIV, active hepatitis B or C.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992<br>BIBW 2992 high dose once daily (allowed dose reduction to medium or low once daily in case of AE) | Drug: BIBW 2992<br>* BIBW 2992 high dose once daily (allowed dose reduction to medium or low once daily in case of AE)<br>|
| Active Comparator: Lapatinib<br>Lapatinib tablets 1500 mg daily. | Drug: lapatinib<br>* lapatinib tablets 1500 mg daily<br>|
| Active Comparator: Trastuzumab<br>Trastuzumab 4mg/kg i.v. week 1, followed by 2mg/kg i.v. weekly. | Drug: trastuzumab<br>* trastuzumab 4mg/kg i.v. week 1, followed by 2mg/kg i.v. weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | Objective response (complete or partial) was assessed according to RECIST 1.0 criteria. | Tumour assessments were performed at screening, day 22 and day 43. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved Clinical Benefit (CB) | CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status. | Tumour assessments were performed at screening, day 22 and day 43. | 
| Change From Baseline in the Diameter of the Primary Target Lesion. | Change was based on the primary lesion only rather that the sum of the target lesions as most patients had only one lesion. | 3 weeks or 6 weeks | 
| Plasma Concentration of Afatinib | Individual drug plasma concentrations of afatinib after multiple oral administrations at day 7 | Day 7 | 
| Changes in Biomarker in Tumour Biopsies | Changes in the biomarkers (Phospho-MAP-Kinase (MAPK), Total MAPK expression, EGFR, HER2, Phospho-EGFR and -HER2, Proliferation marker (Ki67 and p27), Apoptotic index (cleaved caspase 3), Phosphate and tensin homolog (PTEN), HER2 homodimerisation by HERmark assay and Phospho AKT) from biopsy tissue. | Screening, day 22, day 43 |