Phase I Open Label Trial to Assess Safety of BIBW 2992 (Afatinib) in Combination With Herceptin® in Patients With HER2-positive Advanced Breast Cancer.

Study Overview
=================
Brief Summary
-----------------
Study to determine the Maximum Tolerated dose of BIBW 2992 given in combination with Herceptin®

Official Title
-----------------
Phase I Open Label Trial to Assess Safety of BIBW 2992 in Combination With Herceptin® in Patients With HER2-positive Advanced Breast Cancer.

Conditions
-----------------
Breast Neoplasms

Intervention / Treatment
-----------------
* Drug: Trastuzumab
* Drug: BIBW 2992


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Female patients aged >18 years. Advanced or metastatic breast cancer that over-expresses HER2 (immunohistochemistry 3+ or 2+ and gene amplification by FISH). Prior treatment with Herceptin® or Lapatinib® (in the adjuvant or metastatic settings) is permitted but not required. Exclusion criteria: Patients with untreated or symptomatic brain metastases. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2 inhibiting drugs within the past four weeks before the start of therapy or concomitantly with this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992 + Trastuzumab<br>Find maximum tolerated dose of the non-marketed substance:BIBW 2992 given orally with fixed weekly infusion doses of 2mg/kg Herceptin. Escalating doses of BIBW 2992 starting at 20mg daily. | Drug: Trastuzumab<br>* Load: 4mg/kg-maintain:2mg/kg/week<br>Drug: BIBW 2992<br>* Increased dose cohorts from low dose to MTD<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLT) | Number of participants with DLT in the first cycle (28 days) for the determination of the maximum tolerated dose (MTD). Important Limitations and Caveats are provided in the respective section. | 28 days | 
| Maximum Tolerated Dose (MTD) of Afatinib in Combination With Herceptin(R) | The MTD was defined as the highest dose at which no more than 1 of 6 patients experienced DLT. It was determined using a standard 3 + 3 dose escalation cohort design. To confirm the MTD, the MTD cohort was to be expanded to 18 patients with no more than 3/18 patients experiencing a DLT. Please refer to CAVEATs and Limitations. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Objective Response (OR) | Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.1. OR is defined as complete response (CR) or partial response (PR). | Tumor assessment was performed at screening and every 2nd cycle until earliest time of progression, death or end of treatment. | 
| Number of Patients With Best Overall Response | Best overall response based on response evaluation criteria in solid tumors (RECIST) version 1.1. Best overall response is defined as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or not evaluable. | Tumor assessment was performed at screening and every 2nd cycle until earliest time of progression, death or end of treatment. | 
| Progression Free Survival (PFS) | PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by central independent review according to the response evaluation criteria in solid tumors (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates. | Baseline until disease progression, death or data cut-off. | 
| Summary of Concentration of Afatinib in Plasma | Pre-dose Concentrations of Afatinib in Plasma at Steady State on Days 8, 15 and 29 (Cpre,ss,8, Cpre,ss,15 and Cpre,ss,29) and Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss). | 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing | 
| Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state | 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing | 
| Summary of Concentration of Herceptin in Plasma | Pre-dose Concentrations of Herceptin in Plasma on Days 8, 15 and 29 (Cpre,8, Cpre,15 and Cpre,29) and Maximum Concentration of Herceptin in Plasma on Days 1, 15 and 29 (Cmax,1, Cmax,15 and Cmax,29). | 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing |