Breast Neoplasms
Conditions
Brief summary
Study to determine the Maximum Tolerated dose of BIBW 2992 given in combination with Herceptin®
Interventions
DRUGTrastuzumab
Load: 4mg/kg-maintain:2mg/kg/week
DRUGBIBW 2992
Increased dose cohorts from low dose to MTD
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female patients aged \>18 years. 2. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLT) | 28 days | 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. |
| Maximum Tolerated Dose (MTD) of Afatinib in Combination With Herceptin(R) | 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline until disease progression, death or data cut-off. | 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. |
| Summary of Concentration of Afatinib in Plasma | 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing | 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). |
| Number of Patients With Objective Response (OR) | Tumor assessment was performed at screening and every 2nd cycle until earliest time of progression, death or end of treatment. | 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). |
| Summary of Concentration of Herceptin in Plasma | 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing | 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). |
| Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing | tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state |
| Number of Patients With Best Overall Response | Tumor assessment was performed at screening and every 2nd cycle until earliest time of progression, death or end of treatment. | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
This was an open-label dose escalation study using a standard 3+3 dose escalation design, dose cohorts are presented here.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 20mg + Herceptin Patients received continuous daily dosing with Afatinib 20mg film-coated tablets and once weekly an intravenous infusion of Herceptin (4 mg/kg single loading dose to be followed by 2 mg/kg/week i.v.) until disease progression or lack of clinical benefit. | 16 |
| Afatinib 30mg + Herceptin Patients received continuous daily dosing with Afatinib 30mg film-coated tablets and once weekly an intravenous infusion of Herceptin (4 mg/kg single loading dose to be followed by 2 mg/kg/week i.v.) until disease progression or lack of clinical benefit. | 2 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Dose limiting toxicity | 6 | 0 |
| Overall Study | Other Adverse Event | 1 | 0 |
| Overall Study | Progressive Disease | 6 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Afatinib 20mg + Herceptin | Afatinib 30mg + Herceptin | Total |
|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 10.6 | 52.5 years STANDARD_DEVIATION 6.4 | 61.2 years STANDARD_DEVIATION 10.6 |
| Sex: Female, Male Female | 16 Participants | 2 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 16 | 2 / 2 |
| serious Total, serious adverse events | 3 / 16 | 0 / 2 |
Outcome results
Primary
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.
Time frame: 28 days
Population: TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib. 3 patients were excluded as they were not evaluable for determination of maximum tolerated dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20mg + Herceptin | Maximum Tolerated Dose (MTD) of Afatinib in Combination With Herceptin(R) | 20 mg |
Primary
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.
Time frame: 28 days
Population: Treated set (TS). TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib. 3 patients were excluded as they were not evaluable for determination of maximum tolerated dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20mg + Herceptin | Number of Participants With Dose Limiting Toxicities (DLT) | 4 Participants |
| Afatinib 30mg + Herceptin | Number of Participants With Dose Limiting Toxicities (DLT) | 2 Participants |
Secondary
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.
Time frame: Tumor assessment was performed at screening and every 2nd cycle until earliest time of progression, death or end of treatment.
Population: TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 20mg + Herceptin | Number of Patients With Best Overall Response | Partial Response | 2 Participants |
| Afatinib 20mg + Herceptin | Number of Patients With Best Overall Response | Progressive Disease | 0 Participants |
| Afatinib 20mg + Herceptin | Number of Patients With Best Overall Response | Stable Disease | 4 Participants |
| Afatinib 20mg + Herceptin | Number of Patients With Best Overall Response | Not evaluable | 10 Participants |
| Afatinib 20mg + Herceptin | Number of Patients With Best Overall Response | Complete Response | 0 Participants |
| Afatinib 30mg + Herceptin | Number of Patients With Best Overall Response | Not evaluable | 0 Participants |
| Afatinib 30mg + Herceptin | Number of Patients With Best Overall Response | Complete Response | 0 Participants |
| Afatinib 30mg + Herceptin | Number of Patients With Best Overall Response | Partial Response | 0 Participants |
| Afatinib 30mg + Herceptin | Number of Patients With Best Overall Response | Stable Disease | 1 Participants |
| Afatinib 30mg + Herceptin | Number of Patients With Best Overall Response | Progressive Disease | 1 Participants |
Secondary
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).
Time frame: Tumor assessment was performed at screening and every 2nd cycle until earliest time of progression, death or end of treatment.
Population: TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20mg + Herceptin | Number of Patients With Objective Response (OR) | 2 Participants |
| Afatinib 30mg + Herceptin | Number of Patients With Objective Response (OR) | 0 Participants |
Secondary
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.
Time frame: Baseline until disease progression, death or data cut-off.
Population: TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg + Herceptin | Progression Free Survival (PFS) | 113.0 Days |
| Afatinib 30mg + Herceptin | Progression Free Survival (PFS) | 83.5 Days |
Secondary
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).
Time frame: 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing
Population: Patients with no data available for the relevant parameter and dose were excluded from analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib 20mg + Herceptin | Summary of Concentration of Afatinib in Plasma | Cpre,ss,8 (N=11) | 9.75 ng/mL | Geometric Coefficient of Variation 69.5 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Afatinib in Plasma | Cpre,ss,15 (N=13) | 9.94 ng/mL | Geometric Coefficient of Variation 72.4 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Afatinib in Plasma | Cpre,ss,29 (N=8) | 9.15 ng/mL | Geometric Coefficient of Variation 64.7 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Afatinib in Plasma | Cmax,ss (N=10) | 17.9 ng/mL | Geometric Coefficient of Variation 80.9 |
Secondary
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).
Time frame: 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing
Population: Patients with no data available for the relevant parameter and dose were excluded from analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Afatinib 20mg + Herceptin | Summary of Concentration of Herceptin in Plasma | Cpre,8 (N=14) | 43600 ng/mL | Geometric Coefficient of Variation 53.9 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Herceptin in Plasma | Cpre,15 (N=13) | 47200 ng/mL | Geometric Coefficient of Variation 47 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Herceptin in Plasma | Cpre,29 (N=11) | 46200 ng/mL | Geometric Coefficient of Variation 30.9 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Herceptin in Plasma | Cmax,1 (N=14) | 122000 ng/mL | Geometric Coefficient of Variation 27.9 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Herceptin in Plasma | Cmax,15 (N=12) | 93000 ng/mL | Geometric Coefficient of Variation 24.9 |
| Afatinib 20mg + Herceptin | Summary of Concentration of Herceptin in Plasma | Cmax,29 (N=7) | 93200 ng/mL | Geometric Coefficient of Variation 16.9 |
Secondary
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
Time frame: 0.05 hours (h) before dosing and 0.5-1h, 2h, 3h, 4h, 5h, 6h, 8h after dosing
Population: Patients with no data available for the relevant parameter and dose were excluded from analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg + Herceptin | Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) | 4.25 hours |