Breast Neoplasms
Conditions
Brief summary
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.
Interventions
DRUGlapatinib
lapatinib tablets 1500 mg daily
DRUGBIBW 2992
BIBW 2992 high dose once daily (allowed dose reduction to medium or low once daily in case of AE)
DRUGtrastuzumab
trastuzumab 4mg/kg i.v. week 1, followed by 2mg/kg i.v. weekly
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female, age 18 years or older. 2. Histologically proven breast cancer who have not received any prior therapy. 3. Locally advanced disease Stage IIIa with no evidence of distant metastatic disease other than anatomical site lymph nodes. 4. HER2-positive.
Exclusion criteria
1. Absolute neutrophil count (ANC) less than 1500/mm3. 2. Platelet count less than 100 000/ mm3. 3. Hemoglobin level less than 9.0 g/dl. 4. Bilirubin greater than 1.5 mg/dI. 5. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than twice the upper limit of normal. 6. Serum creatinine greater than 1.5 times of the upper normal limit. 7. Significant or recent acute gastrointestinal disorders with diarrhea 8. Pregnancy or breast-feeding. 9. Organ system dysfunction including cardiac (LVEF \< 50%). 10. Prior chemotherapy, radiotherapy or hormone therapy. Previous treatment with trastuzumab, EGFR, or EGFR/HER2-inhibitors. 11. Other malignancies diagnosed within the past five years. 12. Serious active infection. HIV, active hepatitis B or C.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) | Tumour assessments were performed at screening, day 22 and day 43. | Objective response (complete or partial) was assessed according to RECIST 1.0 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Clinical Benefit (CB) | Tumour assessments were performed at screening, day 22 and day 43. | CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status. |
| Change From Baseline in the Diameter of the Primary Target Lesion. | 3 weeks or 6 weeks | Change was based on the primary lesion only rather that the sum of the target lesions as most patients had only one lesion. |
| Plasma Concentration of Afatinib | Day 7 | Individual drug plasma concentrations of afatinib after multiple oral administrations at day 7 |
| Changes in Biomarker in Tumour Biopsies | Screening, day 22, day 43 | 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. |
Countries
Brazil, Colombia, Peru, United States
Participant flow
Recruitment details
Because of slow enrollment and a high screen-failure rate, recruitment became a challenge and the sponsor chose to terminate the trial prior to reaching the target enrollment of 120 patients.
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 50 mg Patients received continuous daily dosing with Afatinib 50 mg orally from Day 1 to Day 21 of each treatment course. 2 treatment courses were to be given in the trial. | 10 |
| Lapatinib 1500 mg Patients received continuous daily dosing with Lapatinib 1500 mg orally from Day 1 to Day 21 of each treatment course. 2 treatment courses were to be given in the trial. | 8 |
| Trastuzumab Patients received weekly trastuzumab infusions of 2 mg/kg following a loading dose of 4 mg/kg per SPC. 6 infusions were to be given over 2 treatment courses. | 11 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Afatinib 50 mg | Lapatinib 1500 mg | Trastuzumab | Total |
|---|---|---|---|---|
| Age, Continuous | 50.7 years STANDARD_DEVIATION 8.7 | 58.5 years STANDARD_DEVIATION 13.4 | 44.1 years STANDARD_DEVIATION 12.2 | 50.3 years STANDARD_DEVIATION 12.5 |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 11 Participants | 29 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 8 / 8 | 8 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 | 0 / 11 |
Outcome results
Primary
Objective Response (OR)
Objective response (complete or partial) was assessed according to RECIST 1.0 criteria.
Time frame: Tumour assessments were performed at screening, day 22 and day 43.
Population: Treated set (TS). TS consisted of all patients who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 50 mg | Objective Response (OR) | 80.0 Percentage of participants |
| Lapatinib 1500 mg | Objective Response (OR) | 75.0 Percentage of participants |
| Trastuzumab | Objective Response (OR) | 36.4 Percentage of participants |
Secondary
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.
Time frame: 3 weeks or 6 weeks
Population: TS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg | Change From Baseline in the Diameter of the Primary Target Lesion. | -27.5 millimeters | Standard Error 5.9 |
| Lapatinib 1500 mg | Change From Baseline in the Diameter of the Primary Target Lesion. | -31.0 millimeters | Standard Error 6.63 |
| Trastuzumab | Change From Baseline in the Diameter of the Primary Target Lesion. | -20.9 millimeters | Standard Error 5.63 |
Secondary
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.
Time frame: Screening, day 22, day 43
Population: TS. The small number of available biomarker samples in this study did not allow for a meaningful statistical analysis.
Secondary
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.
Time frame: Tumour assessments were performed at screening, day 22 and day 43.
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 50 mg | Number of Participants Who Achieved Clinical Benefit (CB) | 10 Participants |
| Lapatinib 1500 mg | Number of Participants Who Achieved Clinical Benefit (CB) | 8 Participants |
| Trastuzumab | Number of Participants Who Achieved Clinical Benefit (CB) | 11 Participants |
Secondary
Plasma Concentration of Afatinib
Individual drug plasma concentrations of afatinib after multiple oral administrations at day 7
Time frame: Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 50 mg | Plasma Concentration of Afatinib | 32.1 ng/mL | Geometric Coefficient of Variation 43 |