Neoplasms
Conditions
Brief summary
* To identify the Maximum Tolerated Dose (MTD) of afatinib in combination with vinorelbine i.v. by assessment of Dose Limiting Toxicities (DLT); * To assess safety and anti-tumour efficacy and determine pharmacokinetic characteristics of afatinib and vinorelbine i.v.
Interventions
DRUGafatinib 20mg
patient to receive afatinib low dose po daily in combination with vinorelbine iv
DRUGafatinib 40mg
patient to receive afatinib high dose po daily in combination with vinorelbine iv
DRUGvinorelbine IV 25 or 20mg/m2
patient to receive standard dose vinorelbine once a week for four times per cycle
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of malignancy that is advanced and for which standard therapies do not exist or are no longer effective. * Life expectancy at least 12 weeks * Eastern Cooperative Oncology Group Performance Status 0 or 1 * Adequate hepatic, renal, haematologic and other organ function * Written informed consent
Exclusion criteria
* Chemotherapy, immunotherapy, surgery and radiotherapy within the past 4 weeks * Prior treatment with afatinib and or vinorelbine * Clinically significant active infectious disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities (DLTs) During 1st Course | during 1st course | DLTs and Maximum Tolerated Dose (MTD) of afatinib in combination with vinorelbine iv. (MTD = not determined) |
| Drug-related Adverse Events | during the treatment period or up to 28 days after the completion of drug administration, up to 730 days | Number of patients with drug-related adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-∞ for Vinorelbine | predose, 10minutes, 0.5, 1, 4, 7 hours, 23hours55minutes after 2nd or 3rd or 4th dose (as with afatinib) and 1st dose (as without afatinib) | area under the blood concentration-time curve of the analyte over the time interval from 0 extrapolated to infinity |
| AUCτ,ss for Afatinib | pre-dose, 1, 2, 3, 4, 6, 7hours, and 23hours55minutes after 7th or 14th or 21th dose (as with Vinorelbine) and 20th dose (as without Vinorelbine) | area under the plasma concentration-time curve following dose at steady state over the dosing interval τ |
| Objective Tumour Response | Pre-treatment, every 8 weeks after start of study treatment, end of treatment | According to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and assessed by CT or MRI: Complete Response (CR), disappearance of all target and non-target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Cmax for Vinorelbine | predose, 10minutes, 0.5, 1, 4, 7 hours, 23hours55minutes after 2nd or 3rd or 4th dose (as with afatinib) and 1st dose (as without afatinib) | maximum measured blood concentration |
| Cmax,ss for Afatinib | pre-dose, 1, 2, 3, 4, 6, 7hours, and 23hours55minutes after 7th or 14th or 21th dose (as with Vinorelbine) and 20th dose (as without Vinorelbine) | maximum measured plasma concentration at steady state |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) Afatinib 20 mg oral administration once a day with vinorelbine 25 mg/m\^2 intravenous injection weekly | 3 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) Afatinib 40 mg oral administration once a day with vinorelbine 25 mg/m\^2 intravenous injection weekly | 5 |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) Afatinib 40 mg oral administration once a day with vinorelbine 20 mg/m\^2 intravenous injection weekly | 3 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) Afatinib 40 mg oral administration once a day with vinorelbine 25 mg/m\^2 intravenous injection weekly; allowed for vinorelbine dose to be skipped for Common Toxicity Criteria for Adverse Effects (CTCAE) Grade 2 or worse neutropenia or thrombocytopenia | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Dose limiting toxicity | 0 | 2 | 0 | 0 |
| Overall Study | Other adverse events | 0 | 1 | 1 | 1 |
| Overall Study | Progressive disease | 2 | 2 | 2 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 2 | 58.8 years STANDARD_DEVIATION 4.1 | 52.7 years STANDARD_DEVIATION 11.8 | 52.3 years STANDARD_DEVIATION 11 | 56.2 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 3 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 2 / 3 | 4 / 5 | 0 / 3 | 2 / 6 |
Outcome results
Primary
Drug-related Adverse Events
Number of patients with drug-related adverse events
Time frame: during the treatment period or up to 28 days after the completion of drug administration, up to 730 days
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | Drug-related Adverse Events | 3 participants |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | Drug-related Adverse Events | 5 participants |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | Drug-related Adverse Events | 3 participants |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | Drug-related Adverse Events | 6 participants |
Primary
Number of Patients With Dose Limiting Toxicities (DLTs) During 1st Course
DLTs and Maximum Tolerated Dose (MTD) of afatinib in combination with vinorelbine iv. (MTD = not determined)
Time frame: during 1st course
Population: Treated set: all patients who received at least 1 dose of investigational medication (afatinib or vinorelbine)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | Number of Patients With Dose Limiting Toxicities (DLTs) During 1st Course | 0 participants |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | Number of Patients With Dose Limiting Toxicities (DLTs) During 1st Course | 3 participants |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | Number of Patients With Dose Limiting Toxicities (DLTs) During 1st Course | 0 participants |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | Number of Patients With Dose Limiting Toxicities (DLTs) During 1st Course | 1 participants |
Secondary
AUC0-∞ for Vinorelbine
area under the blood concentration-time curve of the analyte over the time interval from 0 extrapolated to infinity
Time frame: predose, 10minutes, 0.5, 1, 4, 7 hours, 23hours55minutes after 2nd or 3rd or 4th dose (as with afatinib) and 1st dose (as without afatinib)
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | AUC0-∞ for Vinorelbine | 763 ng*h/mL | Geometric Coefficient of Variation 30.5 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | AUC0-∞ for Vinorelbine | 691 ng*h/mL | Geometric Coefficient of Variation 18.8 |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | AUC0-∞ for Vinorelbine | 934 ng*h/mL | Geometric Coefficient of Variation 24.9 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | AUC0-∞ for Vinorelbine | 860 ng*h/mL | Geometric Coefficient of Variation 21.2 |
Secondary
AUCτ,ss for Afatinib
area under the plasma concentration-time curve following dose at steady state over the dosing interval τ
Time frame: pre-dose, 1, 2, 3, 4, 6, 7hours, and 23hours55minutes after 7th or 14th or 21th dose (as with Vinorelbine) and 20th dose (as without Vinorelbine)
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | AUCτ,ss for Afatinib | 329 ng*h/mL | Geometric Coefficient of Variation 79.5 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | AUCτ,ss for Afatinib | 404 ng*h/mL | Geometric Coefficient of Variation 63.9 |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | AUCτ,ss for Afatinib | 866 ng*h/mL | Geometric Coefficient of Variation 55.3 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | AUCτ,ss for Afatinib | 1010 ng*h/mL | Geometric Coefficient of Variation 70.1 |
Secondary
Cmax for Vinorelbine
maximum measured blood concentration
Time frame: predose, 10minutes, 0.5, 1, 4, 7 hours, 23hours55minutes after 2nd or 3rd or 4th dose (as with afatinib) and 1st dose (as without afatinib)
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | Cmax for Vinorelbine | 1120 ng/mL | Geometric Coefficient of Variation 23 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | Cmax for Vinorelbine | 1380 ng/mL | Geometric Coefficient of Variation 8.73 |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | Cmax for Vinorelbine | 1160 ng/mL | Geometric Coefficient of Variation 36.4 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | Cmax for Vinorelbine | 1330 ng/mL | Geometric Coefficient of Variation 25.3 |
Secondary
Cmax,ss for Afatinib
maximum measured plasma concentration at steady state
Time frame: pre-dose, 1, 2, 3, 4, 6, 7hours, and 23hours55minutes after 7th or 14th or 21th dose (as with Vinorelbine) and 20th dose (as without Vinorelbine)
Population: Treated set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | Cmax,ss for Afatinib | 28.8 ng/mL | Geometric Coefficient of Variation 87.3 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | Cmax,ss for Afatinib | 19.6 ng/mL | Geometric Coefficient of Variation 50.6 |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | Cmax,ss for Afatinib | 52.5 ng/mL | Geometric Coefficient of Variation 46.8 |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | Cmax,ss for Afatinib | 57.1 ng/mL | Geometric Coefficient of Variation 76.4 |
Secondary
Objective Tumour Response
According to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and assessed by CT or MRI: Complete Response (CR), disappearance of all target and non-target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Pre-treatment, every 8 weeks after start of study treatment, end of treatment
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20 mg With Vinorelbine 25 mg/m^2 (Cohort 1) | Objective Tumour Response | 0 participants |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 2) | Objective Tumour Response | 0 participants |
| Afatinib 40 mg With Vinorelbine 20 mg/m^2 (Cohort 2a) | Objective Tumour Response | 1 participants |
| Afatinib 40 mg With Vinorelbine 25 mg/m^2 (Cohort 3) | Objective Tumour Response | 1 participants |