Neoplasms
Conditions
Brief summary
To determine the maximum tolerated dose, safety, pharmacokinetics and anti-tumour efficacy of oral BIBW 2992 in combination with intravenous or oral vinorelbine
Interventions
DRUGBIBW 2992 low (20mg) dosage
Patients will receive 20mg dosage per day of BIBW 2992 plus standard dosage of vinorelbine.
DRUGBIBW 2992 medium (40mg) dosage
Patients will receive 40mg dosage per day of BIBW 2992 plus standard dosage of vinorelbine.
DRUGBIBW 2992 high (50mg) dosage
Patients will receive 50mg dosage of BIBW 2992 plus standard dosage of vinorelbine.
DRUGVinorelbine per os 60 mg/m²
Patients will receive 60 mg/m² Vinorelbine per os at J1 J8 and J15
DRUGVinorelbine per os 80 mg/m²
Patients will receive 80 mg/m² Vinorelbine per os at J22
Patients will receive 25 mg/m² of Vinorelbine i.v.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of malignancy that is now advanced, non resectable and/or metastatic * Tumours historically known to overexpress EGFR and/or HER2
Exclusion criteria
* Prior treatment with HER2 inhibiting drugs within the past 4 weeks before the start of therapy or concomitantly with this trial. * Prior treatment with EGFR inhibiting drugs within the past two weeks before the start of therapy or concomitantly with this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLT) | 28 days | Number of participants with DLT for the determination of the Maximum Tolerated Dose (MTD). 3+3 dose escalation design. MTD based on DLTs during first treatment course. After MTD was determined, additional patients were included at the MTD in an expansion cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Objective Response (OR) | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | OR is defined as confirmed complete response and confirmed partial response (PR) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). |
| Number of Patients With Disease Control (DC) | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | DC is defined as confirmed complete response (CR), partial response (PR) and stable disease (SD) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). |
| Time to Objective Response | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | The time to OR was the duration from the first treatment to the time when the measurement criteria for first documented confirmed CR and/or PR were met according to RECIST 1.0 criteria. |
| Duration of Objective Response | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | The duration of objective response was measured from the time of first documented confirmed CR or PR to the time of progressive disease or death, whichever occured earlier. |
| Duration of Disease Control | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | Duration of disease control was measured from the start of study treatment to the time of progression or death, whichever occured first. |
| Best Percentage Change in Tumour Size | Screening and every 8 weeks after starting of treatment, up to 44 weeks. | Best percentage change in tumour size was the best percentage change in the sum of diameters of target lesions and was calculated as (minimum sum of diameters post baseline - sum of diameters at baseline)/sum of diameters at baseline. Negative values indicate a decrease, positive values an increase. |
| Progression-free Survival (PFS) | From first dose of study medication to the occurrence of progression or death whichever came first, up to 44 months. | PFS was defined as the time from the first dose of study medication to the occurrence of tumour progression or death, whichever came first. It was assessed according to RECIST 1.0. Median time results from unstratified Kaplan-Meier estimates. |
| Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
| Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
| Number of Patients With Best Overall Response | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. | Overall response is defined as complete response, partial response and stable disease and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). Complete response (CR) and partial response (PR) had to be confirmed by a subsequent tumour assessment at least 28 days after the criteria for CR or PR were first met. To confirm a status of stable disease, the duration of stable disease was to be at least 42 days. |
| Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
| Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
| Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
| Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h,, 7h and 24h after dosing | — |
| Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing | — |
| Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing | — |
| Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
| Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing | — |
| Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing | — |
| Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing | — |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Afatinib 20mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | 3 |
| Afatinib 40mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | 19 |
| Afatinib 50mg With Vinorelbine i.v. Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | 6 |
| Afatinib 20mg With Vinorelbine Per os Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | 4 |
| Afatinib 40mg With Vinorelbine Per os Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | 18 |
| Afatinib 50mg With Vinorelbine Per os Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | 5 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 0 | 4 | 1 |
| Overall Study | Disease progression | 3 | 12 | 4 | 4 | 12 | 4 |
| Overall Study | Dose-limiting toxicity (DLT) | 0 | 6 | 0 | 0 | 1 | 0 |
| Overall Study | incl. non compliance, lost to follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 15.3 | 55.3 years STANDARD_DEVIATION 8 | 61.7 years STANDARD_DEVIATION 5 | 55.3 years STANDARD_DEVIATION 6.2 | 50.9 years STANDARD_DEVIATION 9.5 | 51.0 years STANDARD_DEVIATION 8.3 | 54.4 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 1 Participants | 11 Participants | 4 Participants | 0 Participants | 11 Participants | 4 Participants | 31 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 2 Participants | 4 Participants | 7 Participants | 1 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 19 / 19 | 6 / 6 | 4 / 4 | 18 / 18 | 5 / 5 |
| serious Total, serious adverse events | 1 / 3 | 11 / 19 | 4 / 6 | 2 / 4 | 13 / 18 | 1 / 5 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLT)
Number of participants with DLT for the determination of the Maximum Tolerated Dose (MTD). 3+3 dose escalation design. MTD based on DLTs during first treatment course. After MTD was determined, additional patients were included at the MTD in an expansion cohort.
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Number of Participants With Dose-limiting Toxicities (DLT) | First cycle (N=3;6;6;4;6;5) | 0 participants |
| Afatinib 20mg With Vinorelbine i.v. | Number of Participants With Dose-limiting Toxicities (DLT) | Expansion cohort (N=0;13;0;0;12;0) | NA participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Participants With Dose-limiting Toxicities (DLT) | First cycle (N=3;6;6;4;6;5) | 1 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Participants With Dose-limiting Toxicities (DLT) | Expansion cohort (N=0;13;0;0;12;0) | 7 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Participants With Dose-limiting Toxicities (DLT) | First cycle (N=3;6;6;4;6;5) | 4 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Participants With Dose-limiting Toxicities (DLT) | Expansion cohort (N=0;13;0;0;12;0) | NA participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Participants With Dose-limiting Toxicities (DLT) | First cycle (N=3;6;6;4;6;5) | 0 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Participants With Dose-limiting Toxicities (DLT) | Expansion cohort (N=0;13;0;0;12;0) | NA participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Participants With Dose-limiting Toxicities (DLT) | First cycle (N=3;6;6;4;6;5) | 1 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Participants With Dose-limiting Toxicities (DLT) | Expansion cohort (N=0;13;0;0;12;0) | 2 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Participants With Dose-limiting Toxicities (DLT) | First cycle (N=3;6;6;4;6;5) | 3 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Participants With Dose-limiting Toxicities (DLT) | Expansion cohort (N=0;13;0;0;12;0) | NA participants |
Secondary
Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 892 ng*h/mL | Geometric Coefficient of Variation 87.3 |
| Afatinib 40mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 683 ng*h/mL | Geometric Coefficient of Variation 375 |
90% CI: [69.549, 229.012]ANOVA
Secondary
Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h,, 7h and 24h after dosing
Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State | 872 ng*h/mL | Geometric Coefficient of Variation 39.8 |
| Afatinib 40mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State | 1070 ng*h/mL | Geometric Coefficient of Variation 33.8 |
90% CI: [76.071, 106.978]ANOVA
Secondary
Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing
Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 258 ng*h/mL | Geometric Coefficient of Variation 79.8 |
| Afatinib 40mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 334 ng*h/mL | Geometric Coefficient of Variation 70.9 |
90% CI: [56.71, 103.871]ANOVA
Secondary
Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 512 ng*h/mL | Geometric Coefficient of Variation 41.4 |
| Afatinib 40mg With Vinorelbine i.v. | Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 655 ng*h/mL | Geometric Coefficient of Variation 26 |
90% CI: [65.037, 87.837]ANOVA
Secondary
Best Percentage Change in Tumour Size
Best percentage change in tumour size was the best percentage change in the sum of diameters of target lesions and was calculated as (minimum sum of diameters post baseline - sum of diameters at baseline)/sum of diameters at baseline. Negative values indicate a decrease, positive values an increase.
Time frame: Screening and every 8 weeks after starting of treatment, up to 44 weeks.
Population: Patients from Treated Set (TS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Best Percentage Change in Tumour Size | -5.65 percentage change in tumour size | Standard Error 10.91 |
| Afatinib 40mg With Vinorelbine i.v. | Best Percentage Change in Tumour Size | -7.51 percentage change in tumour size | Standard Error 4.22 |
| Afatinib 50mg With Vinorelbine i.v. | Best Percentage Change in Tumour Size | -24.10 percentage change in tumour size | Standard Error 9.57 |
| Afatinib 20mg With Vinorelbine Per os | Best Percentage Change in Tumour Size | 25.89 percentage change in tumour size | Standard Error 4.55 |
| Afatinib 40mg With Vinorelbine Per os | Best Percentage Change in Tumour Size | -1.36 percentage change in tumour size | Standard Error 9.62 |
| Afatinib 50mg With Vinorelbine Per os | Best Percentage Change in Tumour Size | -10.76 percentage change in tumour size | Standard Error 3.47 |
Secondary
Duration of Disease Control
Duration of disease control was measured from the start of study treatment to the time of progression or death, whichever occured first.
Time frame: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: Patients from Treated Set (TS) with disease control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Duration of Disease Control | 110 days |
| Afatinib 40mg With Vinorelbine i.v. | Duration of Disease Control | 167 days |
| Afatinib 50mg With Vinorelbine i.v. | Duration of Disease Control | 168 days |
| Afatinib 40mg With Vinorelbine Per os | Duration of Disease Control | 162 days |
| Afatinib 50mg With Vinorelbine Per os | Duration of Disease Control | 120 days |
Secondary
Duration of Objective Response
The duration of objective response was measured from the time of first documented confirmed CR or PR to the time of progressive disease or death, whichever occured earlier.
Time frame: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: Patients from Treated Set (TS) with Objective Response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40mg With Vinorelbine Per os | Duration of Objective Response | 114 days |
Secondary
Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 62.0 ng/mL | Geometric Coefficient of Variation 97.9 |
| Afatinib 40mg With Vinorelbine i.v. | Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 42.7 ng/mL | Geometric Coefficient of Variation 425 |
90% CI: [72.305, 243.917]ANOVA
Secondary
Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing
Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State | 55.1 ng/mL | Geometric Coefficient of Variation 35.6 |
| Afatinib 40mg With Vinorelbine i.v. | Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State | 67.2 ng/mL | Geometric Coefficient of Variation 29.4 |
95% CI: [66.369, 105.966]ANOVA
Secondary
Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State | 52.8 ng/mL | Geometric Coefficient of Variation 80.8 |
| Afatinib 40mg With Vinorelbine i.v. | Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State | 65.0 ng/mL | Geometric Coefficient of Variation 63.9 |
90% CI: [60.47, 110.369]ANOVA
Secondary
Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 822 ng/mL | Geometric Coefficient of Variation 56.2 |
| Afatinib 40mg With Vinorelbine i.v. | Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 941 ng/mL | Geometric Coefficient of Variation 55.1 |
90% CI: [61.156, 114.823]ANOVA
Secondary
Number of Patients With Best Overall Response
Overall response is defined as complete response, partial response and stable disease and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). Complete response (CR) and partial response (PR) had to be confirmed by a subsequent tumour assessment at least 28 days after the criteria for CR or PR were first met. To confirm a status of stable disease, the duration of stable disease was to be at least 42 days.
Time frame: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: All patients from the Treated Set (TS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Progressive disease | 2 participants |
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Missing | 0 participants |
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Partial response | 0 participants |
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Complete response | 0 participants |
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Stable disease | 1 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Complete response | 0 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Progressive disease | 6 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Missing | 3 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Partial response | 0 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Stable disease | 10 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Missing | 1 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Progressive disease | 0 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Complete response | 0 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Stable disease | 5 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Best Overall Response | Partial response | 0 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Stable disease | 0 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Complete response | 0 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Partial response | 0 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Progressive disease | 4 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Missing | 0 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Stable disease | 6 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Missing | 2 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Progressive disease | 7 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Complete response | 0 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Partial response | 3 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Stable disease | 5 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Partial response | 0 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Missing | 0 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Progressive disease | 0 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Best Overall Response | Complete response | 0 participants |
Secondary
Number of Patients With Disease Control (DC)
DC is defined as confirmed complete response (CR), partial response (PR) and stable disease (SD) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0).
Time frame: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: All patients from the Treated Set (TS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Disease Control (DC) | 1 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Disease Control (DC) | 10 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Disease Control (DC) | 5 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Disease Control (DC) | 0 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Disease Control (DC) | 9 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Disease Control (DC) | 5 participants |
Secondary
Number of Patients With Objective Response (OR)
OR is defined as confirmed complete response and confirmed partial response (PR) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0).
Time frame: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: All patients from the Treated Set (TS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Number of Patients With Objective Response (OR) | 0 participants |
| Afatinib 40mg With Vinorelbine i.v. | Number of Patients With Objective Response (OR) | 0 participants |
| Afatinib 50mg With Vinorelbine i.v. | Number of Patients With Objective Response (OR) | 0 participants |
| Afatinib 20mg With Vinorelbine Per os | Number of Patients With Objective Response (OR) | 0 participants |
| Afatinib 40mg With Vinorelbine Per os | Number of Patients With Objective Response (OR) | 3 participants |
| Afatinib 50mg With Vinorelbine Per os | Number of Patients With Objective Response (OR) | 0 participants |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from the first dose of study medication to the occurrence of tumour progression or death, whichever came first. It was assessed according to RECIST 1.0. Median time results from unstratified Kaplan-Meier estimates.
Time frame: From first dose of study medication to the occurrence of progression or death whichever came first, up to 44 months.
Population: All patients treated in the MTD cohorts.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Progression-free Survival (PFS) | 14.6 weeks |
| Afatinib 40mg With Vinorelbine i.v. | Progression-free Survival (PFS) | 15.9 weeks |
Secondary
Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 3.16 hours |
| Afatinib 40mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State | 2.00 hours |
Secondary
Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing
Population: All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State | 3.54 hours |
| Afatinib 40mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State | 3.00 hours |
Secondary
Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing
Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State | 1.50 hours |
| Afatinib 40mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State | 1.50 hours |
Secondary
Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State
Time frame: 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing
Population: All patients treated in the TS, for which evaluable PK parameters were available for the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 20mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 0.166 hours |
| Afatinib 40mg With Vinorelbine i.v. | Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State | 0.167 hours |
Secondary
Time to Objective Response
The time to OR was the duration from the first treatment to the time when the measurement criteria for first documented confirmed CR and/or PR were met according to RECIST 1.0 criteria.
Time frame: From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.
Population: Patients from the Treated Set (TS) with objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib 40mg With Vinorelbine Per os | Time to Objective Response | 55 days |