Neuroectodermal Tumors, Rhabdomyosarcoma
Conditions
Brief summary
Open-label, dose escalation, monotherapy, basket trial with biomarker specific MTD expansion cohort/Phase II part. The trial will consist of 2 parts: 1. Dose finding part to determine the MTD 2. Biomarker specific MTD expansion cohort/Phase II part to assess clinical anti-tumour activity in included tumour types
Interventions
DRUGafatinib
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Paediatric patients aged 1 year to \<18 years at the time of informed consent * diagnosis of HGG, DIPG, low grade astrocytoma, medulloblastoma/PNET, ependymoma, neuroblastoma, RMS and tumours with ErbB deregulation * recurrent/refractory disease after they received at least one prior standard treatment regimen * no effective conventional therapy exists * Performance status \>= 50% (Lansky for =\<12ys; Karnofsky for \>12ys) * Further inclusion criteria apply
Exclusion criteria
* relevant toxicity from previous treatment * known pre-existing relevant cardiac , hepatic, renal, bone marrow dysfunction, ILD, keratitis * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Response - Maximum Tolerated Dose Expansion (MTD) Cohort | Assessed every 8 weeks until progression of disease, up to 336 days. | Number of participants with objective response for maximum tolerated dose expansion (MTD) cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. |
| Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Dose Finding Part | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8. | Area under the curve over dosing interval τ at steady state (AUCτ,ss) for Dose finding part was reported. |
| Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Dose Finding Part | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8. | Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) for Dose finding part was reported. |
| Number of Participants With Dose Limiting Toxicity Adverse Events - Dose Finding Part | During the first course (28 days) of treatment. | Number of participants with Dose Limiting Toxicity adverse events for Dose finding part was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From (Last) Dosing to the Maximum Measured Concentration (Tmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1. | Time from (last) dosing to the maximum measured concentration (tmax) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. |
| Time From (Last) Dosing to the Maximum Measured Concentration at Steady State (Tmax,ss) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8. | Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. |
| Accumulation (or Effective) Half-life - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8. | Accumulation (or effective) half-life for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. |
| Number of Participants With Objective Response - Dose Finding Part | Assessed every 8 weeks until progression of disease, up to 336 days. | Number of participants with objective response for Dose finding part was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. |
| Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8. | Area under the curve over dosing interval τ at steady state (AUCτ,ss) in maximum tolerated dose (MTD) expansion cohort was reported. |
| Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8. | Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) in maximum tolerated dose (MTD) expansion cohort was reported. |
| Duration of Objective Response - Maximum Tolerated Dose (MTD) Expansion Cohort | From first documented response until the earliest of disease progression or death, up to 336 days. | Duration of objective response in maximum tolerated dose expansion (MTD) cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. |
| Progression Free Survival - Maximum Tolerated Dose (MTD) Expansion Cohort | From the first treatment until date of first progression or death, up to 336 days. | Progression free survival for the MTD expansion cohorts was reported. Progression free survival (PFS) was defined as the duration from the date of first treatment until the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of last adequate tumour assessment. |
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24) - Dose Finding Part | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1. | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) for Dose finding part was reported. |
| Maximum Measured Concentration (Cmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1. | Maximum measured concentration (Cmax) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. |
Countries
Australia, Austria, Canada, Denmark, Faroe Islands, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Phase I/II open label, dose escalation trial to determine the Maximum tolerated dose (MTD), safety, Pharmacokinetics (PK) and efficacy of afatinib monotherapy in children aged ≥1 year to \<18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology.
Pre-assignment details
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
Participants by arm
| Arm | Count |
|---|---|
| Dose Finding - Level 0 Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area \[BSA\] using allometric scaling):
Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets.
Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment.
Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter. | 8 |
| Dose Finding - Level 1 Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area \[BSA\] using allometric scaling):
Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets.
Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment.
Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter. | 9 |
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area \[BSA\] using allometric scaling):
Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets.
Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment.
Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter. | 39 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 3 |
| Overall Study | Dose limiting toxicity | 0 | 1 | 0 |
| Overall Study | Other reason for not completing | 0 | 0 | 1 |
| Overall Study | Progressive disease | 8 | 7 | 34 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Dose Finding - Level 0 | Dose Finding - Level 1 | Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Total |
|---|---|---|---|---|
| Age, Continuous | 9.75 Years STANDARD_DEVIATION 4.83 | 10.44 Years STANDARD_DEVIATION 5.29 | 10.92 Years STANDARD_DEVIATION 4.44 | 10.68 Years STANDARD_DEVIATION 4.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 5 Participants | 37 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 29 Participants | 36 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 16 Participants | 24 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 23 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 8 | 9 / 9 | 29 / 39 |
| other Total, other adverse events | 8 / 8 | 9 / 9 | 38 / 39 |
| serious Total, serious adverse events | 7 / 8 | 6 / 9 | 20 / 39 |
Outcome results
Primary
Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Dose Finding Part
Area under the curve over dosing interval τ at steady state (AUCτ,ss) for Dose finding part was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Dose Finding Part | 681 hours times nanogram per milliliter | Geometric Coefficient of Variation 43.8 |
| Dose Finding - Level 1 | Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Dose Finding Part | 1380 hours times nanogram per milliliter | Geometric Coefficient of Variation 29 |
Primary
Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Dose Finding Part
Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) for Dose finding part was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Dose Finding Part | 53.0 nanogram per mililiter | Geometric Coefficient of Variation 48.8 |
| Dose Finding - Level 1 | Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Dose Finding Part | 115 nanogram per mililiter | Geometric Coefficient of Variation 39.3 |
Primary
Number of Participants With Dose Limiting Toxicity Adverse Events - Dose Finding Part
Number of participants with Dose Limiting Toxicity adverse events for Dose finding part was reported.
Time frame: During the first course (28 days) of treatment.
Population: Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Number of Participants With Dose Limiting Toxicity Adverse Events - Dose Finding Part | 1 Participants |
| Dose Finding - Level 1 | Number of Participants With Dose Limiting Toxicity Adverse Events - Dose Finding Part | 2 Participants |
Primary
Number of Participants With Objective Response - Maximum Tolerated Dose Expansion (MTD) Cohort
Number of participants with objective response for maximum tolerated dose expansion (MTD) cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression.
Time frame: Assessed every 8 weeks until progression of disease, up to 336 days.
Population: Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Number of Participants With Objective Response - Maximum Tolerated Dose Expansion (MTD) Cohort | 3 Participants |
Secondary
Accumulation (or Effective) Half-life - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort
Accumulation (or effective) half-life for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Accumulation (or Effective) Half-life - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 18.7 hours | Geometric Coefficient of Variation 44.3 |
| Dose Finding - Level 1 | Accumulation (or Effective) Half-life - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 31.0 hours | Geometric Coefficient of Variation 56.7 |
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Accumulation (or Effective) Half-life - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 30.3 hours | Geometric Coefficient of Variation 83.6 |
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24) - Dose Finding Part
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) for Dose finding part was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24) - Dose Finding Part | 383 hours times nanogram per mililiter | Geometric Coefficient of Variation 46.4 |
| Dose Finding - Level 1 | Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 24 Hours (AUC0-24) - Dose Finding Part | 512 hours times nanogram per mililiter | Geometric Coefficient of Variation 40.6 |
Secondary
Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort
Area under the curve over dosing interval τ at steady state (AUCτ,ss) in maximum tolerated dose (MTD) expansion cohort was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Area Under the Curve Over Dosing Interval τ at Steady State (AUCτ,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort | 780 hours times nanogram per milliliter | Geometric Coefficient of Variation 60.7 |
Secondary
Duration of Objective Response - Maximum Tolerated Dose (MTD) Expansion Cohort
Duration of objective response in maximum tolerated dose expansion (MTD) cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression.
Time frame: From first documented response until the earliest of disease progression or death, up to 336 days.
Population: Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Duration of Objective Response - Maximum Tolerated Dose (MTD) Expansion Cohort | 62 Days |
Secondary
Maximum Measured Concentration (Cmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort
Maximum measured concentration (Cmax) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Maximum Measured Concentration (Cmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 36.4 nanogram per mililiter | Geometric Coefficient of Variation 55.9 |
| Dose Finding - Level 1 | Maximum Measured Concentration (Cmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 43.8 nanogram per mililiter | Geometric Coefficient of Variation 61.2 |
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Maximum Measured Concentration (Cmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 30.5 nanogram per mililiter | Geometric Coefficient of Variation 90.3 |
Secondary
Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort
Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) in maximum tolerated dose (MTD) expansion cohort was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Maximum Measured Concentration of the Analyte in Plasma at Steady State (Cmax,ss) - Maximum Tolerated Dose (MTD) Expansion Cohort | 52.5 nanogram per mililiter | Geometric Coefficient of Variation 61 |
Secondary
Number of Participants With Objective Response - Dose Finding Part
Number of participants with objective response for Dose finding part was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator's assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression.
Time frame: Assessed every 8 weeks until progression of disease, up to 336 days.
Population: Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Number of Participants With Objective Response - Dose Finding Part | 0 Participants |
| Dose Finding - Level 1 | Number of Participants With Objective Response - Dose Finding Part | 0 Participants |
Secondary
Progression Free Survival - Maximum Tolerated Dose (MTD) Expansion Cohort
Progression free survival for the MTD expansion cohorts was reported. Progression free survival (PFS) was defined as the duration from the date of first treatment until the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of last adequate tumour assessment.
Time frame: From the first treatment until date of first progression or death, up to 336 days.
Population: Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Progression Free Survival - Maximum Tolerated Dose (MTD) Expansion Cohort | 8.0 Months |
Secondary
Time From (Last) Dosing to the Maximum Measured Concentration at Steady State (Tmax,ss) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort
Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Time From (Last) Dosing to the Maximum Measured Concentration at Steady State (Tmax,ss) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 3.00 Hours |
| Dose Finding - Level 1 | Time From (Last) Dosing to the Maximum Measured Concentration at Steady State (Tmax,ss) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 2.75 Hours |
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Time From (Last) Dosing to the Maximum Measured Concentration at Steady State (Tmax,ss) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 4.17 Hours |
Secondary
Time From (Last) Dosing to the Maximum Measured Concentration (Tmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort
Time from (last) dosing to the maximum measured concentration (tmax) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported.
Time frame: Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
Population: Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Time From (Last) Dosing to the Maximum Measured Concentration (Tmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 3.02 Hours |
| Dose Finding - Level 1 | Time From (Last) Dosing to the Maximum Measured Concentration (Tmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 3.43 Hours |
| Maximum Tolerated Dose (MTD) Expansion Cohort - Level 0 | Time From (Last) Dosing to the Maximum Measured Concentration (Tmax) - Dose Finding Part/Maximum Tolerated Dose (MTD) Expansion Cohort | 3.98 Hours |