Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.
Interventions
DRUGCetuximab
BIBW 2992 medium dose plus high dose level of cetuximab
DRUGBIBW 2992
BIBW 2992 medium dose plus high dose level of cetuximab
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1\) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. A tumor which harbors exon 20 insertion or de novo T790M mutation is eligible for the treatment in the sequential arm 2) Objective clinical benefit from treatment with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) as defined by either 1. Documented partial or complete response (Response Evaluation Criteria in Solid Tumors, RECIST), or 2. Stable disease \>=6 months as defined by RECIST in absence of radiographic progression after initiation of gefitinib or erlotinib; or stable disease/PR/CR \>=12 weeks as defined by RECIST after initiation of BIBW 2992 3. Systemic progression of disease (RECIST v1.1) while on continuous treatment with erlotinib or gefitinib or BIBW 2992 within the last 30 days. Patients whose disease progresses only in the central nervous system (CNS) are not eligible 4. No intervening systemic therapy between cessation of gefitinib or erlotinib or BIBW 2992 and initiation of the treatment in the study 5. Adequate tumor-derived material such as fresh or archived tumor tissue or pleural fluid from malignant pleural effusion after disease progression on erlotinib/gefitinib/BIBW 2992 prior to the study entry must be made available for EGFR mutation analyses 6. Patients aged 18 years or older 7. Life expectancy of at least three (3) months 8. Eastern Cooperative Oncology Group (ECOG) performance score 0-2 9. Written informed consent that is consistent with ICH-GCP guidelines
Exclusion criteria
1. Prior treatment with EGFR targeting antibodies; prior severe infusion reaction to a monoclonal antibody 2. Adverse events due to major surgery (at least 28 days after) or minor surgery not recovered to CTC grade 1 or less. Surgical wounds must be healing without clinical evidence of infection prior to study treatment to be eligible. 3. Radiotherapy less than two weeks prior to the start of the study treatment 4. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (except erlotinib/gefitinib/BIBW 2992) \<=30 days before study treatment 5. Less than three days from prior treatment with gefitinib or erlotinib. Patients with adverse events related to gefitinib or erlotinib must recover to CTC AE grade 1 or less to be eligible. No need to stop BIBW 2992 before start of the study treatment for patient who progressed on BIBW 2992 from a separate clinical trial/treatment setting 6. Brain metastases, which are symptomatic. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least four (4) weeks, no history of cerebral oedema or bleeding in the past four (4) weeks. Anticonvulsant therapy will be allowed if patient is stable on anticonvulsant treatment. 7. Other malignancies diagnosed within the past five (5) years (other than non melanomatous skin cancer, ductal carcinoma in situ and in situ cervical cancer) 8. Known pre-existing interstitial lung disease 9. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohns disease, malabsorption, or Common Toxicity Criteria for Adverse Events (CTCAE) grade \>2 diarrhea of any etiology 10. Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT). | from day 1 treatment until progression or undue toxicity, up to 28 days | A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: * CTCAE Grade 2 or higher decrease in cardiac left ventricular function * CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy * CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days * CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days * CTCAE Grade ≥3 rash despite standard medical management * CTCAE Grade ≥3 fatigue lasting for more than 7 days * CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae * All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Highest CTCAE Grade | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0 |
| Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | — |
| Frequency (%) of Patients With Adverse Events Leading to Dose Reduction | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | — |
| Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | Frequency (%) of patients with adverse events leading to treatment discontinuation |
| Frequency (%) of Patients With Adverse Events Leading to Death | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | — |
| Frequency (%) of Patients With Related Serious Adverse Events | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | Frequency (%) of patients with drug-related serious adverse events |
| Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy |
| Concentration of Afatinib in Plasma for the Combination Arm | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss). |
| Peak-trough Fluctuation (PTF) | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100\*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours. |
| t1/2,ss | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | Terminal half-life of Afatinib in plasma at steady state (t1/2,ss) |
| MRTpo,ss | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days |
| CL/F,ss,15 | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss) |
| Vz/F,ss | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days |
| Predose Plasma Concentrations of Afatinib for the Combination Arm | Up to 57 days | Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1. |
| Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) | up to 116 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD. |
| Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) | up to 116 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR. |
| Duration of Objective Response (According to RECIST v1.1) | up to 116 weeks | Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started). |
| Duration of Disease Control (According to RECIST v1.1) | up to 116 weeks | Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR. |
| Progression-Free Survival (PFS) Time | up to 116 weeks | Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death. |
Countries
Netherlands, United States
Participant flow
Pre-assignment details
171 patients were entered and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Total Patients All patients entered and treated. The objective of this study was to determine the maximum tolerated dose of Afatinib using a 3+3 Up-and-Down trial design. Cohorts of three to six participants were entered (not randomized) sequentially into escalating dosage tiers of afatinib/cetuximab. The dose of cetuximab in successive cohorts was increased unless two or more of the six participants (of the current cohort) had dose limiting toxicity events. | 171 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 32 |
| Overall Study | Other reason not defined above | 5 |
| Overall Study | Progressive disease | 128 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Refusal to start/continue medication | 5 |
Baseline characteristics
| Characteristic | Total Patients |
|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 119 Participants |
| Sex: Female, Male Male | 52 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 | 4 / 4 | 126 / 126 | 36 / 37 | 36 / 36 |
| serious Total, serious adverse events | 3 / 4 | 63 / 126 | 12 / 37 | 15 / 36 |
Outcome results
Primary
The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).
A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: * CTCAE Grade 2 or higher decrease in cardiac left ventricular function * CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy * CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days * CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days * CTCAE Grade ≥3 rash despite standard medical management * CTCAE Grade ≥3 fatigue lasting for more than 7 days * CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae * All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.
Time frame: from day 1 treatment until progression or undue toxicity, up to 28 days
Population: Treated set for Cohort One. Cohort one was based on the data from the first treatment cycle where four patients received 'Afatinib 40+Cetuximab 250' and six patients received 'Afatinib 40+Cetuximab 500'.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT). | 0 participants |
| Combination Arm - Afa40+Ctx500 | The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT). | 0 participants |
Secondary
Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm
Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm | 1300 ng*h/mL | Geometric Coefficient of Variation 21.8 |
| Combination Arm - Afa40+Ctx500 | Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm | 935 ng*h/mL | Geometric Coefficient of Variation 59.8 |
Secondary
CL/F,ss,15
Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | CL/F,ss,15 | 511 mL/min | Geometric Coefficient of Variation 21.8 |
| Combination Arm - Afa40+Ctx500 | CL/F,ss,15 | 713 mL/min | Geometric Coefficient of Variation 59.8 |
Secondary
Concentration of Afatinib in Plasma for the Combination Arm
Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Concentration of Afatinib in Plasma for the Combination Arm | Cmin,ss,15 | 33.9 ng/mL | Geometric Coefficient of Variation 19.6 |
| Combination Arm - Afa40+Ctx250 | Concentration of Afatinib in Plasma for the Combination Arm | Cmax,ss,15 | 83.8 ng/mL | Geometric Coefficient of Variation 19.8 |
| Combination Arm - Afa40+Ctx500 | Concentration of Afatinib in Plasma for the Combination Arm | Cmin,ss,15 | 24.4 ng/mL | Geometric Coefficient of Variation 53.7 |
| Combination Arm - Afa40+Ctx500 | Concentration of Afatinib in Plasma for the Combination Arm | Cmax,ss,15 | 52.3 ng/mL | Geometric Coefficient of Variation 73.2 |
Secondary
Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.
Time frame: up to 116 weeks
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) | 75.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) | 70.6 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) | 56.8 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) | 50.0 percentage of patients |
Secondary
Duration of Disease Control (According to RECIST v1.1)
Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.
Time frame: up to 116 weeks
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Duration of Disease Control (According to RECIST v1.1) | 7.40 months | Standard Deviation 5.54 |
| Combination Arm - Afa40+Ctx500 | Duration of Disease Control (According to RECIST v1.1) | 7.40 months | Standard Deviation 5.45 |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Duration of Disease Control (According to RECIST v1.1) | 4.90 months | Standard Deviation 3.08 |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Duration of Disease Control (According to RECIST v1.1) | 5.90 months | Standard Deviation 4.51 |
Secondary
Duration of Objective Response (According to RECIST v1.1)
Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).
Time frame: up to 116 weeks
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Duration of Objective Response (According to RECIST v1.1) | 0 months | Standard Deviation 0 |
| Combination Arm - Afa40+Ctx500 | Duration of Objective Response (According to RECIST v1.1) | 9.00 months | Standard Deviation 6.94 |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Duration of Objective Response (According to RECIST v1.1) | 3.90 months | Standard Deviation 0.07 |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Duration of Objective Response (According to RECIST v1.1) | 5.80 months | Standard Deviation 2.36 |
Secondary
Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters
Time frame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Haemoglobin - low (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Blood urea nitrogen - high (N=missing,105,28,28) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Alkaline phosphatase - high (N=4,124,35,35) | 25.0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - high (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | ALT/GPT, SGPT - high (N=4,123,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - low (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine clearance - low (N=4,123,33,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - low (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | AST/GOT, SGOT - high (N=4,123,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - high (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | White blood cell ct. - low (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - high (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Bilirubin,total - high (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Neutrophils - low (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine - high (N=4,123,33,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Magnesium - low (N=4,124,34,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - low (N=4,124,35,35) | 0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Magnesium - low (N=4,124,34,35) | 9.7 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Blood urea nitrogen - high (N=missing,105,28,28) | 5.7 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | AST/GOT, SGOT - high (N=4,123,35,35) | 3.3 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - high (N=4,124,35,35) | 0.8 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | ALT/GPT, SGPT - high (N=4,123,35,35) | 11.4 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Alkaline phosphatase - high (N=4,124,35,35) | 4.8 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Bilirubin,total - high (N=4,124,35,35) | 4.8 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - low (N=4,124,35,35) | 5.6 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - low (N=4,124,35,35) | 5.6 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | White blood cell ct. - low (N=4,124,35,35) | 3.2 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine clearance - low (N=4,123,33,35) | 3.3 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - high (N=4,124,35,35) | 4.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Haemoglobin - low (N=4,124,35,35) | 12.9 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - low (N=4,124,35,35) | 6.5 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine - high (N=4,123,33,35) | 2.4 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - high (N=4,124,35,35) | 1.6 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Neutrophils - low (N=4,124,35,35) | 4.0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | ALT/GPT, SGPT - high (N=4,123,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Haemoglobin - low (N=4,124,35,35) | 20.0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | White blood cell ct. - low (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Neutrophils - low (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - low (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - low (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - high (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - low (N=4,124,35,35) | 8.6 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - high (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Magnesium - low (N=4,124,34,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | AST/GOT, SGOT - high (N=4,123,35,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Alkaline phosphatase - high (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Blood urea nitrogen - high (N=missing,105,28,28) | 3.6 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine - high (N=4,123,33,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine clearance - low (N=4,123,33,35) | 0 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Bilirubin,total - high (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - high (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Blood urea nitrogen - high (N=missing,105,28,28) | 0 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - high (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Calcium - low (N=4,124,35,35) | 5.7 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | White blood cell ct. - low (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine - high (N=4,123,33,35) | 0 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - high (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Potassium - low (N=4,124,35,35) | 5.7 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Haemoglobin - low (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Creatinine clearance - low (N=4,123,33,35) | 2.9 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - low (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Neutrophils - low (N=4,124,35,35) | 2.9 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | ALT/GPT, SGPT - high (N=4,123,35,35) | 8.6 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Sodium - high (N=4,124,35,35) | 0 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Alkaline phosphatase - high (N=4,124,35,35) | 5.7 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | AST/GOT, SGOT - high (N=4,123,35,35) | 2.9 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Magnesium - low (N=4,124,34,35) | 11.4 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters | Bilirubin,total - high (N=4,124,35,35) | 5.7 percentage of patients |
Secondary
Frequency (%) of Patients With Adverse Events Leading to Death
Time frame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Frequency (%) of Patients With Adverse Events Leading to Death | 0.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency (%) of Patients With Adverse Events Leading to Death | 15.1 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency (%) of Patients With Adverse Events Leading to Death | 10.8 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency (%) of Patients With Adverse Events Leading to Death | 16.7 percentage of patients |
Secondary
Frequency (%) of Patients With Adverse Events Leading to Dose Reduction
Time frame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Frequency (%) of Patients With Adverse Events Leading to Dose Reduction | 25.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency (%) of Patients With Adverse Events Leading to Dose Reduction | 37.3 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency (%) of Patients With Adverse Events Leading to Dose Reduction | 13.5 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency (%) of Patients With Adverse Events Leading to Dose Reduction | 22.2 percentage of patients |
Secondary
Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation
Frequency (%) of patients with adverse events leading to treatment discontinuation
Time frame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation | 50.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation | 23.8 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation | 2.7 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation | 19.4 percentage of patients |
Secondary
Frequency (%) of Patients With Related Serious Adverse Events
Frequency (%) of patients with drug-related serious adverse events
Time frame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Frequency (%) of Patients With Related Serious Adverse Events | 0.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Frequency (%) of Patients With Related Serious Adverse Events | 10.3 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Frequency (%) of Patients With Related Serious Adverse Events | 5.4 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Frequency (%) of Patients With Related Serious Adverse Events | 2.8 percentage of patients |
Secondary
Highest CTCAE Grade
Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0
Time frame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Highest CTCAE Grade | Patients with highest CTCAE Grade 4 | 25.0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Highest CTCAE Grade | Patients with highest CTCAE Grade 2 | 25.0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Highest CTCAE Grade | Patients with highest CTCAE Grade 5 | 0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Highest CTCAE Grade | Patients with highest CTCAE Grade 3 | 50.0 percentage of patients |
| Combination Arm - Afa40+Ctx250 | Highest CTCAE Grade | Patients with highest CTCAE Grade 1 | 0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Highest CTCAE Grade | Patients with highest CTCAE Grade 3 | 54.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Highest CTCAE Grade | Patients with highest CTCAE Grade 4 | 4.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Highest CTCAE Grade | Patients with highest CTCAE Grade 5 | 15.1 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Highest CTCAE Grade | Patients with highest CTCAE Grade 2 | 26.2 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Highest CTCAE Grade | Patients with highest CTCAE Grade 1 | 0.8 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Highest CTCAE Grade | Patients with highest CTCAE Grade 3 | 48.6 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Highest CTCAE Grade | Patients with highest CTCAE Grade 1 | 10.8 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Highest CTCAE Grade | Patients with highest CTCAE Grade 2 | 24.3 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Highest CTCAE Grade | Patients with highest CTCAE Grade 4 | 5.4 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Highest CTCAE Grade | Patients with highest CTCAE Grade 5 | 10.8 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Highest CTCAE Grade | Patients with highest CTCAE Grade 4 | 8.3 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Highest CTCAE Grade | Patients with highest CTCAE Grade 2 | 19.4 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Highest CTCAE Grade | Patients with highest CTCAE Grade 1 | 2.8 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Highest CTCAE Grade | Patients with highest CTCAE Grade 3 | 52.8 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Highest CTCAE Grade | Patients with highest CTCAE Grade 5 | 16.7 percentage of patients |
Secondary
MRTpo,ss
mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | MRTpo,ss | 32.6 h | Geometric Coefficient of Variation 23.4 |
| Combination Arm - Afa40+Ctx500 | MRTpo,ss | NA h | — |
Secondary
Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.
Time frame: up to 116 weeks
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) | 0.0 percentage of patients |
| Combination Arm - Afa40+Ctx500 | Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) | 28.6 percentage of patients |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) | 5.4 percentage of patients |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) | 11.1 percentage of patients |
Secondary
Peak-trough Fluctuation (PTF)
Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100\*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Peak-trough Fluctuation (PTF) | 91.6 % of average concentration | Geometric Coefficient of Variation 15.9 |
| Combination Arm - Afa40+Ctx500 | Peak-trough Fluctuation (PTF) | 73.8 % of average concentration | Geometric Coefficient of Variation 55.2 |
Secondary
Predose Plasma Concentrations of Afatinib for the Combination Arm
Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.
Time frame: Up to 57 days
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,16 (N=3,0) | 36.4 ng/mL | Geometric Coefficient of Variation 15.8 |
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,29 (N=3,20) | 33.4 ng/mL | Geometric Coefficient of Variation 21.8 |
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,15 (N=3,28) | 33.9 ng/mL | Geometric Coefficient of Variation 19.6 |
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,43 (N=3,19) | 33.5 ng/mL | Geometric Coefficient of Variation 14.9 |
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,22 (N=3,21) | 33.5 ng/mL | Geometric Coefficient of Variation 1.3 |
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,57 (N=3,0) | 36.6 ng/mL | Geometric Coefficient of Variation 4.51 |
| Combination Arm - Afa40+Ctx250 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,8 (N=4,25) | 33.2 ng/mL | Geometric Coefficient of Variation 38.3 |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,57 (N=3,0) | NA ng/mL | — |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,8 (N=4,25) | 28.3 ng/mL | Geometric Coefficient of Variation 62.3 |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,15 (N=3,28) | 27.1 ng/mL | Geometric Coefficient of Variation 51.3 |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,16 (N=3,0) | NA ng/mL | — |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,22 (N=3,21) | 28.3 ng/mL | Geometric Coefficient of Variation 64.3 |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,29 (N=3,20) | 27.7 ng/mL | Geometric Coefficient of Variation 56.8 |
| Combination Arm - Afa40+Ctx500 | Predose Plasma Concentrations of Afatinib for the Combination Arm | Cpre,ss,43 (N=3,19) | 26.0 ng/mL | Geometric Coefficient of Variation 98.4 |
Secondary
Progression-Free Survival (PFS) Time
Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.
Time frame: up to 116 weeks
Population: Treated set. 32 patients in the Afa40-mono group had disease progression and were transitioned to treatment with Afa40+Ctx500. Thus the total of 203 patients (4+126+37+36) minus the 32 patients counted in both 'Afa-mono' and 'Afa40+Ctx500' treatments arms equals 171, the total number of patients started in participant flow section.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Arm - Afa40+Ctx250 | Progression-Free Survival (PFS) Time | 4.2 months |
| Combination Arm - Afa40+Ctx500 | Progression-Free Survival (PFS) Time | 4.6 months |
| Sequential Arm - Afatanib Monotherapy (Afa40 Mono) | Progression-Free Survival (PFS) Time | 2.7 months |
| Sequential Arm - Combination Therapy (Afa40+Ctx500) | Progression-Free Survival (PFS) Time | 2.9 months |
Secondary
t1/2,ss
Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | t1/2,ss | 22.4 h | Geometric Coefficient of Variation 24.5 |
| Combination Arm - Afa40+Ctx500 | t1/2,ss | NA h | — |
Secondary
Vz/F,ss
Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days
Time frame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
Population: Pharmacokinetic dataset (PKS)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination Arm - Afa40+Ctx250 | Vz/F,ss | 991 L | Geometric Coefficient of Variation 44.8 |
| Combination Arm - Afa40+Ctx500 | Vz/F,ss | NA L | — |