Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The primary objective of this trial is to identify the Maximum Tolerated Dose of BIBW 2992 therapy when given continuously in combination with Sirolimus. The MTD will be based on the Dose Limiting Toxicity information collected during the first two cycles. Overall safety, pharmacokinetics and anti-tumour efficacy will be evaluated as secondary objectives.
Interventions
DRUGBIBW 2992
Dose escalation (19-40 patients): low or high dose oral + 12 addit. pat. at MTD, until progression or undue AEs
Dose escalation (19-40 patients): several dose levels + 12 addit. pat. at MTD until progression or undue AEs.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
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 diagnosis of Stage IIIB or Stage IV NSCLC 2. Patients who have failed conventional treatment (at least 1 prior treatment line), or for whom no therapy of proven efficacy exists 3. Patients whose tumors: * are EGFR mutation-positive or * are EGFR mutation-negative or unknown provided they had disease progression after achieving either response or stable disease for at least 6 months from a previous treatment with erlotinib (Tarceva®) or gefitinib (Iressa®) 4. Patients aged 18 years or older 5. Life expectancy of at least three (3) months 6. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0-2 7. Written informed consent that is consistent with ICH-GCP guidelines
Exclusion criteria
1. Prior major surgery, chemotherapy or radiation therapy within 4 weeks before start of therapy. 2. Prior treatment with an mTOR inhibitor within the past 4 weeks before start of therapy or concomitantly with this study 3. Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within 14 days of run-in treatment with Sirolimus 4. Active CNS metastases (defined as stable for \<4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants or steroids) 5. Severe alteration in serum fasting cholesterol (equal or more than 350 mg/dL) or triglycerides (equal or more than 400 mg/dL). Patients may be allowed to enrol on the trial after initiation of lipid lowering agents. 6. Requirement for treatment with any of the prohibited concomitant medications: * Concomitant CYP3A4 inhibitors within the past 7 days before start of therapy or concomitantly with this study. * Concomitant CYP3A4 inducers within the past 14 days before start of therapy or concomitantly with this study. 7. Any contraindications for therapy with Sirolimus. 8. Known hypersensitivity to BIBW 2992, Sirolimus or other rapamycin analogues (everolimus, temsirolimus, deforolimus, etc.) or the excipients of any of the trial drugs. 9. Use of any investigational drug within 4 weeks before start of therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Dose Limiting Toxicities (DLT) | 2 first cycles, 56 days | Number of participants with of dose limiting toxicities (DLT) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | Rate of (unconfirmed) objective response, defined as complete response (CR) or partial response (PR) according to RECIST v1.1 |
| Rate of Disease Control | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | Rate of (unconfirmed) disease control defined as CR, PR, or stable disease (SD), according to RECIST v1.1 |
| Exploratory Examination of EGFR Mutations (Exons 19, 20 and 21 and Others) in Serum/Plasma DNA and Tumour DNA. | Multiple time points during the trial | Exploratory examination of Epidermal growth factor (receptor)(EGFR) mutations (Exons 19, 20 and 21 and others) in serum/plasma DNA and tumour DNA. This endpoint was not analysed in the study report as the available data was too limited. |
| Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib | Maximum measured plasma concentration of Afatinib at steady state (Cmax,ss) |
| AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib | Area under the curve (AUC) of Afatinib at steady state over the dosing interval τ (AUCτ,ss) for afatinib. |
| Best Overall Response | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | Best overall response (unconfirmed) according to RECIST v1.1 |
| AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib | Area under the curve (AUC) of sirolimus at steady state over the dosing interval τ (AUCτ,ss) for afatinib. |
| Occurrence of Adverse Events According to CTCAE, Version 3.0 | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | Percentage of participants with adverse events according to highest Common Terminology Criteria for Adverse Events (CTCAE) grade, version 3.0 |
| Percentage of Patients With Drug-related AEs | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | Percentage of patients with drug-related adverse events (AEs). |
| Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days | Evaluation of laboratory parameters included assessment of the frequency of patients with ALT and AST elevations concurrent with elevated bilirubin and indicative of Hy's law cases. |
| Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib | Maximum measured plasma concentration of sirolimus at steady state (Cmax,ss) |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Afa30+Sir01 Patients received Sirolimus (Sir) 1mg tablet orally for 8 days, followed by oral administration of Afatinib (Afa) 30mg tablet once daily plus Sir 1mg tablet once daily. | 12 |
| Afa30+Sir03 Patients received Sirolimus (Sir) 1mg tablet orally for 8 days, followed by oral administration of Afatinib (Afa) 30mg tablet once daily plus Sir 3mg tablet once daily. | 9 |
| Afa30+Sir05 Patients received Sirolimus (Sir) 1mg tablet orally for 8 days, followed by oral administration of Afatinib (Afa) 30mg tablet once daily plus Sir 5mg tablet once daily. | 9 |
| Afa30+Sir10 Patients received Sirolimus (Sir) 1mg tablet orally for 8 days, followed by oral administration of Afatinib (Afa) 30mg tablet once daily plus Sir 10mg tablet once daily. | 3 |
| Afa40+Sir01 Patients received Sirolimus (Sir) 1mg tablet orally for 8 days, followed by oral administration of Afatinib (Afa) 40mg tablet once daily plus Sir 1mg tablet once daily. | 3 |
| Afa40+Sir05 Patients received Sirolimus (Sir) 1mg tablet orally for 8 days, followed by oral administration of Afatinib (Afa) 40mg tablet once daily plus Sir 5mg tablet once daily. | 3 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Discontinued After Starting Course 3 | DLT | 1 | 0 | 2 | 1 | 0 | 0 |
| Discontinued After Starting Course 3 | Other adverse event | 1 | 0 | 1 | 0 | 0 | 0 |
| Discontinued After Starting Course 3 | Progressive Disease | 6 | 4 | 3 | 1 | 3 | 3 |
| Discontinued After Starting Course 3 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Discontinued Before Starting Course 3 | Dose Limiting Toxicity (DLT) | 0 | 0 | 1 | 1 | 0 | 0 |
| Discontinued Before Starting Course 3 | Non compliance with the protocol | 0 | 0 | 2 | 0 | 0 | 0 |
| Discontinued Before Starting Course 3 | Progressive Disease | 2 | 2 | 0 | 0 | 0 | 0 |
| Discontinued Before Starting Course 3 | Withdrawal by Subject | 2 | 2 | 0 | 0 | 0 | 0 |
| Run-in Period (8 Days) | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Run-in Period (8 Days) | Consent withdrawn | 0 | 1 | 0 | 0 | 0 | 0 |
| Run-in Period (8 Days) | Inclusion/exclusion criteria not met | 1 | 0 | 0 | 0 | 0 | 0 |
| Run-in Period (8 Days) | Progressive disease | 0 | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Afa30+Sir01 | Afa30+Sir03 | Afa30+Sir05 | Afa30+Sir10 | Afa40+Sir01 | Afa40+Sir05 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 13.6 | 56.5 Years STANDARD_DEVIATION 12.5 | 65.1 Years STANDARD_DEVIATION 9.6 | 50.8 Years STANDARD_DEVIATION 7.5 | 53.4 Years STANDARD_DEVIATION 12.4 | 56.5 Years STANDARD_DEVIATION 17.2 | 58.9 Years STANDARD_DEVIATION 12.3 |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 24 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 15 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 | 12 / 12 | 9 / 9 | 8 / 9 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 4 / 12 | 6 / 9 | 7 / 9 | 2 / 3 | 1 / 3 | 2 / 3 |
Outcome results
Primary
Occurrence of Dose Limiting Toxicities (DLT)
Number of participants with of dose limiting toxicities (DLT)
Time frame: 2 first cycles, 56 days
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afa30+Sir01 | Occurrence of Dose Limiting Toxicities (DLT) | 3 Participants |
| Afa30+Sir03 | Occurrence of Dose Limiting Toxicities (DLT) | 2 Participants |
| Afa30+Sir05 | Occurrence of Dose Limiting Toxicities (DLT) | 4 Participants |
| Afa30+Sir10 | Occurrence of Dose Limiting Toxicities (DLT) | 3 Participants |
| Afa40+Sir01 | Occurrence of Dose Limiting Toxicities (DLT) | 2 Participants |
| Afa40+Sir05 | Occurrence of Dose Limiting Toxicities (DLT) | 3 Participants |
Secondary
AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss)
Area under the curve (AUC) of Afatinib at steady state over the dosing interval τ (AUCτ,ss) for afatinib.
Time frame: 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib
Population: Pharmacokinetic (PK) set which included all patients in the treated set who had taken at least 1 dose of study medication and for whom at least 1 valid blood or plasma concentration was available. No patients in the Afa40+Sir05 group had analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afa30+Sir01 | AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | 603 ng*h/mL | Geometric Coefficient of Variation 37.3 |
| Afa30+Sir03 | AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | 536 ng*h/mL | Geometric Coefficient of Variation 40.1 |
| Afa30+Sir05 | AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | 1560 ng*h/mL | Geometric Coefficient of Variation 49.6 |
| Afa30+Sir10 | AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | NA ng*h/mL | — |
| Afa40+Sir01 | AUC of Afatinib at Steady State Over the Dosing Interval τ (AUCτ,ss) | 1760 ng*h/mL | — |
Secondary
AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss)
Area under the curve (AUC) of sirolimus at steady state over the dosing interval τ (AUCτ,ss) for afatinib.
Time frame: 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib
Population: PK set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Afa30+Sir01 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus alone (N=6, 4, 7, 1, 2, 2) | 91.5 ng*h/mL | Geometric Coefficient of Variation 28.1 |
| Afa30+Sir01 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus with Afatinib (N=4, 3, 2, 2, 1, 0) | 106 ng*h/mL | Geometric Coefficient of Variation 57.9 |
| Afa30+Sir03 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus alone (N=6, 4, 7, 1, 2, 2) | 193 ng*h/mL | Geometric Coefficient of Variation 35.4 |
| Afa30+Sir03 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus with Afatinib (N=4, 3, 2, 2, 1, 0) | 207 ng*h/mL | Geometric Coefficient of Variation 24.4 |
| Afa30+Sir05 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus alone (N=6, 4, 7, 1, 2, 2) | 502 ng*h/mL | Geometric Coefficient of Variation 51.7 |
| Afa30+Sir05 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus with Afatinib (N=4, 3, 2, 2, 1, 0) | NA ng*h/mL | — |
| Afa30+Sir10 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus alone (N=6, 4, 7, 1, 2, 2) | 497 ng*h/mL | — |
| Afa30+Sir10 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus with Afatinib (N=4, 3, 2, 2, 1, 0) | NA ng*h/mL | — |
| Afa40+Sir01 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus alone (N=6, 4, 7, 1, 2, 2) | NA ng*h/mL | — |
| Afa40+Sir01 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus with Afatinib (N=4, 3, 2, 2, 1, 0) | 141 ng*h/mL | — |
| Afa40+Sir05 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus alone (N=6, 4, 7, 1, 2, 2) | NA ng*h/mL | — |
| Afa40+Sir05 | AUC of Sirolimus at Steady State Over the Dosing Interval τ (AUCτ,ss) | Sirolimus with Afatinib (N=4, 3, 2, 2, 1, 0) | NA ng*h/mL | — |
Secondary
Best Overall Response
Best overall response (unconfirmed) according to RECIST v1.1
Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afa30+Sir01 | Best Overall Response | Stable Disease | 50.0 Percentage of participants |
| Afa30+Sir01 | Best Overall Response | Partial Response | 8.3 Percentage of participants |
| Afa30+Sir01 | Best Overall Response | Missing (baseline data only) | 0.0 Percentage of participants |
| Afa30+Sir01 | Best Overall Response | Not evaluable | 8.3 Percentage of participants |
| Afa30+Sir01 | Best Overall Response | Progressive Disease | 33.3 Percentage of participants |
| Afa30+Sir01 | Best Overall Response | Complete Response | 0.0 Percentage of participants |
| Afa30+Sir03 | Best Overall Response | Progressive Disease | 22.2 Percentage of participants |
| Afa30+Sir03 | Best Overall Response | Complete Response | 0.0 Percentage of participants |
| Afa30+Sir03 | Best Overall Response | Partial Response | 0.0 Percentage of participants |
| Afa30+Sir03 | Best Overall Response | Missing (baseline data only) | 33.3 Percentage of participants |
| Afa30+Sir03 | Best Overall Response | Not evaluable | 0.0 Percentage of participants |
| Afa30+Sir03 | Best Overall Response | Stable Disease | 44.4 Percentage of participants |
| Afa30+Sir05 | Best Overall Response | Complete Response | 0.0 Percentage of participants |
| Afa30+Sir05 | Best Overall Response | Not evaluable | 11.1 Percentage of participants |
| Afa30+Sir05 | Best Overall Response | Progressive Disease | 11.1 Percentage of participants |
| Afa30+Sir05 | Best Overall Response | Missing (baseline data only) | 11.1 Percentage of participants |
| Afa30+Sir05 | Best Overall Response | Partial Response | 22.2 Percentage of participants |
| Afa30+Sir05 | Best Overall Response | Stable Disease | 44.4 Percentage of participants |
| Afa30+Sir10 | Best Overall Response | Complete Response | 0.0 Percentage of participants |
| Afa30+Sir10 | Best Overall Response | Partial Response | 0.0 Percentage of participants |
| Afa30+Sir10 | Best Overall Response | Stable Disease | 33.3 Percentage of participants |
| Afa30+Sir10 | Best Overall Response | Progressive Disease | 33.3 Percentage of participants |
| Afa30+Sir10 | Best Overall Response | Not evaluable | 33.3 Percentage of participants |
| Afa30+Sir10 | Best Overall Response | Missing (baseline data only) | 0.0 Percentage of participants |
| Afa40+Sir01 | Best Overall Response | Not evaluable | 0.0 Percentage of participants |
| Afa40+Sir01 | Best Overall Response | Complete Response | 0.0 Percentage of participants |
| Afa40+Sir01 | Best Overall Response | Missing (baseline data only) | 0.0 Percentage of participants |
| Afa40+Sir01 | Best Overall Response | Stable Disease | 66.7 Percentage of participants |
| Afa40+Sir01 | Best Overall Response | Partial Response | 0.0 Percentage of participants |
| Afa40+Sir01 | Best Overall Response | Progressive Disease | 33.3 Percentage of participants |
| Afa40+Sir05 | Best Overall Response | Complete Response | 0.0 Percentage of participants |
| Afa40+Sir05 | Best Overall Response | Stable Disease | 33.3 Percentage of participants |
| Afa40+Sir05 | Best Overall Response | Partial Response | 66.7 Percentage of participants |
| Afa40+Sir05 | Best Overall Response | Not evaluable | 0.0 Percentage of participants |
| Afa40+Sir05 | Best Overall Response | Missing (baseline data only) | 0.0 Percentage of participants |
| Afa40+Sir05 | Best Overall Response | Progressive Disease | 0.0 Percentage of participants |
Secondary
Exploratory Examination of EGFR Mutations (Exons 19, 20 and 21 and Others) in Serum/Plasma DNA and Tumour DNA.
Exploratory examination of Epidermal growth factor (receptor)(EGFR) mutations (Exons 19, 20 and 21 and others) in serum/plasma DNA and tumour DNA. This endpoint was not analysed in the study report as the available data was too limited.
Time frame: Multiple time points during the trial
Population: Treated set. This endpoint was not analysed in the study report as the available data was too limited.
Secondary
Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin
Evaluation of laboratory parameters included assessment of the frequency of patients with ALT and AST elevations concurrent with elevated bilirubin and indicative of Hy's law cases.
Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afa30+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High total bilirubin | 8.3 Percentage of participants |
| Afa30+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High alkaline phosphatase | 9.1 Percentage of participants |
| Afa30+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High ALT (Alanine aminotransferase) | 16.7 Percentage of participants |
| Afa30+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High AST (Aspartate aminotransferase) | 16.7 Percentage of participants |
| Afa30+Sir03 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High total bilirubin | 0.0 Percentage of participants |
| Afa30+Sir03 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High alkaline phosphatase | 0.0 Percentage of participants |
| Afa30+Sir03 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High ALT (Alanine aminotransferase) | 11.1 Percentage of participants |
| Afa30+Sir03 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High AST (Aspartate aminotransferase) | 11.1 Percentage of participants |
| Afa30+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High ALT (Alanine aminotransferase) | 22.2 Percentage of participants |
| Afa30+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High AST (Aspartate aminotransferase) | 11.1 Percentage of participants |
| Afa30+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High total bilirubin | 0.0 Percentage of participants |
| Afa30+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High alkaline phosphatase | 0.0 Percentage of participants |
| Afa30+Sir10 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High alkaline phosphatase | 0.0 Percentage of participants |
| Afa30+Sir10 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High total bilirubin | 0.0 Percentage of participants |
| Afa30+Sir10 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High ALT (Alanine aminotransferase) | 0.0 Percentage of participants |
| Afa30+Sir10 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High AST (Aspartate aminotransferase) | 0.0 Percentage of participants |
| Afa40+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High AST (Aspartate aminotransferase) | 33.3 Percentage of participants |
| Afa40+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High alkaline phosphatase | 0.0 Percentage of participants |
| Afa40+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High ALT (Alanine aminotransferase) | 0.0 Percentage of participants |
| Afa40+Sir01 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High total bilirubin | 0.0 Percentage of participants |
| Afa40+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High ALT (Alanine aminotransferase) | 0.0 Percentage of participants |
| Afa40+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High AST (Aspartate aminotransferase) | 0.0 Percentage of participants |
| Afa40+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High alkaline phosphatase | 0.0 Percentage of participants |
| Afa40+Sir05 | Frequency of Patients With Possible Clinically-significant Abnormalities in Liver Enzymes or Total Bilirubin | High total bilirubin | 0.0 Percentage of participants |
Secondary
Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss)
Maximum measured plasma concentration of Afatinib at steady state (Cmax,ss)
Time frame: 24 hours (h), 311h 55minutes (min), 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h and 336h after first administration of afatinib
Population: Pharmacokinetic (PK) set which included all patients in the treated set who had taken at least 1 dose of study medication and for whom at least 1 valid blood or plasma concentration was available. No patients in the Afa40+Sir05 group had analyzable data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afa30+Sir01 | Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | 41.4 ng/mL | Geometric Coefficient of Variation 17.6 |
| Afa30+Sir03 | Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | 47.1 ng/mL | Geometric Coefficient of Variation 63.8 |
| Afa30+Sir05 | Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | 98.1 ng/mL | Geometric Coefficient of Variation 33.9 |
| Afa30+Sir10 | Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | NA ng/mL | — |
| Afa40+Sir01 | Maximum Measured Plasma Concentration of Afatinib at Steady State (Cmax,ss) | NA ng/mL | — |
Secondary
Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss)
Maximum measured plasma concentration of sirolimus at steady state (Cmax,ss)
Time frame: 24 hours (h) 5 minutes (min), 24h, 23h, 22h, 20h, 18h, 16h, 5min before first afatinib administration and 144h, 311h 55min, 312h, 313h, 314h, 315h, 316h, 317h, 318h, 320h, 336h, 480h after first administration of afatinib
Population: PK set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Afa30+Sir01 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus with Afatinib (N=6, 3, 2, 2, 1, 0) | 5.81 ng/mL | Geometric Coefficient of Variation 64.6 |
| Afa30+Sir01 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus alone (N=8, 5, 7, 1, 2, 3) | 7.96 ng/mL | Geometric Coefficient of Variation 40.7 |
| Afa30+Sir03 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus with Afatinib (N=6, 3, 2, 2, 1, 0) | 15.3 ng/mL | Geometric Coefficient of Variation 1.31 |
| Afa30+Sir03 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus alone (N=8, 5, 7, 1, 2, 3) | 13.8 ng/mL | Geometric Coefficient of Variation 24.1 |
| Afa30+Sir05 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus alone (N=8, 5, 7, 1, 2, 3) | 32.5 ng/mL | Geometric Coefficient of Variation 43.8 |
| Afa30+Sir05 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus with Afatinib (N=6, 3, 2, 2, 1, 0) | NA ng/mL | — |
| Afa30+Sir10 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus alone (N=8, 5, 7, 1, 2, 3) | 30.2 ng/mL | — |
| Afa30+Sir10 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus with Afatinib (N=6, 3, 2, 2, 1, 0) | NA ng/mL | — |
| Afa40+Sir01 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus with Afatinib (N=6, 3, 2, 2, 1, 0) | 8.53 ng/mL | — |
| Afa40+Sir01 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus alone (N=8, 5, 7, 1, 2, 3) | NA ng/mL | — |
| Afa40+Sir05 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus alone (N=8, 5, 7, 1, 2, 3) | 28.5 ng/mL | Geometric Coefficient of Variation 21.9 |
| Afa40+Sir05 | Maximum Measured Plasma Concentration of Sirolimus at Steady State (Cmax,ss) | Sirolimus with Afatinib (N=6, 3, 2, 2, 1, 0) | NA ng/mL | — |
Secondary
Objective Response
Rate of (unconfirmed) objective response, defined as complete response (CR) or partial response (PR) according to RECIST v1.1
Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afa30+Sir01 | Objective Response | 8.3 Percentage of participants |
| Afa30+Sir03 | Objective Response | 0.0 Percentage of participants |
| Afa30+Sir05 | Objective Response | 22.2 Percentage of participants |
| Afa30+Sir10 | Objective Response | 0.0 Percentage of participants |
| Afa40+Sir01 | Objective Response | 0.0 Percentage of participants |
| Afa40+Sir05 | Objective Response | 66.7 Percentage of participants |
Secondary
Occurrence of Adverse Events According to CTCAE, Version 3.0
Percentage of participants with adverse events according to highest Common Terminology Criteria for Adverse Events (CTCAE) grade, version 3.0
Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Afa30+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 5 | 8.3 Percentage of participants |
| Afa30+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 3 | 58.3 Percentage of participants |
| Afa30+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 2 | 33.3 Percentage of participants |
| Afa30+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 1 | 0.0 Percentage of participants |
| Afa30+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 4 | 0.0 Percentage of participants |
| Afa30+Sir03 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 5 | 22.2 Percentage of participants |
| Afa30+Sir03 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 2 | 0.0 Percentage of participants |
| Afa30+Sir03 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 3 | 55.6 Percentage of participants |
| Afa30+Sir03 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 4 | 0.0 Percentage of participants |
| Afa30+Sir03 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 1 | 22.2 Percentage of participants |
| Afa30+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 4 | 0.0 Percentage of participants |
| Afa30+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 1 | 11.1 Percentage of participants |
| Afa30+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 2 | 22.2 Percentage of participants |
| Afa30+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 5 | 0.0 Percentage of participants |
| Afa30+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 3 | 66.7 Percentage of participants |
| Afa30+Sir10 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 3 | 100.0 Percentage of participants |
| Afa30+Sir10 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 1 | 0.0 Percentage of participants |
| Afa30+Sir10 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 2 | 0.0 Percentage of participants |
| Afa30+Sir10 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 5 | 0.0 Percentage of participants |
| Afa30+Sir10 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 4 | 0.0 Percentage of participants |
| Afa40+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 3 | 66.7 Percentage of participants |
| Afa40+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 1 | 0.0 Percentage of participants |
| Afa40+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 2 | 0.0 Percentage of participants |
| Afa40+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 4 | 33.3 Percentage of participants |
| Afa40+Sir01 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 5 | 0.0 Percentage of participants |
| Afa40+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 3 | 100.0 Percentage of participants |
| Afa40+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 2 | 0.0 Percentage of participants |
| Afa40+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 1 | 0.0 Percentage of participants |
| Afa40+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 5 | 0.0 Percentage of participants |
| Afa40+Sir05 | Occurrence of Adverse Events According to CTCAE, Version 3.0 | Grade 4 | 0.0 Percentage of participants |
Secondary
Percentage of Patients With Drug-related AEs
Percentage of patients with drug-related adverse events (AEs).
Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afa30+Sir01 | Percentage of Patients With Drug-related AEs | 100.0 Percentage of participants |
| Afa30+Sir03 | Percentage of Patients With Drug-related AEs | 100.0 Percentage of participants |
| Afa30+Sir05 | Percentage of Patients With Drug-related AEs | 100.0 Percentage of participants |
| Afa30+Sir10 | Percentage of Patients With Drug-related AEs | 100.0 Percentage of participants |
| Afa40+Sir01 | Percentage of Patients With Drug-related AEs | 100.0 Percentage of participants |
| Afa40+Sir05 | Percentage of Patients With Drug-related AEs | 100.0 Percentage of participants |
Secondary
Rate of Disease Control
Rate of (unconfirmed) disease control defined as CR, PR, or stable disease (SD), according to RECIST v1.1
Time frame: From first trial medication intake in the first treatment course until last trial medication intake plus 28 days, up to 367 days
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afa30+Sir01 | Rate of Disease Control | 58.3 Percentage of participants |
| Afa30+Sir03 | Rate of Disease Control | 44.4 Percentage of participants |
| Afa30+Sir05 | Rate of Disease Control | 66.7 Percentage of participants |
| Afa30+Sir10 | Rate of Disease Control | 33.3 Percentage of participants |
| Afa40+Sir01 | Rate of Disease Control | 66.7 Percentage of participants |
| Afa40+Sir05 | Rate of Disease Control | 100.0 Percentage of participants |