Glioma
Conditions
Brief summary
Phase I Part: To determine the maximum tolerated dose (MTD) and pharmacokinetics of BIBW 2992 administered in combination with TMZ in patients with recurrent malignant gliomas (WHO Grade III and IV). Phase II Part: To estimate the efficacy and safety of BIBW 2992 monotherapy and BIBW 2992 / TMZ combination therapy compared to TMZ monotherapy (three treatment arms) in patients with recurrent GBM. To evaluate molecular determinants of response to BIBW 2992.
Interventions
DRUGBIBW 2992
BIBW 2992 once daily
DRUGTMZ
TMZ 21/28
DRUGBIBW 2992 plus TMZ
BIBW 2992 once daily plus TMZ 21/28 days
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase I Part: 1. Histologically-confirmed WHO Grade III or IV malignant glioma that is recurrent after prior chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade III or IV malignant glioma. 2. Age at least 18 years at entry 3. KPS at least 60% 4. Patients must have recovered from previous surgery and chemotherapy. 5. Written informed consent that is consistent with local law and ICH-GCP guidelines. Phase II Part: 1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence after prior combined chemoradiotherapy. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Grade IV malignant glioma and if prior treatment included temozolomide chemotherapy and radiotherapy. 2. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on Gd MRI performed within 14 days prior to first treatment (Day 1). 3. Age at least 18 years at entry 4. KPS at least 70% 5. Patients must have recovered from previous surgery and chemotherapy. 6. Written informed consent that is consistent with local law and ICH-GCP guidelines. 7. Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of study treatment.
Exclusion criteria
Phase I and Phase II Parts: 1. Less than 12 weeks between radiotherapy and start of study treatment, unless new enhancing lesion outside of radiation field or radiologically progressive on two consecutive MRI scans at least four weeks apart or biopsy-proven recurrence. 2. Less than two weeks from surgical resection (one week from prior stereotactic biopsy) or major surgical procedure. 3. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas). 4. Treatment with other investigational drugs; participation in another clinical study within the past 2 weeks before start of therapy or concomitantly with this study. 5. Progressive disease or toxicity =CTCAEv3 Grade 3 to protracted temozolomide dosing (defined as temozolomide administered more than 5 days/28 day cycle). 6. Active infectious disease requiring intravenous therapy. 7. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. 8. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea. 9. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol. 10. Patient is \<3 years free of another primary malignancy except: if the other primary malignancy is either not currently clinically significant or does not require active intervention (such as a basal cell skin cancer or a cervical carcinoma in situ). Existence of any other malignant disease is not allowed. 11. Cardiac left ventricular function with resting ejection fraction \<50%. 12. Absolute neutrophil count (ANC) less than 1500/mm3. 13. Platelet count less than 100,000/mm3. 14. Bilirubin greater than 1.5 x upper limit of institutional norm. 15. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm. 16. Serum creatinine greater than 1.5 x upper limit of institutional norm. 17. Patients who are sexually active and unwilling to use a medically acceptable method of contraception. 18. Pregnancy or breast-feeding. 19. Patients unable to comply with the protocol. 20. Known pre-existing interstitial lung disease (ILD). Phase I part only: 1\. Less than four weeks from prior treatment with bevacizumab. Phase II Part only: 1. Prior EGFR-directed therapy. 2. Prior bevacizumab therapy. 3. Patients presenting with second or higher number of episodes of recurrence. 4. Requirement of treatment with any of the prohibited concomitant medications listed in Section 4.2.2 (Restrictions regarding concomitant treatment).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With DLT- Phase I | From randomization till data cut-off (10 Jun 2009), with a mean treatment duration of 51 days | Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part |
| Progression-free Survival (PFS-6) at Six Months - Phase II | At six months after randomization | PFS-6 is defined as probability of patients surviving to six months after randomization without progression. Disease progression was evaluated by an independent review committee and by the investigators, independently. The evaluation by the independent review committee was used for the primary outcome measure. The measurement Number the estimated PFS-6 value from the Kaplan-Meier curve of PFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS)- Phase II Part | from date of randomization until the date of first documented progression or death by any cause, whichever came first, assessed up to 9 Months. | Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death. |
| AUCτ,ss for Afatinib | Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24 h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1 | Area under the plasma concentration-time curve of afatinib after multiple administration (AUCτ,ss) of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide (TMZ). |
| Cmax,ss for Afatinib | Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1 | maximum measured plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide. |
| Tmax,ss for Afatinib | Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1 | time from dosing to the maximum plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide |
| AUC (0-8) for Temozolomide | Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1 | Area under the plasma concentration-time curve over the time interval from zero to 08h (AUC (0-8)) of temozolomide in presence and absence of afatinib. |
| Cmax for Temozolomide | Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1 | maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib. |
| Tmax for Temozolomide | Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1 | time from dosing to the maximum plasma concentration following the first dose of uniform intervals τ (tmax) of temozolomide in presence and absence of afatinib. |
| t1/2 for Temozolomide | Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1 | terminal half-life (t1/2) of temozolomide in presence and absence of afatinib |
| Phase II - Trough Plasma Concentration of Afatinib | Before (-0.05 h) the drug administration of afatinib on Day 15 of Cycle 2 & 3 | Trough plasma concentration of afatinib after multiple administration of 40 mg afatinib administered as monotherapy or in combination with 75 mg/m² temozolomide |
| Number of Participants With EGFRvIII Assessed by IHC Test. | Baseline (during screening) | Number of participants with the epidermal growth factor receptor variant III (EGFRvIII) assessed by IHC test for the evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFRvIII by immunohistochemistry (IHC) test. |
| Number of Participants With MGMT Marker Assessed by IHC Test. | Baseline (during screening) | Number of participants with MGMT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry (IHC) test. |
| Number of Participants With EGFR Marker Assessed by IHC Test. | Baseline (during screening) | Number of participants with EGFR marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (IHC) test |
| Number of Participants With PTEN Marker Assessed by IHC Test. | Baseline (during screening) | Number of participants with PTEN marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Phosphatase and Tensin Homologue - a tumor suppressor gene/protein (PTEN) by immunohistochemistry (IHC) test. |
| Objective Tumor Response in Phase I | From treatment start until the date of first documented progression or data cutoff at May 12, 2011, whichever came first, with a mean treatment duration of 69.7 days. | Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review. |
| Number of Participants With EGFR Assessed by FISH | Baseline (during screening) | Number of participants with EGFR assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFR by fluorescent in situ hybridization (FISH). |
| Number of Participants With PTEN Assessed by FISH | Baseline (during screening) | Number of participants with PTEN assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for PTEN by fluorescent in situ hybridization (FISH). |
| Number of Participants With Chromosomes (CEP7) Assessed by FISH | Baseline (during screening) | Number of participants with Chromosomes (CEP7) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP7) by fluorescent in situ hybridization (FISH). |
| Number of Participants With Chromosomes (CEP10) Assessed by FISH | Baseline (during screening) | Number of participants with Chromosomes (CEP10) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP10) by fluorescent in situ hybridization (FISH). |
| Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | From first administration of treatment until 28 days after last drug administration, up to 491 days. | Safety was assessed based on number of participants with investigator defined drug-related AEs, AEs leading to discontinuation of trial drug, All Serious Adverse events (AE) and other significant AEs (according to International Conference on Harmonisation (ICH) E3). |
| Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | From first administration of treatment until 28 days after last drug administration, up to 491 days. | Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological |
| Number of Participants With Adverse Events, Graded According CTCAE - Phase I | From first administration of treatment until 28 days after last drug administration, up to 491 days. | Safety of Afatinib assesed based on Number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE). |
| Causes of Death - Phase I | From first administration of treatment until 28 days after last drug administration, up to 491 days. | Cause of the death reported during on treatment was due to disease progression. |
| Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | From first administration of treatment until 28 days after last drug administration, up to 518 days. | Safety was assessed based on number of participants with investigator defined drug-related AEs, AE leading to dose reduction, Adverse events (AEs) leading to discontinuation of trial drug and All Serious Adverse events (SAE). |
| Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | From first administration of treatment until 28 days after last drug administration, up to 518 days. | Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological. |
| Number of Participants With Adverse Events, Graded According CTCAE - Phase II | From first administration of treatment until 28 days after last drug administration, up to 518 days. | Safety of Afatinib assessed based on the number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE). |
| Causes of Death - Phase II | From first administration of treatment until 28 days after last drug administration, up to 518 days. | Causes of death during on treatment. |
| Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II | From first administration of treatment until 28 days after last drug administration, up to 518 days. | Number of participants with Clinically Relevant Abnormalities for decreased Cardiac left ventricular function. |
| Number of Participants With PAKT Marker Assessed by IHC Test. | Baseline (during screening) | Number of participants with PAKT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Serinethreonine kinase (PAKT) by immunohistochemistry (IHC) test. |
| Objective Tumor Response in Phase II | From randomization to until the date of first documented progression or data cutoff on July 15, 2016, whichever came first, with a mean treatment duration of 110.0 days | Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review. Only data collected until cut-off date July 15, 2016 were considered. |
Countries
Canada, United States
Participant flow
Pre-assignment details
This study consists of 2 parts (phase I and phase II) with separate participants.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 Patients receiving Afatinib 20mg once daily (q.d.) plus Temozolomide 75 mg/m\^2 for 21 days followed by 7 days off - Phase I part | 6 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m\^2 for 21 days followed by 7 days off - Phase I part | 8 |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 Patients receiving Afatinib 50mg once daily (q.d.) plus Temozolomide 75 mg/m\^2 for 21 days followed by 7 days off - Phase I part | 18 |
| Phase II - Temozolomide 75mg/m^2 Patients receiving Temozolomide monotherapy 75 mg/m\^2 for 21 days followed by 7 days off - Phase II part | 39 |
| Phase II - Afatinib 40mg Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part | 41 |
| Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 Patients receiving Afatinib 40mg once daily (q.d.) plus Temozolomide 75 mg/m\^2 for 21 days followed by 7 days off - Phase II part | 39 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 4 | 4 | 1 | 8 |
| Overall Study | Dose Limiting Toxicity (DLT) | 2 | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Other reason not described above | 0 | 0 | 1 | 4 | 1 | 1 |
| Overall Study | Progressive disease | 4 | 7 | 9 | 28 | 38 | 28 |
| Overall Study | Refused to continue medication | 0 | 1 | 2 | 3 | 1 | 2 |
Baseline characteristics
| Characteristic | Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Total | Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 | Phase II - Afatinib 40mg | Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Phase II - Temozolomide 75mg/m^2 | Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 51.6 years STANDARD_DEVIATION 14.2 | 56.3 years STANDARD_DEVIATION 10.3 | 55.4 years STANDARD_DEVIATION 11.02 | 56.6 years STANDARD_DEVIATION 9.44 | 51.7 years STANDARD_DEVIATION 12.4 | 56.9 years STANDARD_DEVIATION 10.62 | 51.0 years STANDARD_DEVIATION 9.4 |
| Karnofsky performance score 100 | 2 Number of participants | 19 Number of participants | 3 Number of participants | 3 Number of participants | 2 Number of participants | 5 Number of participants | 4 Number of participants |
| Karnofsky performance score 70 | 1 Number of participants | 33 Number of participants | 12 Number of participants | 9 Number of participants | 1 Number of participants | 9 Number of participants | 1 Number of participants |
| Karnofsky performance score 80 | 1 Number of participants | 38 Number of participants | 9 Number of participants | 12 Number of participants | 1 Number of participants | 13 Number of participants | 2 Number of participants |
| Karnofsky performance score 90 | 4 Number of participants | 61 Number of participants | 15 Number of participants | 17 Number of participants | 2 Number of participants | 12 Number of participants | 11 Number of participants |
| Race/Ethnicity, Customized Asian | 1 Number of participants | 3 Number of participants | 1 Number of participants | 1 Number of participants | 0 Number of participants | 0 Number of participants | 0 Number of participants |
| Race/Ethnicity, Customized Black/African American | 0 Number of participants | 6 Number of participants | 2 Number of participants | 0 Number of participants | 0 Number of participants | 2 Number of participants | 2 Number of participants |
| Race/Ethnicity, Customized Hawaiian/Pacific Isle | 0 Number of participants | 1 Number of participants | 1 Number of participants | 0 Number of participants | 0 Number of participants | 0 Number of participants | 0 Number of participants |
| Race/Ethnicity, Customized White | 7 Number of participants | 141 Number of participants | 35 Number of participants | 40 Number of participants | 6 Number of participants | 37 Number of participants | 16 Number of participants |
| Sex: Female, Male Female | 2 Participants | 58 Participants | 18 Participants | 14 Participants | 2 Participants | 14 Participants | 8 Participants |
| Sex: Female, Male Male | 6 Participants | 93 Participants | 21 Participants | 27 Participants | 4 Participants | 25 Participants | 10 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 | 6 / 6 | 8 / 8 | 18 / 18 | 36 / 39 | 40 / 41 | 37 / 39 |
| serious Total, serious adverse events | 2 / 6 | 1 / 8 | 10 / 18 | 6 / 39 | 10 / 41 | 13 / 39 |
Outcome results
Primary
Number of Participants With DLT- Phase I
Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part
Time frame: From randomization till data cut-off (10 Jun 2009), with a mean treatment duration of 51 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With DLT- Phase I | 2 participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With DLT- Phase I | 0 participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With DLT- Phase I | 4 participants |
Primary
Progression-free Survival (PFS-6) at Six Months - Phase II
PFS-6 is defined as probability of patients surviving to six months after randomization without progression. Disease progression was evaluated by an independent review committee and by the investigators, independently. The evaluation by the independent review committee was used for the primary outcome measure. The measurement Number the estimated PFS-6 value from the Kaplan-Meier curve of PFS.
Time frame: At six months after randomization
Population: Randomised Set (RS). The randomised set includes all patients who were randomised to receive treatment in the Phase II part of the trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Progression-free Survival (PFS-6) at Six Months - Phase II | 0.230 probablity of survival |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Progression-free Survival (PFS-6) at Six Months - Phase II | 0.030 probablity of survival |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Progression-free Survival (PFS-6) at Six Months - Phase II | 0.103 probablity of survival |
p-value: 0.148z-test
p-value: 0.008z-test
Secondary
AUC (0-8) for Temozolomide
Area under the plasma concentration-time curve over the time interval from zero to 08h (AUC (0-8)) of temozolomide in presence and absence of afatinib.
Time frame: Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1
Population: PKS set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | AUC (0-8) for Temozolomide | 8380 ng·h/mL | Geometric Coefficient of Variation 24.1 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | AUC (0-8) for Temozolomide | 8160 ng·h/mL | Geometric Coefficient of Variation 27.8 |
Secondary
AUCτ,ss for Afatinib
Area under the plasma concentration-time curve of afatinib after multiple administration (AUCτ,ss) of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide (TMZ).
Time frame: Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24 h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1
Population: PKS Set and the patients who had enough PK samples for calculation of AUC. Pharmacokinetic set (PKS) : All patients who provided at least one blood sample were included in the Pharmacokinetic (PK) analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | AUCτ,ss for Afatinib | 1070 ng·h/mL | Standard Deviation 63.7 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | AUCτ,ss for Afatinib | 918 ng·h/mL | Standard Deviation 65.3 |
Secondary
Causes of Death - Phase I
Cause of the death reported during on treatment was due to disease progression.
Time frame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase I | 0 deaths |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase I | 0 deaths |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase I | 1 deaths |
Secondary
Causes of Death - Phase II
Causes of death during on treatment.
Time frame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Malignant Neoplasm Progression | 1 deaths |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Tumor progression | 1 deaths |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Respiratory failure | 0 deaths |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Respiratory failure | 0 deaths |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Malignant Neoplasm Progression | 0 deaths |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Tumor progression | 1 deaths |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Tumor progression | 0 deaths |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Malignant Neoplasm Progression | 1 deaths |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Causes of Death - Phase II | Respiratory failure | 1 deaths |
Secondary
Cmax for Temozolomide
maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib.
Time frame: Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1
Population: PKS set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Cmax for Temozolomide | 2520 ng/mL | Geometric Coefficient of Variation 33.3 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Cmax for Temozolomide | 2690 ng/mL | Geometric Coefficient of Variation 39.7 |
Secondary
Cmax,ss for Afatinib
maximum measured plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide.
Time frame: Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1
Population: PKS set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Cmax,ss for Afatinib | 63.2 ng/mL | Standard Deviation 62.1 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Cmax,ss for Afatinib | 50.5 ng/mL | Standard Deviation 58 |
Secondary
Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I
Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological
Time frame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | acne | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Vomiting | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Nausea | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Diarrhoea | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Rash | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Haemorrhage intracranial | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Convulsion | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Syncope | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Hemiparesis | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Aphasia | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Brain oedema | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Cerebrovascular accident | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Headache | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Paralysis | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Peroneal nerve palsy | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Vasogenic cerebral oedema | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Haemorrhage intracranial | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Convulsion | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Syncope | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Paralysis | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Hemiparesis | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Aphasia | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Vasogenic cerebral oedema | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Brain oedema | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Rash | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Peroneal nerve palsy | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Vomiting | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Cerebrovascular accident | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Nausea | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Diarrhoea | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | acne | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Headache | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Brain oedema | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Haemorrhage intracranial | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Headache | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Nausea | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Convulsion | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Vasogenic cerebral oedema | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Rash | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Syncope | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Cerebrovascular accident | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | acne | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Hemiparesis | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Paralysis | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Vomiting | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Aphasia | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Diarrhoea | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I | Peroneal nerve palsy | 1 Participants |
Secondary
Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II
Safety of afatinib as indicated by number of participants with adverse events based on intensity and incidence of AE's, especially skin reactions (rash, acne), gastrointestinal (GI) (Vomiting, nausea, diarrhea) and neurological.
Time frame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Memory impairment | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Hemiparesis | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Neurological decompensation | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Vomiting | 8 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Dysgeusia | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Cerebral haemorrhage | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Rash | 3 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Acne | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Headache | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Nausea | 7 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Speech disorder | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Ataxia | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Diarrhoea | 4 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Cerebral haemorrhage | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Rash | 19 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Acne | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Vomiting | 4 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Nausea | 6 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Diarrhoea | 29 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Neurological decompensation | 2 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Dysgeusia | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Hemiparesis | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Ataxia | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Headache | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Memory impairment | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Speech disorder | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Hemiparesis | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Nausea | 13 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Memory impairment | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Ataxia | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Vomiting | 10 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Rash | 22 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Headache | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Cerebral haemorrhage | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Neurological decompensation | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Acne | 4 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Dysgeusia | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Diarrhoea | 32 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase II | Speech disorder | 0 Participants |
Secondary
Number of Participants With Adverse Events, Graded According CTCAE - Phase I
Safety of Afatinib assesed based on Number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Time frame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 4 | 2 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 3 | 0 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 1 | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 2 | 3 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 5 | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 3 | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 1 | 2 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 2 | 4 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 4 | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 5 | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 5 | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 4 | 3 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 1 | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 3 | 7 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase I | Grade 2 | 7 Participants |
Secondary
Number of Participants With Adverse Events, Graded According CTCAE - Phase II
Safety of Afatinib assessed based on the number of participants with adverse events, graded according to United States National Cancer Institute Common terminology Criteria for Adverse Events (US NCI CTCAE) Version 3.0. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).
Time frame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 4 | 5 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 3 | 13 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 1 | 3 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 2 | 14 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 5 | 2 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 3 | 15 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 1 | 5 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 2 | 18 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 4 | 2 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 5 | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 5 | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 4 | 5 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 1 | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 3 | 19 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Adverse Events, Graded According CTCAE - Phase II | Grade 2 | 10 Participants |
Secondary
Number of Participants With Chromosomes (CEP10) Assessed by FISH
Number of participants with Chromosomes (CEP10) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP10) by fluorescent in situ hybridization (FISH).
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 abnormal (Loss) | 10 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 normal (Gain) | 2 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 normal (Intact) | 4 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | No Sample for test | 18 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 abnormal (Loss) | 19 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 normal (Intact) | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 normal (Gain) | 3 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 normal (Gain) | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 normal (Intact) | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP10) Assessed by FISH | CEP10 abnormal (Loss) | 24 Participants |
Secondary
Number of Participants With Chromosomes (CEP7) Assessed by FISH
Number of participants with Chromosomes (CEP7) assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Chromosomes (CEP7) by fluorescent in situ hybridization (FISH).
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | CEP7 normal (Intact) | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | CEP7 abnormal (Gain) | 15 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | CEP7 normal (Intact) | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | CEP7 abnormal (Gain) | 24 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | No Sample for test | 17 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | CEP7 abnormal (Gain) | 27 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Chromosomes (CEP7) Assessed by FISH | CEP7 normal (Intact) | 1 Participants |
Secondary
Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II
Number of participants with Clinically Relevant Abnormalities for decreased Cardiac left ventricular function.
Time frame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II | 0.0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II | 0.0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Clinically Relevant Abnormalities for Decreased Cardiac Left Ventricular Function - Phase II | 0.0 Participants |
Secondary
Number of Participants With EGFR Assessed by FISH
Number of participants with EGFR assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFR by fluorescent in situ hybridization (FISH).
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR abnormal (Amplification) | 5 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR normal (Intact) | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR abnormal (Gain) | 10 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | No Sample for test | 18 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR abnormal (Amplification) | 14 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR abnormal (Gain) | 9 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR normal (Intact) | 0 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR normal (Intact) | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR abnormal (Gain) | 16 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Assessed by FISH | EGFR abnormal (Amplification) | 11 Participants |
Secondary
Number of Participants With EGFR Marker Assessed by IHC Test.
Number of participants with EGFR marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (IHC) test
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | EGFR wt- | 2 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | EGFR wt+ | 14 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | EGFR wt- | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | EGFR wt+ | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | No Sample for test | 18 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | EGFR wt+ | 24 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFR Marker Assessed by IHC Test. | EGFR wt- | 4 Participants |
Secondary
Number of Participants With EGFRvIII Assessed by IHC Test.
Number of participants with the epidermal growth factor receptor variant III (EGFRvIII) assessed by IHC test for the evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for EGFRvIII by immunohistochemistry (IHC) test.
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: + | 5 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: ++/+++ | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: ++ | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: Negative | 6 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | No Sample for test | 23 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: +++ | 3 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: +/++ | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: ++ | 4 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: Negative | 8 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: + | 3 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: +/++ | 3 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: ++/+++ | 3 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: +++ | 5 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | No Sample for test | 15 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: ++/+++ | 3 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: + | 4 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: +++ | 10 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: ++ | 4 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: +/++ | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With EGFRvIII Assessed by IHC Test. | Sample tested: Negative | 5 Participants |
Secondary
Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II
Safety was assessed based on number of participants with investigator defined drug-related AEs, AE leading to dose reduction, Adverse events (AEs) leading to discontinuation of trial drug and All Serious Adverse events (SAE).
Time frame: From first administration of treatment until 28 days after last drug administration, up to 518 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | drug-related AEs | 22 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | AE leading to dose reduction | 2 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | AEs leading to discontinuation of trial drug | 9 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | Serious AE's | 6 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | Serious AE's | 10 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | drug-related AEs | 35 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | AEs leading to discontinuation of trial drug | 8 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | AE leading to dose reduction | 4 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | Serious AE's | 13 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | AE leading to dose reduction | 7 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | AEs leading to discontinuation of trial drug | 14 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AE Leading to Dose Reduction, AEs Leading to Discontinuation of Trial Drug and All SAE- Phase II | drug-related AEs | 36 Participants |
Secondary
Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I
Safety was assessed based on number of participants with investigator defined drug-related AEs, AEs leading to discontinuation of trial drug, All Serious Adverse events (AE) and other significant AEs (according to International Conference on Harmonisation (ICH) E3).
Time frame: From first administration of treatment until 28 days after last drug administration, up to 491 days.
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | drug-related AEs | 4 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | AEs leading to discontinuation of trial drug | 2 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | Serious AE's | 2 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | other significant AEs | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | other significant AEs | 0 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | drug-related AEs | 8 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | Serious AE's | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | AEs leading to discontinuation of trial drug | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | other significant AEs | 5 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | AEs leading to discontinuation of trial drug | 10 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | Serious AE's | 10 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With Investigator Defined Drug-Related AEs, AEs Leading to Discontinuation of Trial Drug, All Serious Adverse Events (AE) and Other Significant AEs - Phase I | drug-related AEs | 17 Participants |
Secondary
Number of Participants With MGMT Marker Assessed by IHC Test.
Number of participants with MGMT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry (IHC) test.
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | MGMT- | 7 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | MGMT+ | 9 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | MGMT- | 15 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | MGMT+ | 8 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | No Sample for test | 18 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | MGMT+ | 12 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | No Sample for test | 12 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With MGMT Marker Assessed by IHC Test. | MGMT- | 15 Participants |
Secondary
Number of Participants With PAKT Marker Assessed by IHC Test.
Number of participants with PAKT marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Serinethreonine kinase (PAKT) by immunohistochemistry (IHC) test.
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | PAKT- | 11 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | PAKT+ | 5 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | PAKT- | 13 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | PAKT+ | 11 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | No Sample for test | 17 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | PAKT+ | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | No Sample for test | 12 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PAKT Marker Assessed by IHC Test. | PAKT- | 16 Participants |
Secondary
Number of Participants With PTEN Assessed by FISH
Number of participants with PTEN assessed by FISH for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for PTEN by fluorescent in situ hybridization (FISH).
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN abnormal (Loss) | 11 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN normal (Gain) | 1 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN normal (Intact) | 4 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | No Sample for test | 18 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN abnormal (Loss) | 20 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN normal (Intact) | 1 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN normal (Gain) | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN normal (Gain) | 1 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN normal (Intact) | 2 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Assessed by FISH | PTEN abnormal (Loss) | 25 Participants |
Secondary
Number of Participants With PTEN Marker Assessed by IHC Test.
Number of participants with PTEN marker assessed by IHC test for evaluation of molecular determinants of response to afatinib. Archival tumor samples from enrolled patients were collected and analyzed for Phosphatase and Tensin Homologue - a tumor suppressor gene/protein (PTEN) by immunohistochemistry (IHC) test.
Time frame: Baseline (during screening)
Population: Randomized set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | PTEN loss | 11 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | PTEN intact | 5 Participants |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | No Sample for test | 23 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | PTEN loss | 19 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | PTEN intact | 4 Participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | No Sample for test | 18 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | PTEN intact | 7 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | No Sample for test | 11 Participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Number of Participants With PTEN Marker Assessed by IHC Test. | PTEN loss | 21 Participants |
Secondary
Objective Tumor Response in Phase I
Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.
Time frame: From treatment start until the date of first documented progression or data cutoff at May 12, 2011, whichever came first, with a mean treatment duration of 69.7 days.
Population: Patients treated in Phase I part
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Objective Tumor Response in Phase I | 0 participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Objective Tumor Response in Phase I | 1 participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Objective Tumor Response in Phase I | 0 participants |
Secondary
Objective Tumor Response in Phase II
Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review. Only data collected until cut-off date July 15, 2016 were considered.
Time frame: From randomization to until the date of first documented progression or data cutoff on July 15, 2016, whichever came first, with a mean treatment duration of 110.0 days
Population: RS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Objective Tumor Response in Phase II | 4 participants |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Objective Tumor Response in Phase II | 1 participants |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Objective Tumor Response in Phase II | 3 participants |
p-value: 1Fisher Exact
p-value: 0.1954Fisher Exact
Secondary
Phase II - Trough Plasma Concentration of Afatinib
Trough plasma concentration of afatinib after multiple administration of 40 mg afatinib administered as monotherapy or in combination with 75 mg/m² temozolomide
Time frame: Before (-0.05 h) the drug administration of afatinib on Day 15 of Cycle 2 & 3
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Phase II - Trough Plasma Concentration of Afatinib | predose at Day 15 of Cycle 2 (n=17; 15) | 19.8 ng/mL | Geometric Coefficient of Variation 69.5 |
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Phase II - Trough Plasma Concentration of Afatinib | predose at Day 15 of Cycle 3 (n=10; 10) | 19.6 ng/mL | Geometric Coefficient of Variation 70.8 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Phase II - Trough Plasma Concentration of Afatinib | predose at Day 15 of Cycle 2 (n=17; 15) | 29.7 ng/mL | Geometric Coefficient of Variation 72.1 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Phase II - Trough Plasma Concentration of Afatinib | predose at Day 15 of Cycle 3 (n=10; 10) | 20.2 ng/mL | Geometric Coefficient of Variation 79.1 |
Secondary
Progression-free Survival (PFS)- Phase II Part
Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.
Time frame: from date of randomization until the date of first documented progression or death by any cause, whichever came first, assessed up to 9 Months.
Population: Randomized set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Progression-free Survival (PFS)- Phase II Part | 1.87 Months |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Progression-free Survival (PFS)- Phase II Part | 0.99 Months |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | Progression-free Survival (PFS)- Phase II Part | 1.53 Months |
Comparison: Hazard ratio was calculated from Cox proportional hazard model stratified by age class (\<=50 vs. \>50 years old) and baseline Karnofsky Performance Scale (KPS) score (70, 80 vs. 90, 100). P-value was two-sided from log-rank test stratified by the same variables.p-value: 0.03295% CI: [1.088, 2.912]Log Rank
Comparison: Hazard ratio was calculated from Cox proportional hazard model stratified by age class (\<=50 vs. \>50 years old) and baseline KPS score (70, 80 vs. 90, 100). P-value was two-sided from log-rank test stratified by the same variables.p-value: 0.204495% CI: [0.841, 2.301]Log Rank
Secondary
t1/2 for Temozolomide
terminal half-life (t1/2) of temozolomide in presence and absence of afatinib
Time frame: Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1
Population: PKS set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | t1/2 for Temozolomide | 2.17 hours | Geometric Coefficient of Variation 34.3 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | t1/2 for Temozolomide | 2.08 hours | Geometric Coefficient of Variation 58.4 |
Secondary
Tmax for Temozolomide
time from dosing to the maximum plasma concentration following the first dose of uniform intervals τ (tmax) of temozolomide in presence and absence of afatinib.
Time frame: Before (-0.05 h) the first drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h after drug administration on Day 1 (in absence of afatinib) and Day 15 (in presence of afatinib) of treatment Cycle 1
Population: PKS set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Tmax for Temozolomide | 1.22 h |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Tmax for Temozolomide | 1.00 h |
Secondary
Tmax,ss for Afatinib
time from dosing to the maximum plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide
Time frame: Before (-0.05 h) the drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8 h and 24h after drug administration on Day 15 (in presence of temozolomide) and Day 28 (in absence of temozolomide) of treatment Cycle 1
Population: PKS set
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | Tmax,ss for Afatinib | 4.00 hour | Full Range 58 |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | Tmax,ss for Afatinib | 3.50 hour | Full Range 62.1 |