Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioma

Glioblastoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Temozolomide

Afatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

BIBW 2992

BIBW 2992 plus TMZ

Boehringer Ingelheim

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.

BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma

Phase I/II Trial of BIBW 2992 (Afatinib) in Treating Patients With Recurrent Glioblastoma Multiforme

Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part

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.

Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.

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.

Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.

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).

maximum measured plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide.

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

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.

maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib.

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.

terminal half-life (t1/2) of temozolomide in presence and absence 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

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 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 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 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.

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.

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 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 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 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).

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).

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

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).

Cause of the death reported during on treatment was due to disease progression.

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).

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.

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).

Number of participants with Clinically Relevant Abnormalities for decreased Cardiac left ventricular function.

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

Phase I - Afatinib 20 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

Phase I - Afatinib 40 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

Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2

Patients receiving Temozolomide monotherapy 75 mg/m\^2 for 21 days followed by 7 days off - Phase II part

Phase II - Temozolomide 75mg/m^2

Patients receiving Afatinib monotherapy 40mg once daily (q.d.) - Phase II part

Phase II - Afatinib 40mg

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.

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

Total

Age, Continuous

Sex: Female, Male

Asian

Black/African American

Hawaiian/Pacific Isle

White

Race/Ethnicity, Customized

The scale range is from 100 (Normal no complaints) to 0 (dead). This score was used in Phase II randomization stratification and in some efficacy analyses.

Karnofsky performance score

For Phase I part, all patients who were treated with at least one dose of the study medication. For Phase II part, all patients who were randomized and have taken at least one dose of the study medication.

Boehringer Ingelheim, Call Center

Number of Participants With DLT- Phase I

Randomised Set (RS). The randomised set includes all patients who were randomised to receive treatment in the Phase II part of the trial.

Progression-free Survival (PFS-6) at Six Months - Phase II

Objective Tumor Response in Phase I

Objective Tumor Response in Phase II

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.

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.

Progression-free Survival (PFS)- Phase II Part

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 (in presence of temozolomide).

Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ)

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 (in absence of temozolomide).

Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ)

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.

AUCτ,ss for Afatinib

Cmax,ss for Afatinib

Tmax,ss for Afatinib

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 (in presence of Afatinib).

Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib)

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 (in absence of Afatinib).

Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib)

AUC (0-8) for Temozolomide

Cmax for Temozolomide

Tmax for Temozolomide

t1/2 for Temozolomide

predose at Day 15 of Cycle 2 (n=17; 15)

predose at Day 15 of Cycle 3 (n=10; 10)

Phase II - Trough Plasma Concentration of Afatinib

Sample tested: Negative

Sample tested: +

Sample tested: +/++

Sample tested: ++

Sample tested: ++/+++

Sample tested: +++

No Sample for test

Number of Participants With EGFRvIII Assessed by IHC Test.

MGMT+

MGMT-

Number of Participants With MGMT Marker Assessed by IHC Test.

EGFR wt+

EGFR wt-

Number of Participants With EGFR Marker Assessed by IHC Test.

PTEN intact

PTEN loss

Number of Participants With PTEN Marker Assessed by IHC Test.

PAKT+

PAKT-

Number of Participants With PAKT Marker Assessed by IHC Test.

EGFR abnormal (Amplification)

EGFR normal (Intact)

EGFR abnormal (Gain)

Number of Participants With EGFR Assessed by FISH

PTEN abnormal (Loss)

PTEN normal (Gain)

PTEN normal (Intact)

Number of Participants With PTEN Assessed by FISH

CEP7 abnormal (Gain)

CEP7 normal (Intact)

Number of Participants With Chromosomes (CEP7) Assessed by FISH

CEP10 abnormal (Loss)

CEP10 normal (Gain)

CEP10 normal (Intact)

Number of Participants With Chromosomes (CEP10) Assessed by FISH

drug-related AEs

AEs leading to discontinuation of trial drug

Serious AE's

other significant AEs

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

Rash

Vomiting

Nausea

Diarrhoea

acne

Haemorrhage intracranial

Convulsion

Syncope

Hemiparesis

Aphasia

Brain oedema

Cerebrovascular accident

Headache

Paralysis

Peroneal nerve palsy

Vasogenic cerebral oedema

Number of Participants With Adverse Events (AEs) Based on Intensity and Incidence of AE's - Phase I

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants With Adverse Events, Graded According CTCAE - Phase I

Causes of Death - Phase I

AE leading to dose reduction

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

Spots Global Cancer Trial Database for bibw 2992 plus tmz