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BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma
Phase 2 trial testing BIBW 2992 in Glioma in 151 participants. Completed in 25 May 2016.
| Lead sponsor | Boehringer Ingelheim |
|---|---|
| Phase | Phase 2 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 151 |
| Start date | 14 July 2008 |
| Primary completion | 12 May 2011 |
| Estimated completion | 25 May 2016 |
| Sites | 28 locations across Canada, United States |
Boehringer Ingelheim — full company profile →
18 and older, any sex, with Glioma. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
Number of Participants With Dose Limiting Toxicities (DLT) - Phase I Part
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | 2 | |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | 0 | |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | 4 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Phase II - Temozolomide 75mg/m^2 | 0.230 | 0.09 – 0.37 |
| Phase II - Afatinib 40mg | 0.030 | 0.00 – 0.09 |
| Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 | 0.103 | 0.00 – 0.21 |
Objective Tumor Response is defined as complete response (CR) and partial response (PR) according to the MacDonald criteria assessed by central independent review.
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 20 mg Plus Temozolomide 75mg/m^2 | 0 | |
| Phase I - Afatinib 40 mg Plus Temozolomide 75mg/m^2 | 1 | |
| Phase I - Afatinib 50 mg Plus Temozolomide 75mg/m^2 | 0 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Phase II - Temozolomide 75mg/m^2 | 4 | 2.9 – 24.2 |
| Phase II - Afatinib 40mg | 1 | 0.1 – 12.9 |
| Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 | 3 | 1.6 – 20.9 |
Progression-free survival was defined as the duration between randomization and the date of the first of the two following events: progression or death.
| Group | Value | 95% CI |
|---|---|---|
| Phase II - Temozolomide 75mg/m^2 | 1.87 | 1.15 – 3.68 |
| Phase II - Afatinib 40mg | 0.99 | 0.95 – 1.84 |
| Phase II - Afatinib 40mg Plus Temozolomide 75 mg/m^2 | 1.53 | 0.99 – 1.87 |
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).
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ) | 1070 | ± 63.7 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ) | 918 | ± 65.3 |
maximum measured plasma concentration of afatinib after multiple administration of 50 mg afatinib in presence and absence of 75 mg/m² temozolomide.
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ) | 63.2 | ± 62.1 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ) | 50.5 | ± 58.0 |
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
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of TMZ) | 4.00 | 1.50 – 8.00 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of TMZ) | 3.50 | 1.00 – 7.92 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) | 8380 | ± 24.1 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib) | 8160 | ± 27.8 |
maximum measured plasma concentration following the first dose of uniform intervals τ (Cmax) of temozolomide in presence and absence of afatinib.
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) | 2520 | ± 33.3 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib) | 2690 | ± 39.7 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) | 1.22 | 1.00 – 3.25 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib) | 1.00 | 0.500 – 2.00 |
terminal half-life (t1/2) of temozolomide in presence and absence of afatinib
| Group | Value | 95% CI |
|---|---|---|
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Presence of Afatinib) | 2.17 | ± 34.3 |
| Phase I - Afatinib 50mg+TMZ 75mg/m^2 (in Absence of Afatinib) | 2.08 | ± 58.4 |
Time frame: From first administration of treatment until 28 days after last drug administration, up to 491 days (Phase I) and 518 days (Phase II).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Phase I - Afatinib 20 mg P… | Phase I - Afatinib 40 mg P… | Phase I - Afatinib 50 mg P… | Phase II - Temozolomide 75… | Phase II - Afatinib 40mg | Phase II - Afatinib 40mg P… |
|---|---|---|---|---|---|---|---|
| Seizure | Nervous system disorders | — | — | — | — | — | — |
| Thrombocytopenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Diarrhoea | Gastrointestinal disorders | — | — | — | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — | — | — | — |
| Dehydration | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Hemiparesis | Nervous system disorders | — | — | — | — | — | — |
| Confusional state | Psychiatric disorders | — | — | — | — | — | — |
| Mental status changes | Psychiatric disorders | — | — | — | — | — | — |
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | — | — | — | — | — | — |
| Convulsion | Nervous system disorders | — | — | — | — | — | — |
| Anaemia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Febrile neutropenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Spontaneous haematoma | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Palpitations | Cardiac disorders | — | — | — | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — | — | — | — |
| Dysphagia | Gastrointestinal disorders | — | — | — | — | — | — |
| Cholecystitis | Hepatobiliary disorders | — | — | — | — | — | — |
| Cellulitis | Infections and infestations | — | — | — | — | — | — |
| Necrotising fasciitis | Infections and infestations | — | — | — | — | — | — |
| Sepsis | Infections and infestations | — | — | — | — | — | — |
| Femoral neck fracture | Injury, poisoning and procedural complications | — | — | — | — | — | — |
| Hyponatraemia | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Muscular weakness | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Altered state of consciousness | Nervous system disorders | — | — | — | — | — | — |
| Cerebral haemorrhage | Nervous system disorders | — | — | — | — | — | — |
| Reaction | System | Phase I - Afatinib 20 mg P… | Phase I - Afatinib 40 mg P… | Phase I - Afatinib 50 mg P… | Phase II - Temozolomide 75… | Phase II - Afatinib 40mg | Phase II - Afatinib 40mg P… |
|---|---|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | — | — | — | — | — | — |
| Rash | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Nausea | Gastrointestinal disorders | — | — | — | — | — | — |
| Decreased appetite | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Fatigue | General disorders | — | — | — | — | — | — |
| Headache | Nervous system disorders | — | — | — | — | — | — |
| Dry skin | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Seizure | Nervous system disorders | — | — | — | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — | — | — | — |
| Constipation | Gastrointestinal disorders | — | — | — | — | — | — |
| Weight decreased | Investigations | — | — | — | — | — | — |
| Hypokalaemia | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Muscular weakness | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Cough | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Contusion | Injury, poisoning and procedural complications | — | — | — | — | — | — |
| Aphasia | Nervous system disorders | — | — | — | — | — | — |
| Hypoaesthesia | Nervous system disorders | — | — | — | — | — | — |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Lymphopenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Dehydration | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Dizziness | Nervous system disorders | — | — | — | — | — | — |
| Depression | Psychiatric disorders | — | — | — | — | — | — |
| Acne | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Pruritus | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Thrombocytopenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Nasopharyngitis | Infections and infestations | — | — | — | — | — | — |
| Oral candidiasis | Infections and infestations | — | — | — | — | — | — |
| Hyperglycaemia | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Arthralgia | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Back pain | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Muscle spasms | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Pain in extremity | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Brain oedema | Nervous system disorders | — | — | — | — | — | — |
| Dysgeusia | Nervous system disorders | — | — | — | — | — | — |
| Hemiparesis | Nervous system disorders | — | — | — | — | — | — |
| Memory impairment | Nervous system disorders | — | — | — | — | — | — |
| Paraesthesia | Nervous system disorders | — | — | — | — | — | — |
| Speech disorder | Nervous system disorders | — | — | — | — | — | — |
| Insomnia | Psychiatric disorders | — | — | — | — | — | — |
Most-reported serious reactions: Seizure, Thrombocytopenia, Diarrhoea, Vomiting, Dehydration, Hemiparesis, Confusional state, Mental status changes.
Data from ClinicalTrials.gov NCT00727506 adverse events section.
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.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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