Open Label Trial to Explore Safety of Combining Afatinib (BIBW 2992) and Radiotherapy With or Without Temozolomide in Newly Diagnosed Glioblastoma Multiform

Phase I, Open Label Trial to Explore Safety of Combining BIBW 2992 and Radiotherapy With or Without Temozolomide in Newly Diagnosed GBM

This study is a phase I, open label trial to determine the Maximum Tolerated Dose (MTD), safety, pharmacokinetics, and efficacy of BIBW 2992 (an epidermal growth factor receptor(EGFR)inhibitor) to be used in combination with:

• radiotherapy alone (in patients with an unmethylated (functioning) MGMT gene regulator) or
• radiotherapy and Temozolomide (in patients with a methylated (silenced) O6-methylguanine-DNA methyltransferase gene (MGMT) to treat newly diagnosed patients with Grade IV Glioblastoma (primary brain cancer).

Inclusion criteria:

1. Histologically-confirmed WHO Grade IV newly diagnosed malignant glioma.
2. Proven MGMT gene promoter methylation status
3. Available early postoperative Gd-enhanced MRI (within 72 hours after initial surgery). In case a patient did not perform a Gd-enhanced MRI within 72 hours post surgery, a Gd-MRI is to be performed prior to start of study treatment.
4. Age more or equal to 18 years and less than 70 years at entry
5. Karnofsky Performance Scale (KPS) more or equal to 70%
6. Patients receiving corticosteroids have to receive a stable or decreasing dose for at least 14 days before start of treatment.
7. Written informed consent that is consistent with local law and ICH- Good Clinical Practice (GCP) guidelines.

Exclusion criteria:

1. Less than two weeks from surgical resection or other major surgical procedure at start of treatment.
2. Planned surgery for other diseases
3. Placement of Gliadel® wafer at surgery.
4. Prior or planned radiotherapy of the cranium including brachytherapy and/or radiosurgery for GBM.
5. Treatment with other investigational drugs; participation in another clinical study including exposure to the investigational product within the past 4 weeks before start of therapy or concomitantly with this study.
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 diarrhoea.
9. Patients with known pre-existing interstitial lung disease
10. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
11. Patient is less than 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.
12. Cardiac left ventricular function with resting ejection fraction less than 50%.
13. Absolute neutrophil count (ANC) less than 1500/mm3.
14. Platelet count less than 100,000/mm3.
15. Bilirubin greater than 1.5 x upper limit of institutional norm.
16. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm.
17. Serum creatinine greater than 1.5 x upper limit of institutional norm.
18. Patients who are sexually active and unwilling to use a medically acceptable method of contraception.
19. Pregnancy or breast-feeding.
20. Patients unable to comply with the protocol.
21. Known or suspected active drug or alcohol abuse.
22. Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs.