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

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).