A phase II/III study of high-dose, intermittent sunitinib in patients with recurrent glioblastoma multiforme: the STELLAR study

1. Signed (by the patient or legally acceptable representative) and dated Informed Consent Form

2. Histologically confirmed de novo or secondary glioblastoma with unequivocal first progression, at least 3 months off radiotherapy.

3. No more than one line of chemotherapy (concurrent and adjuvant temozolomide based chemotherapy including in combination with another investigational agent is considered one line of chemotherapy). Chemotherapy must have been completed at least 4 weeks prior to randomization.

4. Patients may have undergone surgery for recurrence. If operated, residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence.

5. No radiotherapy, stereotactic radiosurgery or brachytherapy as treatment for recurrence.

6. Patients must have a Karnofsky Performance Score ¡Ý 70%

7. Patients need to have adequate hematological, renal and hepatic function as assessed by the following laboratory requirements to be conducted within seven days prior to start study treatment:

a. Hemoglobin ¡Ý 7.0 mmol/L

b. Absolute neutrophil count (ANC) ¡Ý 1.5 x 109/L

c. Platelet count ¡Ý 100 x 109/L

d. ALAT and ASAT ¡Ü 2.5 x ULN

e. Serum creatinine eGFR ¡Ý 50 ml/min

f. Albumin ¡Ý 25 g/L

8. Age ¡Ý 18 years

9. Male and female patients with reproductive potential must use an approved contraceptive method during and for three months after discontinuation of study treatment.

10. Patients must be able to swallow oral medication.

1. Evidence of a significant uncontrolled concomitant disease, such as cardiovascular disease (including stroke, New York Heart Association Class III or IV cardiac disease or myocardial infarction within 6 months prior to screening, unstable arrhythmia, clinically significant valvular heart disease and unstable angina); nervous system, pulmonary (including obstructive pulmonary disease and history of symptomatic bronchospasm), renal, hepatic, endocrine, or gastrointestinal disorders; or a serious non-healing wound or fracture.

2. Patients with a prior (< 5 years) or concomitant second malignancy.

3. Prior radiotherapy in the abdomen or in the lungs or in more than 3 vertebrae in the spine (Less than 3 vertebrae are considered a small radiation field and eligibility will be decided on an individual basis from the PI)

4. Poorly controlled hypertension despite adequate blood pressure medication. Blood pressure must be ¡Ü 160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 2 separate measurements.

5. Known active bacterial, viral, fungal, mycobacterial, or other infection (including HIV and atypical mycobacterial disease, but excluding fungal infection of the nail beds.)

6. Initial MR-scan of the brain showing intratumoral hemorrhage, except for stable post-operative grade 1 hemorrhage.

7. Known hypersensitivity to sunitinib or to its excipients.

8. Presence of any significant central nervous system or psychiatric disorder(s) that would interfere with the patient¡¯s compliance.

9. Use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes.

10. Drug or alcohol abuse.

11. Females who are pregnant or breast-feeding.

12. Any evidence of a disease or condition that might affect compliance with the protocol or interpretation of the study results or render the patient at high risk from treatment complications.

13. Unwillingness or inability to comply with study and follow-up procedures.

14. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.