A Phase II/III Study of High-dose, Intermittent Sunitinib in Patients With Recurrent Glioblastoma Multiforme

In this study the investigators will evaluate the effect of high-dose, intermittent sunitinib versus treatment with lomustine in patients with recurrent glioblastoma multiforme. The investigators hypothesize that sunitinib, when given in a high-dose, intermittent schedule, will achieve adequate concentration levels in the tumor and will, besides its anti-angiogenic properties, inhibit gliomagenesis by inhibition of multiple kinases.

Study design: Multicenter, phase II/III, randomized clinical trial with high-dose sunitinib versus lomustine (CCNU) in patients with recurrent GBM.

Hypothesis: Sunitinib, when given in a high-dose, intermittent schedule, may exhibit improved efficacy in patients with recurrent GBM with an acceptable toxicity profile, compared to lomustine.

Study population: Adult patients with recurrent GBM.

Primary objective:

- To determine the effect of high-dose sunitinib versus lomustine on six-month progression-free survival (PFS6) in patients with recurrent GBM, using the RANO criteria.

Secondary objectives:

* To determine the effect of high-dose sunitinib on overall survival (OS 9, OS 12) in patients with recurrent GBM.
* To assess the objective radiological response rate, using the RANO criteria.
* To assess toxicity, using the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
* To assess patient-oriented criteria: steroid use and health-related quality of life (reported by patients and caregivers/relatives).
* To explore the potential value of blood markers for molecular diagnostics, disease and response monitoring.
* To explore if MGMT promoter methylation status modulates the response to sunitinib.

Treatment: After randomization, 100 patients will be divided equally over two treatment groups and will receive:

* Group 1 (experimental arm): Sunitinib, 700 mg administered orally every 2 weeks.
* Group 2 (control arm): Lomustine 110 mg/m2, taken orally on day 1 every 6 weeks.

Disease will be assessed by MRI according to an uniform neuro-oncology protocol every 6 weeks for the first 6 months and every 12 weeks until documented progression. Safety profile of both treatment strategies will be assessed separately for each cycle of therapy and every 12 weeks after the end of treatment if adverse effects have not resolved or are newly emerging. Furthermore, quality of life assessment takes place every 6 weeks using questionnaires.

Eligibility Criteria:
Inclusion Criteria:

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 ≥ 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:

   1. Hemoglobin ≥ 7.0 mmol/L
   2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   3. Platelet count ≥ 100 x 109/L
   4. ALAT and ASAT ≤ 2.5 x ULN
   5. Serum creatinine eGFR ≥ 50 ml/min
   6. Albumin ≥ 25 g/L
8. Age ≥ 18 years

Exclusion Criteria:

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 ≤ 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. Use of strong hepatic enzyme-inducing antiepileptic drugs, such as carbamazepine, phenobarbital and phenytoin. If a patient uses one or more of these specific antiepileptic drugs, they must switch to an antiepileptic drug that does not interact with cytochrome P450 (CYP450) liver enzymes, such as levetiracetam, prior to the start of study treatment.
11. Drug or alcohol abuse.
12. Females who are pregnant or breast-feeding.
13. 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.
14. Unwillingness or inability to comply with study and follow-up procedures.
15. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.