Know Cancer

forgot password

SUTENT (SUNITINIB, SU11248)in Patients With Recurrent or Progressive Glioblastoma Multiforme An Academic Prospective Single-arm Phase II Clinical Trial Including Ranslational Research Studies

Phase 2
18 Years
Open (Enrolling)
Glioblastoma Multiforme

Thank you

Trial Information

SUTENT (SUNITINIB, SU11248)in Patients With Recurrent or Progressive Glioblastoma Multiforme An Academic Prospective Single-arm Phase II Clinical Trial Including Ranslational Research Studies

Background Glioblastoma multiforme (GBM) is the most common and most aggressive primary
brain tumor in adults and shows an incidence of 5/100.000 inhabitants per year1. In Austria,
approximately 350 patients are diagnosed with malignant glioma annually. Advances in
surgery, radiotherapy and chemotherapy do only have a minor impact on the natural course of
these hardly treatable tumors. The mean survival time of adult patients with GBM is only
9-15 months from the time of diagnosis1,2. Thus, there is an urgent need for more effective
therapeutic approaches based on a better molecular understanding of tumor progression and
tumor neovascularization.

Molecular Neurooncology has begun to elucidate the complexity of the transformed phenotype
of GBM with the goal to identify important molecular changes in the tumor cell that may be
amenable for targeted therapies3.

The elucidation of growth factor receptor signaling pathways responsible for the malignant
phenotype is now being translated into molecular therapies. At present, targeted therapies
with small molecule inhibitors directed against receptor tyrosine kinases (RTKs) or
downstream signaling pathways seem to be the most promising therapeutic approaches by
directly influencing oncogenetically altered signaling pathways4. Imatinib Mesylate (STI571,
Gleevec) is a potent inhibitor of the Bcr-Abl, PDGFR-α/ß, c-Fms and c-KIT tyrosine kinases.
Its ability to inhibit PDGFR signaling suggested therapeutic potential in malignant gliomas,
but single-agent imatinib showed only minimal therapeutic activity5. Erlotinib (OSI-774,
Tarceva) and Gefitinib (ZD1839, Iressa) are potent inhibitors of the
Epidermal-Growth-Factor-Receptor (EGFR). However, both inhibitors have also demonstrated
only limited activity in GBMs with response rates of 10 to 15% and no significant
prolongation of survival6. Tipifarnib (R115777, Zarnestra) is a potent and selective
inhibitor of the farnesyl-transferase and influences the Ras oncogene pathway.
Overexpression of Ras is implicated in the pathogenesis of malignant gliomas, but also
amplified receptors as EGFR, PDGFR and VEGFR can lead to its downstream activation. Clinical
trials with inhibition of the Ras signaling pathway showed also only limited biologic
effects in GBM patients7.

3.2. Rationale for SUTENT treatment of GBM Patients Reason for the limited activity of
selective targeting single agents, but also chemotherapeutic treatments, in GBM patients is
the heterogeneity and redundancy of the molecular pathways in glioma cells8. Therefore, a
multi-targeted therapy approach, inhibiting multiple molecular signaling pathways involved
in tumor progression and tumor neovascularization seems to be a more promising treatment

SUTENT (SUNITINIB, SU11248) is a potent multi-target inhibitor of VEGFR1-3, PDGFR-α/β, FLT3,
c-KIT, RET and CSF-1R. This drug has shown good solubility, bioavailability and
protein-binding characteristics9 and was highly effective in metastatic clear-cell renal
cell carcinoma (MRCC)10-12 and gastrointestinal stromal tumor (GIST)13,14.

The aggressiveness of GBM is reflected by a diffuse local infiltration into the brain
parenchyma and a high tumor vascularization15,16. Neuropathological hallmarks of GBMs are
pseudopalisades and microvascular hyperplasia. Pseudopalisades are characterized by an
accumulation of hypoxic tumor cells around a central necrosis (Fig. 3A), resulting from
increased metabolic demands of tumor cells or vascular occlusion. Such tumor cells express
high levels of hypoxia-inducible regulators of angiogenesis, including the hypoxia-inducible
factor (HIF)-α. HIF-α accumulates in the tumor cell and binds with its constitutively
present partner HIF-β. The HIF complex leads to transcription of hypoxia-induced genes, such
as VEGF and PDGF17. These growth factors are secreted into the extracellular space by tumor
cells and bind to its high-affinity receptors located on

1. tumor cells (autocrine action), leading to tumor cell proliferation and survival, but
also stimulation of the HIF-α protein synthesis and

2. endothelial cells, vascular smooth muscle cells and pericytes (paracrine action),
leading to tumor-related neoangiogenesis18-21.

Therefore, VEGF may induce microvascular hyperplasia (Fig. 1B), a typical form of
neoangiogenesis immediately related to pseudopalisading cells16,22. Since necrosis and
hypoxia are located in the GBM's core, the most biologically relevant hypoxia-induced
neovascularization occurs further peripherally, favouring diffuse infiltration by individual
glioma cells and allows peripheral GBM expansion.

Summary of molecular and clinical rationales for SUTENT treatment of GBM patients

- The target molecules of SUTENT (i.e. VEGFR, PDGFR, FLT-3, c-KIT, RET) are strongly
expressed in GBM tissue and have a crucial role in tumor progression and tumor

- The vascular density in GBMs is among the highest of all human neoplasm

- Clinical studies with SUTENT demonstrated a radiological response and a significant
improvement in progression free survival due to SUTENT treatment in MRCC and
Imatinib-resistant GIST

- In clinical trials using SUTENT the incidence and severity of adverse events and
laboratory abnormalities was relatively low (MRCC and GIST patients)

Inclusion Criteria:

- Patients present with a first recurrence or first progression of a histological
confirmed primary supratentorial glioblastoma multiforme WHO Grade IV (Classification
following WHO criteria).

- Patients with surgical resection of first tumor progression: Following standard
therapy patients must have evidence of first tumor progression. In general, patients
may have undergone prior surgical resection of the first tumor progression and will
be eligible if the following conditions apply:

- Patients must have recovered from the effects of surgery

- To adequately asses the GBM before surgery and the extent of residual disease
postoperatively, two MRIs scans have to be performed:

- The first MRI scan within 2 weeks before surgery to document a progressed or
recurrent GBM. The second MRI scan within 48 hours after surgery.

- Patients without surgical resection of first tumor progression:

- Patients must have evidence of first tumor progression following standard therapy as
measured by a baseline MRI within 2 weeks prior to study enrollment (Macdonald
criteria: i.e. tumor growth > 25% or new lesion).

- Resolution of all acute toxic effects of prior therapy to grade ≤ 1 (except alopecia)

- Patients must have an ECOG performance status of 0-2

- Patients must be ≥ 18 years and ≤ 75 years of age, with a life expectancy of greater
than 8 weeks

- Patients must have adequate organ function as defined by the following criteria:

Bone Marrow Reserve - Platelets ≥ 75.000/μL

- Absolute Neutrophil Count (ANC) ≥ 1500/μL

- Hemoglobin ≥ 10.0 g/dL Blood Coagulation - aPTT ≤ 1.5 times upper limit of normal
(ULN) Hepatic Function - ASAT and ALAT ≤ 1.5 times ULN

- ALP ≤ 2.5 times ULN

- Total Serum Bilirubin < 1 times ULN Renal Function - Serum Creatinine ≤ 1.5
times ULN Metabolism - Serum Albumin ≥ 3.0 g/dL Heart Function - Left
Ventricular Ejection Fraction (LVEF) ≥ 50% as measured by transthoracic
echocardiogram ECHO) All tests must be performed ≤ 3 days prior to study enrollment.
Eligibility for hemoglobin count may be reached by transfusion

- Signed and dated informed consent document by the patient, indicating that the
patient has been informed of all the pertinent aspects of the trial prior to study

- Willingness and ability of the patient to comply with scheduled visits, treatment
plans, laboratory tests, and other study procedures

Exclusion Criteria:

- The patient is active participant in another clinical trial.

- Exclusion of patients in the event of

- surgery for recurrence/progression within 1 week prior to study enrollment

- chemotherapy within 4 weeks prior to study enrollment

- treatment with more than one chemotherapy regime

- radiation therapy within 8 weeks to study enrollment

- evidence in baseline MRI of intratumoral or peritumoral hemorrhage deemed
clinically significant by the treating physician (area of hemorrhage > 25% of
tumor area)

- Significant Co-Morbidities within 12 months prior to study enrollment

- myocardial infarction, severe/unstable angina pectoris, coronary/peripheral
artery bypass graft, congestive heart failure

- pulmonary embolus

- cerebro-vascular accident including TIA (transient ischemic attack)

- Significant Co-Morbidities at Baseline Evaluation

- Clinically significant ongoing cardiac dysrhythmias of grade ≥ 2, atrial
fibrillation of any grade, QTc interval > 470 ms measured by electrocardiogram

- Hypertension that cannot be controlled by medications (>150/100 mmHg despite
optimal medical therapy)

- A known HIV (human immunodeficiency virus) or Hepatitis B/C infection or severe
acute infection

- Anticoagulation: Current treatment with therapeutic doses of Marcoumar / Sintrom
excluding thrombosis prophylaxis with low dose Heparin.

- Antiepileptic Drugs: Concurrent use of EIADs within 2 weeks of study enrollment
(patients must discontinue EIAD treatment ≥ 14 days prior to study enrollment)

- Pregnancy, Breastfeeding and Non-Contraception

- Female patients who are pregnant or nursing

- Patients who are sexually active and unwilling or unable to use a medically
acceptable method of contraception during the trial.

- Evidence of increased intracranial pressure

- midline shift > 5 mm

- distinct nausea and vomiting

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that would impart excess risk associated with study participation or
study drug administration, or which would make the patient inappropriate for entry
into this study. The decision to enroll the patient in this study is in the judgment
of the investigator.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival rate at 6 months

Outcome Time Frame:

6 months after tumor progression

Safety Issue:


Principal Investigator

Guenther Stockhammer, MD, Prof.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical University Innsbruck


Austria: Agency for Health and Food Safety

Study ID:

EUDRACT-Nr. 2007-002142-37



Start Date:

October 2007

Completion Date:

January 2011

Related Keywords:

  • Glioblastoma Multiforme
  • glioblastoma multiforme
  • sunitinib
  • recurrent
  • progressive
  • Glioblastoma