First or Second Recurrence of Glioblastoma Clinical Trial
Official title:
The Multi-targeted Tyrosine Kinase Inhibitor Dovitinib (TKI258) in the Treatment of Patients With Relapsed Glioblastoma
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
Despite intensive treatment efforts combining surgery, radio- and chemotherapy, the
prognosis of patients suffering from glioblastoma (GBM) remains poor. Virtually all GBMs
progress despite therapy. Patients receiving the standard therapy at primary disease have a
median overall survival of 12-15 months. There is currently no defined standard treatment
regimen for recurrent GBM. Tyrosine kinase receptor-targeted therapy is widely used in
preclinical and clinical experimental brain tumor research. Increased tyrosine kinase
activity has been asssociated with GBM oncogenesis and several tyrosine kinase receptors,
e.g. VEGFR, FGFR, PDGFR are upregulated in malignant glioma. In the past and in the present,
targeting of VEGF- and PDGF-signaling (amongst others) has shown promising preclinical and
clinical results in human glioblasto-ma.
In that context our own in vitro studies lead to the assumption that application of a
multi-targeted tyrosine kinase inhibitor could be a most effective treatment approach for
GBM patients. We were able to demonstrate that GBM cells from different tumor regions
express different set of tyrosine kinase receptors that all could be targeted by the
multi-targeted tyrosine kinase inhibitor TKI258, including PDGFRß, CSF 1R, KIT, FLT3, VEGFR,
TrkA, RET and FGFRs. In combination with its ability to cross the blood-brain-barrier (BBB),
the exploration of TKI258 for patients with recurrent GBM appears very promising.
Recently, safety and feasibility of TKI258 was demonstrated in adult patients with advanced
solid malignan-cies. The maximum tolerated dose (MTD) was determined and a recommended dose
for phase II trials was established. Meanwhile, TKI258 is in phase III development in renal
cell carcinoma, and in phase II devel-opment in advanced breast cancer, relapsed multiple
myeloma and urothelial cancer.
Since the toxicity profile for compounds that could cross the BBB might be different in
patients with CNS diseases/disorders (e.g. brain tumors) compared to patients with
malignancies outside the CNS, we here propose a phase I trial exploring TKI258 in patients
with recurrent glioblastoma.
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258
in patients with relapsed glioblastoma should be established.
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Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment