A Phase I/II Study of Pazopanib in Combination With Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme After Surgery and RT-CT

Glioblastoma (GBM), the most common and most malignant primary brain tumor, represents a major medical challenge considering its extremely poor prognosis (Wen 2008). Current standard of care includes maximal surgical resection, followed by concomitant radio-chemotherapy (temozolomide - TMZ) (RT-CT) followed by 6 months of maintenance TMZ, with a median overall survival (mOS) of 14.6 vs. 12.1 months with RT alone (Stupp 2005). Non operable GBM, represents around 30% of cases of GBM, with a poorer prognosis, a median PFS of 3-4 months and a median OS between 6-9 months (Chinot 2007, Stupp 2009), with concomitant RT-CT treatment. Therefore, innovative treatment strategies are urgently needed and new treatment combinations evaluated in phase I studies are highly encouraged (Wen 2011).

Since GBM is one of the most vascularised cancers, antiangiogenic agents have been tested and used firstly in recurrent GBM. Among them, Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has shown high response rate between 19% and 62% in several Phase 2 and multiple retrospective studies, alone or in combination with chemotherapy (Chamberlain 2011). Two randomized phase III trials, AVAGLIO and RTOG 0825, investigating the efficacy of Bevacizumab added or not to the Stupp protocol in patients with newly diagnosed GBM, have been presented at the annual meeting of the American Society of Clinical Oncology (ASCO 2013). While both studies exhibited a significant progression-free survival (PFS) improvement (RTOG 0825:10.7 vs. 7.3m, p=0.007; AVAGLIO: 10.6 vs. 6.2m, p<0.0001), there was no gain in overall survival.

Other antiangiogenic agents have been studied in GBM patients (Sathornsumetee 2009, Van Meir 2010, Wick 2011), with encouraging results but still insufficient when used as single agents. Among them, pazopanib is thought to be promising. It is an orally tyrosine kinase inhibitor with potently inhibition of VEGFR-1, -2, -3, c-kit and PDGFR-α, -β (Castaneda 2009, Schutz 2011). Interestingly, these 2 PDGFR subtypes are overexpressed in malignant gliomas (Verhaak 2010). Furthermore, pazopanib is already validated in patients with advanced renal cell carcinoma and soft-tissue sarcomas (Sleijfer 2009, Sternberg 2010).

A phase II trial evaluated efficacy and safety of pazopanib in 35 patients with recurrent GBM (Iwamoto 2010). Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks and mOS was 35 weeks. Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents and with unexpected toxicity.

Given the emerging concern that pure anti-VEGF inhibition may promote malignant glial cell invasiveness (Keunen 2011), we consider essential to combine a multitargeted antiangiogenic agent, such as pazopanib, with the current standard treatment. TMZ was chosen not only because it represents the current standard of care but because of its very good penetration in the brain parenchyma and its low hepatic metabolism, making very unlikely the occurrence of a pharmacokinetic interaction with pazopanib (Friedman 2000). Indeed, phase I trials of TMZ in combination with molecules such as RAD001, cilengitide, gefitinib or irinotecan showed no need for dose modification of TMZ. Similarly, the Phase I trials of pazopanib association with paclitaxel or FOLFOX6 have been conducted up to a dose of 800 mg daily, the recommended dose of pazopanib in monotherapy, with standard doses of chemotherapy (Tan 2010, Brady 2009). Finally, the study of the toxicity profile of pazopanib and TMZ does not suggest a specific limiting dose escalation adverse event, except perhaps asthenia, thrombocytopenia or ALAT elevation. However, considering the high level of potential toxicity when an ITK is administered with radiations, pazopanib should not be administered in the induction phase of the Stupp protocol.