A Phase II trial of tandutinib (MLN 518) in combination with bevacizumab for patients with recurrent glioblastoma

Abstract

Aim: A Phase II trial of bevacizumab plus tandutinib.

Methods: We enrolled 41 recurrent, bevacizumab-naive glioblastoma patients for a trial of bevacizumab plus tandutinib. Median age was 55 and 71% were male. Treatment consisted of tandutinib 500 mg two-times a day (b.i.d.) and bevacizumab 10 mg/kg every 2 weeks starting day 15. Of 37 (90%) evaluable, nine (24%) had partial response.

Results & conclusion: Median overall and progression-free survival was 11 and 4.1 months; progression-free survival at 6 months was 23%. All patients suffered treatment-related toxicities; common grade ≥3 toxicities were hypertension (17.1%), muscle weakness (17.1%), lymphopenia (14.6%) and hypophosphatemia (9.8%). Four of six with grade ≥3 tandutinib-related myasthenic-like muscle weakness had electromyography-proven neuromuscular junction pathology. Tandutinib with bevacizumab was as effective but more toxic than bevacizumab monotherapy.

Trial registration: ClinicalTrials.gov NCT00667394.

Keywords: bevacizumab; glioblastoma; tandutinib.

Conflict of interest statement

Financial & competing interests disclosure

The National Cancer Institute Intramural Research Program provided grant funding for this Phase II trial of tandutinib (MLN518) and bevacizumab (NCT00667394]) This trial was also sponsored and funded by Millennium Pharmaceuticals via a Clinical Trial Agreement. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. Progression and overall survival.

Kaplan–Meier curves for (A) progression-free survival and (B) overall survival are depicted along with the corresponding median survival in months.

Figure 2.. Tandutinib targets type III receptor tyrosine kinases.

Tandutinib targets the family of type III receptor tyrosine kinases (RTKs), specifically c-Kit, PDGFRβ and FLT3 [27]. Type III RTKs consist of an EC region with five immunoglobulin-like domains, a TM domain and intracellular JM and TK domains. Genetic alterations of FLT3, PDGFRβ and cKIT have been linked to the pathogenesis and malignant transformation of various hematologic malignancies [32]. The key downstream targets of class III RTKs are the Ras-mediated Raf–MEK–ERK and PI3K–Akt–mTOR pathways, though mutated FLT3 also targets the STAT factors. These transcription factors promote cell proliferation, inhibited differentiation and/or genetic instability [33]. Diamond arrow: Inhibitory effect; Circle arrow: Site of genetic alteration; Triangle arrow: Activating effect. EC: Extracellular; ITD: Internal tandem duplication; JM: Juxtamembrane; TK: Tyrosine kinase; TM: Transmembrane.