Here we report a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were Grade 1 and Grade 2, with one Grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients the median progression free survival (PFS) was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFR; and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78α expression to overall survival. Our data argue that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

The authors have declared no competing interest.

NCT01817751

This trial was supported by research funding from the NIH-NCI Cancer Center Support Grant (P30-CA016059; PI: Robert Winn, MD)

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Virginia Commonwealth University institutional review board approved the study protocol. All procedures were performed in accordance with the ethical standards of the Helsinki Declaration.

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All data produced in the present study are available upon reasonable request to the authors