Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma

Abstract

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.

Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

“…44 In our library of 1200 drugs, there was only one HDAC inhibitor, Vorinostat, which was previously indicated as an anti-cancer agents and also studied as a TRAIL sensitizing agent in various cancers including leukemia and lung cancer. 43,45,46 Consistent with these observations, Vorinostat cooperated with TRAIL and scored as a hit in our screen, highlighting the validity of our screen findings. Given the growing interest in the field of epigenetic enzyme inhibitors as therapies, Vorinostat and TRAIL combination can also offer promise in the future for GBMs.…”

Histone Deacetylase Inhibitors Interact with Melanoma Differentiation Associated-7/Interleukin-24 to Kill Primary Human Glioblastoma Cells

“…In vivo we noted in mice carrying GBM tumors that Ad.5/3-mda-7 prolonged animal survival and that this effect was augmented by HDACI treatment. There have been multiple phase I and phase II trials of HDACIs in glioma patients (Galanis et al, 2009;Chinnaiyan et al, 2012;Friday et al, 2012;Lee et al, 2012). Alone, although it is well tolerated by patients, vorinostat has modest single-agent activity in GBM, which is in agreement with our findings.…”

“…Alone, although it is well tolerated by patients, vorinostat has modest single-agent activity in GBM, which is in agreement with our findings. Vorinostat has been combined with ionizing radiation, temozolomide, bortezomib, and bevacizumab and CPT-11 (camptothecin-11) in GBM patients, with some partial responses evident (Galanis et al, 2009;Chinnaiyan et al, 2012;Friday et al, 2012;Lee et al, 2012).…”

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

“…Considering the pleiotropic effects of HDAC inhibitors against malignant tumors, their true therapeutic potential most likely lies in combinations with other anticancer drugs (24). Recent clinical trials have indicated that HDAC inhibitors enhance the antitumor activities of several conventional chemotherapeutic and molecular-target drugs (25)(26)(27). Additionally, a previous study showed that HDACs were highly expressed in RCC, suggesting that HDAC inhibitors may be effective on RCC (28).…”