Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma

Abstract

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells

“…Naturally, based on our data we cannot exclude potential contribution of other PP2A target proteins in mediating at least partly the PME-1-driven kinase inhibitor resistance phenotype. Clearly highlighting the potential clinical applicability of our results for future GBM therapy, Panobinostat and FK228 have been approved for therapy of multiple myeloma and cutaneous T cell lymphoma, respectively (42,43), and with Panobinostat clinical trials have been conducted in adult gliomas and are underway in pediatric gliomas (44,45) BAD was shown to be essential for synthetic lethality induced by either PME-1 or HDAC4 depletion. BAD acts as a node between upstream survival signaling pathways and downstream apoptosis signaling.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…138 For example, fatigue, thrombocytopenia, nausea, and diarrhea have been reported in GBM patients treated with vorinostat 121,139 and similar toxic side effects can be accompanied by hypophosphatemia and hemorrhage with panobinostat. 120 In addition to the evaluation of anti-cancer activity based on tumor size, and to the evaluation of molecular effects of therapy through analysis of biopsy tissue obtained before and/or after treatment, it is relevant to have a detailed understanding of the molecular impact of a drug on healthy CNS cells as well as on peripheral organs if the drug is administered systemically. Much progress and improvement are still needed in the treatment of malignant brain tumors, both in the preclinical and clinical settings.…”

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model

“…The phase 1 results describe a maximum tolerated dose of 30 mg three times per week, every other week when given in combination with bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody. 20 The phase 2 trial was stopped prematurely as it did not show a significant survival benefit when compared to control. 21 In a recent clinical study of patients treated with panobinostat as a method of reactivating latent HIV to a therapeutic advantage, panobinostat was not detectable in the cerebrospinal fluid (CSF) at multiple time points post treatment, suggesting that treatment failure in patients with HGG may be due to poor BBB penetrance.…”