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High-grade gliomas, which include glioblastomas (GBMs) and anaplastic gliomas (AGs), are the most common malignant primary brain tumors in adults1 and are associated with poor survival despite maximal surgery, radiation, and chemotherapy.2–4 Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is frequently used to treat recurrent high-grade glioma (HGG). Bevacizumab monotherapy received accelerated approval for recurrent GBM by the United States Food and Drug Administration in 2009 on the basis of phase II clinical trials demonstrating response rates of 20%–26%, 6-month progression-free survival (PFS6) rates of 29%–42.6%, and median overall survival (OS) of 7.1–9.2 months.5,6 Phase II studies in recurrent AG suggest that bevacizumab plus irinotecan also has activity in this patient population with response rates of 55%–66% and PFS6 rates of 56%–61%.7,8 However, responses to bevacizumab are not durable, and some patients fail to benefit.9 Panobinostat is a potent, small-molecule inhibitor of classes I, II, and IV histone deacetylases (HDACs) with greater potency than vorinostat.10 HDAC inhibitors, including panobinostat, may inhibit angiogenesis by reducing VEGF secretion and modulating the expression of other VEGF family members via inhibition of HIF-1α.11–14 In addition, the SDF-1α/CXCR4 pathway has been implicated in bevacizumab resistance,15–17 and panobinostat depletes CXCR4 levels and signaling.18 A phase I study of panobinostat in combination with bevacizumab for recurrent HGG suggested that oral panobinostat 30 mg 3 times per week, every other week, can be safely combined with bevacizumab 10 mg/kg every other week.19 We conducted a multicenter, phase II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. We also examined the same combination of agents in patients with recurrent AG as an exploratory arm.

Intro: Patients with DLBCL after at least two lines of therapy have limited effective treatments options. The nuclear export protein exportin 1 (XPO1) is upregulated in hematologic malignancies including DLBCL with pleiotropic effects on tumorigenesis such as functional downregulation of tumor suppressor proteins (TSPs) as well as increased export and translation of mRNAs for oncoproteins c-Myc and key survival proteins such as Bcl-2. Selinexor (SEL), an oral XPO1 inhibitor, causes sequestration of TSPs including p53, p21, and IκBα, the latter of which serves to suppress NF-κB driven transcription, along with reductions in c-Myc and Bcl family proteins. SEL has shown activity in canine and rodent models of non-Hodgkin’s lymphoma (NHL), as well as in phase 1 clinical studies including DLBCL. Pts with relapsed/refractory (R/R) DLBCL treated with SEL, had an overall response rate (ORR) of 32% including 4 CRs. Interestingly, 2 of these pts remain in CR for >1 yr. In this clinical study we assess the utility of single agent SEL in pts with R/R DLBCL after ≥2 prior regimens. Methods: Pts with R/R DLBCL were randomized to 60 or 100 mg of SEL twice weekly (8 doses) per 28-day cycle. Pts were also grouped by DLBCL subtype (GCB or non-GCB). The primary objectives are to determine the ORR, and safety of 60 v 100 mg doses. Disease response was assessed using the Lugano Classification (Cheson, 2014). Pt tissue samples were also collected to evaluate cytogenetics. Results: In 67 pts (33 pts 60 mg, 34 pts 100 mg) enrolled; the most common related adverse effects (AEs) across both dosing groups (Grade 1/2) were: nausea (46%), anorexia (43%), vomiting (36%), and fatigue (34%). Common Grade 3/4 AEs were: thrombocytopenia (39%), fatigue (18%), neutropenia (16%), and anemia (10%). These were managed with dose interruption/reduction, platelet stimulators, and/or standard supportive care. Grade 3/4 fatigue (13% v 4%) and thrombocytopenia (22% v 16%) were higher in 100 mg arm as compared to the 60 mg arm. Among 65 evaluable pts, the ORR was 21.5%. Responders had a median of 3 prior treatment regimens. 8 pts (12.3%) had a complete response (CR) and 6 pts (9.2%) achieved a partial response. 9 responders, including 7 CR, remain on treatment. Median time on study for CR is 8.8+ mos. ORR by subtype: GCB 23.5%, non-GCB 19.3%. The ORR (26.4%) in the 60 mg arm was higher than 100 mg arm (16.1%), possibly due to better tolerability and less time without drug exposure. Conclusion: SEL monotherapy shows anti-cancer activity in pts with R/R DLBCL including in pts with GCB subtype. 60 mg SEL twice weekly was more tolerable than 100 mg twice weekly, with less dosing interruptions due to toxicity and a trend towards higher response rates. Objective responses to SEL were durable, suggesting these responses were associated with clinical benefit. Molecular predictors of response are being evaluated. Citation Format: Marie Maerevoet, Jason Westin, Catherine Thieblemont, Josee Zijlstra, Brian T. Hill, Fatima De La Cruz Vicente, Sylvain Choquet, Paolo Caimi, Jason Kaplan, Miguel Albendea Canales, John Kuruvilla, George Follows, Eric Van den Neste, Julie Meade, Brendan Wrigley, Marissa Devlin, Conny Nippgen, Humphrey Gardner, Sharon Shacham, Michael G. Kauffman, Rene-Olivier Casasnovas. A Phase 2b randomized study of selinexor in patients with relapsed/refractory Diffuse Large B-Cell Lymphoma (DLBCL) demonstrates durable responses in both GCB & Non-GCB subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT132. doi:10.1158/1538-7445.AM2017-CT132

Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as the exploratory study. Patients received oral panobinostat 30 mg 3 x per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was PFS6 in the GBM cohort and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). At planned interim analysis, 13 of the first 21 patients accrued to the GBM cohort had progressed within 6 months of initiating study treatment. The GBM cohort did not meet criteria for continued accrual and was closed early. In the GBM cohort, PFS6 rate was 30.4%, median PFS 5 months, median OS 9 months. Accrual in the AG cohort continued to completion and a total of 15 patients were enrolled. In the AG cohort, PFS6 rate was 46.7%, median PFS 7 months, median OS 17 months. The most common grade 3 or 4 toxicities in the GBM arm were hypophosphatemia (12.5%), thrombocytopenia (12.5%), lymphopenia (8.3%), neutropenia (8.3%), and ALT elevation (8.3%). In the AG arm, the most common toxicities were thrombocytopenia (20.0%) and hypophosphatemia (13.3%). Although reasonably well-tolerated, this phase II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the GBM cohort of the study was closed. In the recurrent AG cohort, the PFS6 rate was similar to historical controls. Updated data will be presented.

2020 Background: Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic ...