Lipinski, Lindsay

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).

The etiology of intraneural ganglion cysts has been poorly understood. This has resulted in the development of multiple surgical treatment strategies and a high recurrence rate. We sought to analyze these recurrences in order to provide a pathoanatomic explanation and staging classification for intraneural cyst recurrence. An expanded literature search was performed to identify frequencies and patterns in cases of intraneural ganglion cyst recurrences following primary surgery. Two univariate analyses were completed to identify associations between the type of revision surgery and repeat cyst recurrences. The expanded literature search found an 11% recurrence rate following primary surgery, including 64 recurrences following isolated cyst decompression (Group 1); six after articular branch resection (Group 2); and none following surgical procedures that addressed the joint (Group 3). Eight cases did not specify the type of primary surgery. In group 1, forty‐eight of the recurrences (75%) were in the parent nerve, three involved only the articular branch, and one travelled along the articular branch in a different distal direction without involving the main parent nerve. In group 2, only one case (17%) recurred/persisted within the parent nerve, one recurred within a persistent articular branch, and one formed within a persistent articular branch and travelled in a different distal direction. Intraneural recurrences most commonly occur following surgical procedures that only target the main parent nerve. We provide proven or theoretical explanations for all identified cases of intraneural recurrences for an occult or persistent articular branch pathway. Clin. Anat. 28:1058–1069, 2015. © 2015 Wiley Periodicals, Inc.