ACNS1821: A Phase 1/2 Trial of Selinexor (KPT-330) and Radiation Therapy in Newly-Diagnosed Pediatric Diffuse Intrinsic Pontine Glioma (DIPG) and High-Grade Glioma (HGG)

Abstract Pediatric oncology cure rates have risen dramatically over the last generation, but those for brain tumors still lag behind. For HGG, they range from 20% for supratentorial tumors to 0% for DIPG.1 These two tumors affect approximately 1,000 patients a year in the United States, 300 of which are DIPG, and now represent the most common cause of death from childhood cancer.2 They have no predilection for sex, race, or ethnicity. DIPG, despite numerous past clinical trials, has never been shown to respond to chemotherapy.1 The current standard treatment is radiation therapy (RT), which is usually effective in extending life by several months but is never curative.1 While temozolomide and radiation are standard of care for a subset of adults with HGG3 based on data from a large clinical trial demonstrating a survival benefit over radiation alone, this regimen has not demonstrated the same benefit in pediatric patients, as demonstrated in COG ACNS0126.4 Combining lomustine (CCNU) with temozolomide for maintenance chemotherapy after RT/temozolomide (ACNS0423) appeared to show some benefit in pediatric patients over RT/temozolomide alone,5 with an event-free (EFS) and overall survival (OS) benefit for patients compared to those treated on ACNS0126 (3y OS 28% ACNS0423, 19% ACNS0126, p=0.019). The benefit was especially pronounced for those who could not undergo complete tumor resection and those with overexpression of MGMT, which is common in adult HGG but very rare in H3K27M-mutant tumors that are common in children. However, it is unclear which HGG subgroups benefited otherwise, and neither of these regimens is considered standard of care in pediatrics. It is thus critical to study novel therapies with the potential to improve on current poor outcomes for pediatric HGG, as experimental options for patients in addition to previously studied treatment options. XPO1 is a nuclear transport protein that mediates the facilitated nuclear export of 221 proteins6 and is the sole nuclear exporter of most major tumor suppressors, including p53, Rb, and p27.7 XPO1 is overexpressed in many cancers8-10 including HGG11 and DIPG,12 leading to mislocalization of tumor suppressor proteins outside the nucleus. Therefore, inhibiting XPO1 to restore tumor suppressor function is an attractive and novel strategy for cancer therapy that potentially may affect many anti-cancer functions in the cell. Previously studied XPO1 inhibitors proved highly toxic to normal cells.13 Now, a novel class of small molecule XPO1 inhibitors, the Selective Inhibitors of Nuclear Export (SINE), has shown a high degree of preclinical efficacy and specificity in several hematologic and solid malignancies.14-17 The lead clinical compound in this class, selinexor, has been chosen for this trial because there is clear preclinical rationale in relevant models (including in combination with radiation), the drug crosses the blood brain barrier (BBB), and there is pediatric data for dosing of the single agent. As such, the drug holds the potential to improve outcomes for HGG/DIPG patients. The Phase 1/2 trial design was chosen to provide a brief dose-finding phase to test for any increase in toxicity when radiation is added to selinexor. This will be followed by an efficacy phase, in which HGG and DIPG patients will be treated on a single treatment arm with separate strata because of the differences in historical survival outcomes between DIPG, non-DIPG H3 K27M-mutant DMG, and other pHGG. The most relevant outcomes in each disease, PFS in HGG and OS in DIPG, will be compared to outcomes from historical cohorts, since outcomes have remained stable over time.