Grants and Contracts Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 3/1/21 → 2/28/25 |
Funding
- Public Health Institute: $2.00
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