Project Summary/Abstract
There is a critical need to develop novel effective, well-tolerated therapies for children and young adults with
recurrent or progressive high-grade central nervous system (CNS) tumors and meningiomas, who currently have
limited treatment options and an extremely poor prognosis. Somatostatin receptors regulate cell growth through
complex downstream modulation of both proliferation and apoptosis signaling pathways, and thus represent a
potential therapeutic target. 177Lu-DOTATATE, a radionuclide therapy which binds type-2A somatostatin
receptors (SST2A) and delivers local radiation via beta particle emission, has recently gained FDA approval for
the treatment of gastroenteropancreatic neuroendocrine tumors given efficacy and safety data in adults with
these SST2A-expressing tumors. There is potential for successful expansion of 177Lu-DOTATATE to pediatric
and young adult neuro-oncology, based upon growing evidence that many CNS tumors are characterized by
high SST2A expression, exhibit corresponding uptake on somatostatin receptor imaging (e.g., DOTATATE PET),
and have preliminary data demonstrating response (disease stabilization or regression) to somatostatin receptor-
targeted therapy in case reports/series, suggesting sufficient CNS penetration to achieve therapeutic benefit.
Minimal toxicity has been observed aside from a low prevalence of myelosuppression. We, therefore, are
conducting a phase I/II trial assessing safety and efficacy of 177Lu-DOTATATE in pediatric and young
adult patients with refractory SST2A-expressing high-grade CNS tumors (medulloblastoma and other
embryonal tumors, high-grade gliomas including DIPG, and anaplastic ependymomas) and
meningiomas, using both SST2A immunohistochemistry and DOTATATE PET imaging as screening
criteria for eligibility to ensure presence of the target. The primary aims of this proposal are to (1) establish
the maximally tolerated dose (MTD)/ recommended phase II dose (RP2D) of 177Lu-DOTATATE in pediatric
patients with recurrent or progressive CNS tumors [Phase I arm] and (2) evaluate efficacy of 177Lu-DOTATATE
in adolescent and young adult patients, administered at the FDA-approved adult dosing, assessed via 6-month
progressive-free survival compared to historical controls [Phase II arm]. Several exploratory studies will be
incorporated, with goals of (1) determining the prevalence, heterogeneity, and key clinical, radiographic,
histopathologic, and molecular correlates of SST2A expression across pediatric and young adult CNS tumors,
(2) identifying imaging (DOTATATE PET and MRI) and peripheral blood or cerebrospinal fluid (‘liquid biopsy’)-
based molecular biomarkers predictive of response to 177Lu-DOTATATE, and (3) characterizing radiation
dosimetry of 177Lu-DOTATATE to estimate tumor dose/CNS penetration and minimize toxicity risk, including in
patients who received prior cranial radiation. If a preliminary efficacy signal is detected, further research will be
planned to expand this targeted radiotherapy to a larger patient population with refractory brain/spine tumors
and eventually incorporate 177Lu-DOTATATE into upfront treatment backbones for these aggressive diseases.
