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Neoplasms, Neuroepithelial

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Neuroectodermal Tumors, Primitive

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Neoplasms, Glandular and Epithelial

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All Drugs and Chemicals

Somatostatin

Lutetium Lu 177 dotatate

Radiopharmaceuticals

Pediatric patients (4 -12 years, Phase I) and adolescent and young adult patients (\>12years, Phase II) with recurrent/progressive high-grade central nervous system tumors and meningiomas that express SST2A and demonstrate uptake on DOTATATE PET will receive Lutathera once every 8 weeks (1 cycle) for a total of 4 doses over 8 months

Phase I starting dose will be 200 mCi\*(BSA/1.73m2), corresponding to the BSA-adjusted FDA approved adult Lutathera dosing. The first cycle will be used as the DLT period. Once MTD/RP2D is established, an efficacy expansion cohort of up to 10 patients will be opened to determine the preliminary efficacy of MTD/RP2D of Lutathera in this cohort

Phase II patients will receive the adult RP2D of 200 mCi every 8 weeks to determine the anti-tumor activity of Lutathera in this patient population, through evaluation of 6-month PFS as the primary efficacy endpoint. Response will be assessed on imaging (brain/spine MRI and DOTATATE PET) following every cycle.

Lutathera: IV administration maximum dose of 200 mCi once every 8 weeks (one cycle) for total of 4 cycles (8 months)

LUTATHERA® (Lutetium Lu 177 dotatate)

Leonie Mikael

Kathleen Dorris, MD

Ashley Plant, MD

Susan Chi, MD

David H Ashley

Peter de Blank, MD

Margot Lazow, MD

Melinda Triplet

Michael J Fisher

Patricia Baxter, MD

Sarah Leary, MD

Margot Lazow

This study will evaluate the safety and efficacy of Lutathera (177Lu-DOTATATE) in patients with progressive or recurrent High-Grade Central Nervous System (CNS) tumors and meningiomas that demonstrate uptake on DOTATATE PET. The drug will be given intravenously once every 8 weeks for a total of up to 4 doses over 8 months in patients aged 4-12 years (Phase I) or older than 12 yrs (Phase II) to test its safety and efficacy, respectively.

Funding Source - FDA OOPD (grant number FD-R-0532-01)

Somatostatin receptors regulate cell growth through downstream modulation of both proliferation and apoptosis signaling pathways, and thus represent a potential therapeutic target. Lutathera (Lutetium \[Lu\]177 Dotatate) is a radionuclide therapy which binds type-2A somatostatin receptors (SST2A) and has recently gained FDA approval for the treatment of adult gastroenteropancreatic neuroendocrine tumors expressing SST2A.

High SST2A expression has been consistently observed in medulloblastoma and other embryonal tumors (75-100% of cases) as well as in some HGGs and anaplastic ependymomas (13-80%), with corresponding uptake on radiolabeled somatostatin receptor nuclear imaging (e.g. DOTATATE PET).

Emerging data has demonstrated treatment response (disease stabilization or regression) to somatostatin receptor-targeted therapy in children and young adults with relapsed medulloblastoma, HGG, meningioma, and brain metastases of neuroendocrine tumors, suggesting sufficient CNS penetration to achieve therapeutic benefit.

The proposed Phase I-II study will investigate the safety and efficacy of Lutathera treatment in patients whose tumors demonstrate uptake on DOTATATE PET (functional evidence of SST2A expression). In both Phase cohorts, Lutathera will be administered as an intravenous infusion on day 1 of each 8-week cycle for up to 4 cycles.

Phase I: (4-12 years) To determine the safety, define the dose-limiting toxicities, and establish the maximally tolerated dose (MTD)/ recommended Phase II dose (RP2D) of Lutathera in this patient population. The first cycle (first 8 weeks) will be used as the dose-limiting toxicity (DLT) observation period. The starting dose will be dose level 1, 200 mCi\*(body surface area \[BSA\]/1.73m2), which corresponds to the BSA-adjusted FDA approved adult dosing of Lutathera (200 mCi every 8 weeks). Once the MTD/RP2D is established, an efficacy expansion cohort of up to 10 patients will be opened to determine the preliminary efficacy of the MTD/RP2D of Lutathera in this cohort.

Phase II: (\>12 years) Enroll patients at the recommended adult dose of 200 mCi every 8 weeks to determine the anti-tumor activity of Lutathera at this dosing in this population. Response will be assessed on imaging (brain and/or spine MRI and DOTATATE PET) following every cycle.

Phase I (4-12 yrs) Lutathera (maximum dose of 200 mCi) once every 8 weeks (one cycle) for 4 cycles.

Level 0: 150 mCi\*(BSA/1.73m2). Level 1#: 200 mCi\*(BSA/1.73m2). Level 2: 250 mCi\*(BSA/1.73m2).

#starting dose

Phase II (\>12 yrs) RP2D 200 mCi once every 8 weeks

Lutathera for Treatment of Recurrent or Progressive High-Grade CNS Tumors

Phase I/II Study of Lutathera in Patients With Recurrent and/or Progressive High-Grade Central Nervous System Tumors and Meningiomas That Demonstrate Uptake on DOTATATE PET

Document anti-tumor activity of Lutathera through assessment of ORR, PFS in patients with recurrent or progressive High-Grade CNS tumors or meningiomas

Describe prevalence and heterogeneity of SST2A expression (IHC) in patients with recurrent or progressive High-Grade CNS tumors or meningiomas

Assess correlation of SST2A expression with uptake on DOTATATE PET, response to Lutathera therapy, and relevant clinical and molecular features within the confines of a Phase I/II study in patients with recurrent or progressive High-Grade CNS tumors or meningiomas treated with Lutathera

To estimate the maximum tolerated dose (MTD) of Lutathera in pediatric patients between 4 and \<12 years of age with recurrent and/or progressive high-grade CNS tumors or meningiomas that demonstrate uptake on DOTATATE PET.

To estimate the recommended Phase II dose (RP2D) of Lutathera in pediatric patients between 4 and \<12 years of age with recurrent and/or progressive high-grade CNS tumors or meningiomas that demonstrate uptake on DOTATATE PET.

To define and describe the toxicities of Lutathera in pediatric patients with recurrent and/or progressive high-grade CNS tumors or meningiomas that demonstrate uptake on DOTATATE PET. This will include calculating the number of participants with Lutathera-related adverse events as assessed by CTCAE v 5.0

To assess efficacy, evaluated by 6 month progression-free survival, of treatment with Lutathera in adolescent and young adult patients age ≥12 years with recurrent and/or progressive high-grade CNS tumors or meningiomas that demonstrate uptake on DOTATATE PET

To evaluate the objective response rate of Lutathera in adolescent and young adult patients age ≥12 years with recurrent and/or progressive high-grade CNS tumors or meningiomas that demonstrate uptake on DOTATATE PET.

To establish the safety and toxicity of Lutathera 200 mCi every 8-week dosing in adolescent and young adult patients age ≥12 years with recurrent and/or progressive high-grade CNS tumors or meningiomas that demonstrate uptake on DOTATATE PET. This will include calculating the number of participants with, as well as severity and frequency of, Lutathera-related adverse events as assessed by CTCAE v 5.0

Spots Global Cancer Trial Database for lutathera® (lutetium lu 177 dotatate)