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

Phase 1

Recruiting

• Conditions: Recurrent Diffuse Intrinsic Pontine Glioma; High Grade Glioma; Meningioma; Recurrent Malignant Glioma; Refractory Malignant Glioma; Refractory Primary Central Nervous System Neoplasm; Embryonal Tumor; Recurrent Medulloblastoma; Refractory Diffuse Intrinsic Pontine Glioma; Recurrent Primary Central Nervous System Neoplasm
• Interventions: Drug: LUTATHERA® (Lutetium Lu 177 dotatate)

• Registration Number: NCT05278208
• Lead Sponsor: Nationwide Children's Hospital

Brief Summary

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)

Detailed Description

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.

Study Timeline

• Study First Submitted: 2022-02-07
• Study First Submitted QC: 2022-03-03
• Study First Posted: 2022-03-14
• Study Start: 2022-11-21
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-07
• Last Update Posted: 2024-11-08
• Primary Completion: 2027-11
• Study Completion: 2027-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 65

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I-II	LUTATHERA® (Lutetium Lu 177 dotatate)	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.

Primary Outcome Measures

Name	Time	Method
Calculate the incidence of treatment related adverse events as assessed by CTCAE v5.0 in pediatric (4-12 yo) CNS patients treated with Lutathera	up to 2 months	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
Estimate RP2D of Lutathera in pediatric CNS patients 4-12 years	up to 8 months	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.
Assess PFS of Lutathera in CNS patients >12 years	up to 6 months	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
Estimate MTD of Lutathera in pediatric CNS patients 4-12 years	up to 8 months	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.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate of Lutathera in CNS patients >12 years	up to 8 months	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.
Calculate the incidence of treatment related adverse events as assessed by CTCAE v5.0 in CNS patients older than 12 yrs treated with Lutathera	up to 8 months	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

Trial Locations

Locations (4)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States