Lutathera for Treatment of Recurrent or Progressive High-Grade CNS Tumors or Meningiomas Expressing SST2A

Lutathera for Treatment of Recurrent or Progressive High-Grade CNS Tumors or Meningiomas Expressing SST2A

Phase I/II Study of Lutathera in Pediatric and Young Adult Patients With Recurrent and/or Progressive High-Grade Central Nervous System Tumors and Meningiomas That Express Somatostatin Type2A Receptors and Demonstrate Uptake on DOTATATE PET

This study will evaluate the safety and efficacy of Lutathera (177Lu-DOTATATE) in pediatric and young adult patients with progressive or recurrent High-Grade Central Nervous System (CNS) tumors and meningiomas (any grade) that express Somatostatin Type 2A Receptors by immunohistochemistry and 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 pediatric and young adult patients whose tumors express SST2A (measured by immunohistochemistry) and demonstrate uptake on DOTATATE PET. 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.

High Grade Glioma, Meningioma, Embryonal Tumor, Medulloblastoma, Anaplastic Ependymoma, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Primary Central Nervous System Neoplasm, Refractory Diffuse Intrinsic Pontine Glioma, Refractory Malignant Glioma, Refractory Medulloblastoma, Refractory Primary Central Nervous System Neoplasm

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

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)

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 express SST2A receptors and 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 express SST2A receptors and demonstrate uptake on DOTATATE PET.

Calculate the incidence of treatment related adverse events as assessed by CTCAE v5.0 in pediatric (4-12 yo) CNS patients treated with Lutathera

To define and describe the toxicities of Lutathera in pediatric patients with recurrent and/or progressive high-grade CNS tumors or meningiomas that express SST2A receptors and 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 express SST2A receptors and 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 express SST2A receptors and 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

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 express SST2A receptors and 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

Document anti-tumor activity of Lutathera through assessment of ORR, PFS in patients with recurrent or progressive High-Grade CNS tumors or meningiomas expressing SST2A

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

Correlation of SST2A expression with clinical and molecular features in high-grade CNS tumor patients treated with Lutathera

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

All subjects must meet the following inclusion and exclusion criteria. No exceptions will be given. Imaging studies to establish eligibility must be done within three weeks prior to enrollment. All other clinical evaluations to establish eligibility (except for SST2A IHC) must be done within 7 days prior to enrollment. Screening Criteria 1.1 Diagnosis Patient must have a diagnosis of primary high-grade CNS tumor (any histopathologic diagnosis that is WHO grade III-IV) or meningioma (any histologic grade) that is recurrent, progressive, or refractory. Note that patients with DIPG (based on radiographic/clinical diagnosis) who have undergone biopsy will be eligible with histologic diagnosis of grade II-IV infiltrating glioma. All tumors must have histologic verification either at the time of diagnosis or recurrence, except for patients meningioma who have not previously undergone biopsy or resection. Note: Refractory disease is defined as the presence of persistent abnormality on conventional MRI imaging that is further distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR as determined by the treating physician and discussed with the primary investigator prior to enrollment. 1.2 Adequate Pre-trial Tumor Tissue Patient must have adequate pre-trial tumor material (from initial diagnosis and/or recurrence) available for SST2A IHC preparation and interpretation. Patients with meningioma who have pre-trial tumor tissue available are required to submit tissue; however, this is not required for eligibility for meningioma patients if no prior biopsy/resection has been performed. 1.3 Prior Therapy Patients must have recurred/progressed following prior standard therapy for their tumor. Note: with meningioma, atypical meningioma, or anaplastic meningioma must have received at least surgical resection or radiation. 1.4 Screening Consent Participant/legal guardian is willing to sign a screening consent. The screening consent is for SST2A IHC analysis and if there is evidence of SST2A expression by IHC, DOTATATE PET imaging. The screening consent is to be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines. Eligibility Criteria Phase I Age Patient must be ≥ 4 and < 12 years of age at the time of enrollment. Disease Status: Patients who participate in the efficacy expansion cohort must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions Patients with measurable extraneural disease only are also eligible. Phase II Age Patient must be ≥ 12 years at the time of enrollment. Inclusion Criteria 3.1 Screening Process SST2A Expression by IHC (Step 1 of 2-Step Screening Process) Patients must have evidence of SST2A expression measured by IHC in their tumor, confirmed by central pathology review (membranous staining, >10% tumor cell immunoreactivity, and at least weak staining intensity). This is required of all patients, except patients with meningioma without pre-trial tumor tissue. Uptake on DOTATATE PET (Step 2 of 2-Step Screening Process) Only patients whose tumors have positive SST2A expression by IHC (i.e., who pass Step 1 of 2-Step Screening Process) or patients with meningioma without pre-trial tumor tissue will undergo this next screening step-functional confirmation by DOTATATE PET imaging. Patients must have uptake on DOTATATE PET/CT in at least one tumor lesion (corresponding to known disease) equivalent to a Krenning score ≥2 (confirmed by central radiology review). 3.2 Prior Therapy Patients must have recovered from the acute treatment related toxicities (defined as ≤ grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy, radiotherapy, or any other treatment modality prior to entering this study. 3.3 Chemotherapy Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea. 3.4 Investigational/Biologic Agent ●Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. ●Monoclonal Antibodies and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent ≥ 28 days prior to study enrollment. 3.5 Radiation Patients must have had their last fraction of: Craniospinal irradiation or total body irradiation or radiation to > 50% of pelvis > 3 months prior to enrollment. Focal irradiation > 4 weeks prior to enrollment 3.6 Stem Cell Transplant Patient must be: ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft vs. host disease ≥ 3 months since autologous stem cell transplant prior to enrollment 3.7 Growth Factors Patients must be off all colony-forming growth factor(s) for at least 1 week prior to enrollment (e.g. filgrastim, sargramostim or erythropoietin). Two weeks must have elapsed if patients received long-acting formulations. 3.8 Somatostatin analogs Patients must be off long-acting somatostatin analogs for at least 4 weeks and off short-acting somastatin analogs (i.e., octreotide) for at least 24 hours. 3.9 Neurologic Status Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment, documented by a detailed neurological exam. Patients with seizure disorders may be enrolled if seizures are well controlled. 3.10 Performance Status Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within two weeks of enrollment must be ≥ 50. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score 3.11 Organ Function Patients must have adequate organ and marrow function, both for eligibility for enrollment, and to begin each subsequent cycle of Lutathera, as defined below: Adequate Bone Marrow Function as defined as: Absolute neutrophil count ≥ 1.0 x 109 cells/ L Platelets ≥100 x 109 cells/ L (unsupported, defined as no platelet transfusion within 7 days) Hemoglobin ≥8 g/dl (may receive transfusions) Adequate Renal Function as defined as: Glomerular filtration rate (GFR) estimated by cystatin C ≥ 60ml/min/1.73 m2 A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6 to < 10 years: maximum serum creatinine 1.0 mg/dL for males and females. 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for males and females. 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for males and 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dL for males and 1.4 mg/dL for females. Adequate Liver Function as defined as: Total bilirubin ≤ 3 times institutional upper limit of normal (ULN) for age AST(SGOT)/ALT(SGPT) ≤ 3 times institutional ULN Serum albumin ≥ 2g/dL Coagulation parameters: INR <1.5 times ULN and aPTT <1.5 times ULN unless patients are receiving therapeutic anticoagulation which affects these parameters Adequate Cardiac Function as defined as: Ejection fraction of ≥ 55% by echocardiogram Serum electrolytes (Sodium, Potassium, Chloride) within institutional limits of normal (patients can be on enteral supplementation) 3.12 Corticosteroids Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment, with a maximum dexamethasone dose of 2.5mg/m2/day. 3.13 Pregnancy Status Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 3.14 Pregnancy Prevention Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for at least 7 months after drug cessation in females of childbearing potential and for at least 4 months after drug cessation in males of child fathering potential. 3.15 Informed Consent The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Exclusion Criteria 4.1 Confirmed bone marrow metastatic disease Patients with confirmed metastatic disease to bone marrow are ineligible. 4.2 Presence of bulky disease Patients with bulky disease on imaging as described below are ineligible. Treating physicians are encouraged to request a rapid central imaging review to confirm fulfillment of these criteria if there are questions or concerns. Bulky disease is defined as: Tumor with evidence of clinically significant uncal herniation or midline shift. Tumor with diameter of >5cm in one dimension on T2/FLAIR. Tumor that in the opinion of the site investigator shows significant mass effect in either the brain or spine. Note that patients with metastatic or multi-focal disease (with exception of bone marrow) are eligible as long as no sites of disease meet above criteria for bulky disease. 4.3 Breast-feeding Nursing mothers are excluded from this study. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Lutathera. 4.4 Concurrent Illness Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient's prior malignancy has been in remission for at least 5 years from the end of treatment. Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results. Patients with type I diabetes. 4.5 Concomitant Medications Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible. Prior or current treatment with 177Lu-DOTATATE/TOC or 90Y-DOTATATE/TOC. 4.6 Prisoners will be excluded from this study. 4.7 Inability to participate: Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits, obtain follow-up studies required to assess toxicity to therapy, or adhere to drug administration plan, other study procedures, and study restrictions. Inclusion of Women and Minorities Both males and females of all races and ethnic groups are eligible for this study. Criteria to Start Treatment Subjects must start therapy within seven (7) days of enrollment. Laboratory values must be no older than 7 days prior to the start of therapy. If a test that is repeated post enrollment and prior to the start of therapy is outside the limits for eligibility, it must be rechecked within 48 hours prior to the start of therapy. If rechecks are still outside the limits for eligibility, the patient may not receive protocol therapy and will be considered off study.

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