Lutathera for the Treatment of Patients with Recurrent, Progressive or Refractory Central Nervous System Tumors and Meningiomas

Inclusion Criteria

• SCREENING CRITERIA: Patient must have a diagnosis of primary high-grade CNS tumor (any histopathologic diagnosis that is World Health Organization [WHO] grade 3-4) or meningioma (any histologic grade) that is recurrent, progressive, or refractory. Note that patients with diffuse intrinsic pontine glioma (DIPG) (based on radiographic/clinical diagnosis) who have undergone biopsy will be eligible with histologic diagnosis of grade 2-4 infiltrating glioma. All tumors must have histologic verification either at the time of diagnosis or recurrence, except for meningioma patients 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
• SCREENING CRITERIA: 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
• SCREENING CRITERIA: Participant/legal guardian is willing to sign a screening consent for DOTATATE PET imaging. The screening consent should be obtained according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines. Remote consent and assent may be utilized for screening informed consent. Participating sites will follow their local institutional policy for the remote consent process
• PHASE I: Patient must be ≥ 4 and < 12 years of age at the time of enrollment
• PHASE I: 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: Patient must be ≥ 12 years at the time of enrollment
• BOTH PHASES: All patients will undergo screening involving functional confirmation of SST2A expression 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 at Cincinnati Children's Hospital Medical Center (CCHMC). For patients who have already undergone DOTATATE PET imaging for clinical purposes, prior images can be submitted for central review without having to repeat the scan
• BOTH PHASES: 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
• BOTH PHASES: 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
• BOTH PHASES: 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
• BOTH PHASES: 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
• BOTH PHASES: Patients must have had their last fraction of: * Craniospinal irradiation (CSI) or total body irradiation or radiation to ≥ 50% of pelvis > 3 months prior to enrollment * Focal irradiation > 4 weeks prior to enrollment
• BOTH PHASES: Patient must be: * ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease * ≥ 3 months since autologous stem cell transplant prior to enrollment
• BOTH PHASES: 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
• BOTH PHASES: Patients must be off long-acting somatostatin analogs for at least 4 weeks and off short-acting somatostatin analogs (i.e., octreotide) for at least 24 hours
• BOTH PHASES: Patients with neurological deficits must 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
• BOTH PHASES: 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
• BOTH PHASES: Absolute neutrophil count ≥ 1.0 x 10^9 cells/ L
• BOTH PHASES: Platelets ≥ 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
• BOTH PHASES: Hemoglobin ≥ 8 g/dl (may receive transfusions)
• BOTH PHASES: Glomerular filtration rate (GFR) estimated by cystatin C ≥ 60ml/min/1.73 m^2 AND serum creatinine based on age/gender: * Maximum serum creatinine (mg/dL) ** Age 1 to < 2 years: male 0.6, female 0.6 ** Age 2 to < 6 years: male 0.8, female 0.8 ** Age 6 to < 10 years: male 1, female 1 ** Age 10 to < 13 years: male 1.2, female 1.2 ** Age 13 to < 16 years: male 1.5, female 1.4 ** Age ≥ 16 years: male 1.7, female 1.4
• BOTH PHASES: Total bilirubin ≤ 3 times institutional upper limit of normal (ULN) for age
• BOTH PHASES: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 times institutional ULN
• BOTH PHASES: Serum albumin ≥ 2g/dL
• BOTH PHASES: Coagulation parameters: International normalized ratio (INR) < 1.5 (or < 1.5 x baseline if on anticoagulation) and activated partial thromboplastin time (aPTT) < 1.5 times ULN
• BOTH PHASES: Ejection fraction of ≥ 55% by echocardiogram
• BOTH PHASES: Serum electrolytes (sodium, potassium, chloride) within institutional limits of normal (patients can be on enteral supplementation)
• BOTH PHASES: 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/m^2/day
• BOTH PHASES: 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
• BOTH PHASES: 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
• BOTH PHASES: 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

• BOTH PHASES: Patients with confirmed metastatic disease to bone marrow are ineligible
• BOTH PHASES: 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/fluid attenuated inversion recovery (FLAIR) * Tumor that in the opinion of the site investigator shows significant mass effect in either the brain or spine 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
• BOTH PHASES: 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
• BOTH PHASES: 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
• BOTH PHASES: 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
• BOTH PHASES: Patients with type I diabetes
• BOTH PHASES: Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
• BOTH PHASES: Prior or current treatment with 177Lu-DOTATATE/TOC or 90Y-DOTATATE/TOC
• BOTH PHASES: Prisoners will be excluded from this study
• BOTH PHASES: 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
• BOTH PHASES: Both males and females of all races and ethnic groups are eligible for this study
• BOTH PHASES: Subjects must start therapy within seven (7) days of enrollment
• BOTH PHASES: 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