Overview

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)

Eligibility

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.
          1. 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 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.
             1.3 Screening Consent Participant/legal guardian is willing to sign a screening
             consent for DOTATATE PET imaging. The screening consent is to be obtained according to
             institutional guidelines. Assent, when appropriate, will be obtained according to
             institutional guidelines.
          2. 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.
          3. Inclusion Criteria
             3.1Uptake on DOTATATE PET 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.
          4. 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.
          5. Inclusion of Women and Minorities Both males and females of all races and ethnic
             groups are eligible for this study.
          6. 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.