Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs

A Multicenter Open-label Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With Somatostatin Receptor Positive Gastroenteropancreatic Neuroendocrine (GEP-NET) Tumors, Pheochromocytoma and Paragangliomas (PPGL)

This is a multicenter, open-label, single-arm study to evaluate the safety and dosimetry of Lutathera in adolescent patients 12 to <18 years old with somatostatin receptor positive GEP-NETs and PPGLs. The study will enroll at least 8 patients in the GEP-NET cohort and as many adolescents with PPGL as possible in the exploratory PPGL cohort.

The study schedule for each patient consists of the screening period (up to 2 weeks) followed by the treatment period (4 treatment administrations at 8-week interval), and the follow-up period (10 years).

The treatment period will consist of 4 Lutathera treatments administered at 8-week intervals. Lutathera administration will occur on Week 1 Day 1 of each cycle. Each patient will receive a total of 4 doses of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative dose: 29.6 GBq/800 mCi). An infusion of 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered with each Lutathera dose for renal protection according to the approved Lutathera local prescribing information. An antiemetic will be administered prior to infusion of the AA solution for prevention of infusion-related nausea and vomiting.

The dosimetry and PK assessments will be performed during the first week after the 1st Lutathera dose, i.e. one time during the study treatment period for each patient. The dosimetry analysis will allow for estimation from the 1st Lutathera administration of the cumulative absorbed radiation dose from 4 Lutathera doses and also for taking a decision on the next dose levels. In the exceptional circumstances when dosimetry cannot be performed in a particular patient after the first Lutathera dose, it should be completed as soon as feasible upon a later dose. In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety data will be performed for each patient in the study, to enable the Investigator to take a decision for the subsequent Lutathera doses. The results of dosimetry assessments (imaging and blood dosimetry) will be provided to the investigators for their evaluation prior to administration of subsequent therapeutic cycles in each patient.

A total follow-up period of 10 years (120 months) after the last Lutathera dose will take place for each patient who received at least one dose of Lutathera. This follow-up period will be comprised of a short-term follow-up of 6 months to evaluate cumulative Lutathera toxicities, followed by a long-term follow up of another 114 months.

An external Data and Safety Monitoring Board (DSMB) will also operate in the study to evaluate accumulating safety and dosimetry data, to ensure the safety of adolescents enrolled in the study, and to provide recommendations to investigators as well as to the clinical team in charge of conducting the study.

Key Inclusion Criteria:

1. GEP-NET cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven, G1 or G2 (Ki-67 index =< 20%), well differentiated GEP-NET.

   or PPGL cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven PPGL.

2. Patients from 12 to < 18 years of age at the time of enrollment.

3. Expression of somatostatin receptors confirmed by a somatostatin receptor imaging (SRI) modality within 3 months prior to enrollment, with tumor uptake observed in the target lesions more or equal to the normal liver uptake.

4. Performance status as determined by Karnofsky score >= 50 or Lansky Play-Performance Scale score >= 50.

5. Parent's ability to understand and the willingness to sign a written informed consent document for adolescents as determined by local regulations. Adolescents will sign assent along with parental/legal guardian consent or will co-sign consent with parent/legal guardian in accordance with local regulation, prior to participation in the study.

Key Exclusion Criteria:

1. Laboratory parameters:

   1. Estimated creatinine clearance calculated by the Cockroft-Gault method < 70 mL/min
   2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L; platelets <75x109/L.
   3. Total bilirubin >3 x ULN for age.
   4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.

2. Established or suspected pregnancy.

3. Breastfeeding female patients unless they accept to discontinue breastfeeding from the 1st dose until 3 months after the last administration of study drug.

4. Female patients of child-bearing potential, unless they are using highly effective methods of contraception during treatment and for 6 months after the last dose of Lutathera.

5. Sexually active male patients, unless they agree to remain abstinent or be willing to use effective methods of contraception.

6. Patients for whom in the opinion of the investigator other therapeutic options are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics.

7. Current spontaneous urinary incontinence.

8. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.

9. Hypersensitivity to the study drug active substance or to any of the excipients.

10. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.

11. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.

12. Patients who received any investigational agent within the last 30 days.