A Study of 177Lu-DTPA-Omburtamab in Children and Adolescents With Brain Cancer or Cancer That Has Spread to the Central Nervous System (CNS)

A Phase I Dose Escalation Trial of Compartmental Radioimmunotherapy (cRIT) Using 177Lu-DTPA-omburtamab in Pediatric and Adolescent Patients With Recurrent or Refractory B7H3 Expressing Primary or Metastatic CNS Tumors

The purpose of this study is to find out whether 177Lu-DPTA-omburtamab is a safe treatment for children and adolescents with recurrent/refractory medulloblastoma or another type of cancer with CNS metastases.

Inclusion Criteria:

- Disease type:

• Histologically confirmed diagnosis of a tumor that is known to express B7-H3 including but not limited to neuroblastoma, medulloblastoma, rhabdoid tumors, pineoblastoma, retinoblastoma, CNS embryonal tumor, rhabdomyosarcoma, Ewing's sarcoma and ependymoma.

  • Disease status:

• Patients must have recurrent or refractory disease with CNS parenchymal and/or leptomeningeal disease which has been treated with conventional therapies or for which no conventional therapy exists. Measurable or evaluable disease is not required at time of enrollment.

  - Age: Patients must be ≥ 3 and < 22 years of age at the time of enrollment.

  • Prior Therapy: The participant must have recovered from acute toxic effects of prior anti-cancer therapies with the following minimum duration from prior therapy:

• Chemotherapy: Patients must have received their last dose of known myelosuppressive anticancertherapy at least 21 days (3 weeks) prior to enrollment or at least 42 days (6 weeks) if prior nitrosourea.

• Anti-GD2 monoclonal antibody (neuroblastoma patients): Patients must have received their last dose of anti-GD2 mAb at least 14 days (2 weeks) before enrollment.

• Radiation: Patients must have had their last fraction of:

  • Craniospinal irradiation, whole brain radiation, or total body irradiation at least 21 days (3 weeks) prior to study enrollment.
  • Focal radiation to areas of symptomatic metastatic disease at least 14 days (2 weeks) prior to study enrollment.

• Stem Cell Transplant (SCT): For autologous SCT, 60 days (≥ 2 months) must have elapsed before study enrollment. Patients who have received an autologous hematopoietic stem cell injection to support non- myeloablative therapy (such as 131 I-MIBG) are eligible at any time as long as they meet the other criteria for eligibility. 131

• I-MIBG therapy or treatment with other radiopharmaceuticals (neuroblastoma 131 patients): A minimum of 42 days (6 weeks) must have elapsed after I-MIBG therapy before start of protocol therapy.

• Investigational/Biologic 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 (1 week) prior to study enrollment.

• Molecular targeted therapies: Patients must complete a washout period from last therapy that is either 7 days (1 week) or 3 half-lives, whichever is longer.

  • Patients with neurological deficits should have deficits that are stable for a minimum of 7 days (1 week) prior to enrollment.
  • Patients with seizure disorders may be enrolled if seizures are controlled.
  • Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 14 days (2 weeks) prior to study 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.

  • Peripheral absolute neutrophil count (ANC) ≥ 0.5x 109/ L (must not have received G-CSF within 7 days (1 week) prior to enrollment or pegfilgrastim within 14 days (2 weeks) prior to enrollment.
  • Platelet count ≥ 75 x 109/ L. Growth factor support (romiplostim or biosimilar) is permitted both prior to and during therapy.

• For patients with neuroblastoma (regardless of marrow disease status) and other solid tumors known bone marrow infiltration from disease: platelet count ≥ 50 x 109/ L (with no platelet transfusion within 7 days prior to study enrollment).

  - Adequate Renal Function Defined as:

  - A creatinine based on age/gender as follows: Age; Maximum Serum Creatinine (mg/dL) Male and Female

  1 month to < 6 months; 0.4, 0.4 6 months to < 1 year; 0.5, 0.5

  1. to < 2 years; 0.6, 0.6
  2. to < 6 years; 0.8, 0.8

  6 to < 10 years; 1, 1 10 to < 13 years; 1.2. 1.2 13 to < 16 years; 1.5, 1.4

  ≥ 16 years; 1.7, 1.4

  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.
  • Adequate Liver Function Defined as: - Bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (or ≤ 3 x ULN if Gilbert's syndrome) - SGPT (ALT) < 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
  • Presence of an appropriate intraventricular access device (e.g., programmable ventriculoperitoneal [VP] shunt or Ommaya reservoir). Patients are not required to have an existing programmable VP shunt or Ommaya at the time of study enrollment but must be willing and able to undergo a surgical procedure to have one placed prior to cRIT.

• Note: Patients with an existing intraventricular VP shunt without a programmable component must be willing and able to undergo modification of the shunt.

  • Patients may have active malignancy outside the central nervous system but do not immediately require treatment for systemic disease. Neuroblastoma patients with CNS and systemic disease will only receive 1 dose of cRIT 177Lu- omburtamab while patients with CNS metastases in the absence of systemic disease can receive 2 doses of cRIT 177Lu-omburtamab.
  • Patients may be on standing steroids, as long as the dosage is either stable or decreasing for at least 7 days (1 week) prior to enrollment.
  • Human Anti-Mouse Antibody (HAMA) testing will be performed prior to 177Lu-DTPAomburtamab.

Exclusion Criteria:

• Patients with obstructive or symptomatic communicating hydrocephalus.

• Patients with an uncontrolled life-threatening infection.

• Patients who are pregnant:

  o A negative pregnancy test is required for all women of childbearing age, and appropriate contraception for 3 months after the last dose of 177Lu-DTPAomburtamab is required during the study period.

• Severe major organ toxicity:

  • Cardiac, pulmonary, and gastrointestinal system toxicity should all be < grade 2
  • Patients with grade 4 hearing loss are excluded