MEKTOVI® for the Treatment of Pediatric Adamantinomatous Craniopharyngioma

Inclusion Criteria:

1. Age: Patients must be ≥ 12 months and ≤ 25 years of age at the time of studyenrollment.

2. Diagnosis: Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) Histologic confirmation of ACP may be made on solid tumor or, if no solidtumor can be safely obtained, cyst fluid with classic ACP characteristics of thick,cholesterol-rich, greenish-brown liquid in the context of imaging featuresconsistent with craniopharyngioma, including lobulated, cystic/solid mass withcalcifications that originates in the sellar/suprasellar region.

3. Disease Status: Patients must have measurable disease.

• Stratum 1: Patients with progressive or recurrent ACP who demonstrate cysticand/or solid recurrence or progression at least 6 months post completion ofradiation therapy

• Stratum 2: Patients with measurable ACP who have undergone surgery but have NOTpreviously undergone irradiation (but may have received prior systemic orintracystic therapy). Progressive disease is allowed but not required.

4. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50for patients ≤ 16 years of age (See Appendix I). Note: Neurologic deficits inpatients with CNS tumors must have been stable for at least 7 days prior to studyenrollment. Patients who are unable to walk because of paralysis, but who are up ina wheelchair, will be considered ambulatory for the purpose of assessing theperformance score.

5. Prior Therapy: Patients must have recovered or stabilized from the acute toxiceffects of prior treatments

• Biologic (anti-neoplastic agent): At least 7 days must have elapsed after thelast (systemic or intracystic) dose of a biologic agent. For agents that haveknown adverse events occurring beyond 7 days after administration, this periodmust be extended beyond the time during which adverse events are known tooccur. The duration of this interval must be discussed with the study chair

• Immunotherapy: At least 42 days after the completion of any type of systemicimmunotherapy, e.g. tumor vaccines.

• Monoclonal antibodies: At least 21 days after the last dose of a monoclonalantibody.

• Radiation therapy: Patients must have had their last (conventional orhypofractionated) fraction of: a) Focal irradiation > 6 months prior toenrollment and b) No prior craniospinal irradiation is permitted.

• Corticosteroids: Patients receiving dexamethasone must be on a stable ordecreasing dose for at least 1 week prior to enrollment

• Myelosuppressive systemic therapy: At least 21 days must have elapsed after thelast systemic myelosuppressive therapy.

• Surgery: At least 6 weeks must have elapsed since major or intermediatesurgery. Major surgery includes major craniotomy for tumor resection of cystfenestration, organ resection, and exploratory laparotomy. Intermediateprocedures include ventriculoperitoneal shunt placement, stereotactic brainbiopsy, and intraventricular catheter placement. Minor procedures that are notexcluded include skin biopsy/incision and drainage, bone marrow aspirate, andcentral venous catheter placement, ommaya aspirations, lumbar punctures, andnasal endoscopy to remove packing.

6. Organ Function Requirements Adequate Bone Marrow Function Defined as:

• Peripheral absolute neutrophil count (ANC) ≥1000/mm3

• Platelet count ≥100,000/mm3 (transfusion independent, defined as not receivingplatelet transfusions for at least 7 days prior to enrollment)

• Hemoglobin >8 g/dL (may be transfused) Adequate Renal Function Defined as:

• Creatinine clearance or radioisotope GFR > 70ml/min/1.73 m2 or

• A serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/genderas follows:

1. to < 2 years: maximum serum creatinine 0.6 mg/dL for males and females. 2to < 6 years: maximum serum creatinine 0.8 mg/dL for males and females. 6to < 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 andfemales. 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for malesand 1.4 mg/dL for females. ≥ 16 years: maximum serum creatinine 1.7 mg/dLfor males and 1.4 mg/dL for females. Adequate Liver Function Defined as:

• Total bilirubin ≤ 1.5 × institutional upper limit of normal

• AST (SGOT) ≤ 2.5 × institutional upper limit of normal

• ALT (SGPT) ≤ 2.5 × institutional upper limit of normal Adequate Cardiac Function Defined as:

• Left Ventricular Ejection Fraction greater than the institutional lower limitof normal by echocardiogram

• QTc ≤ 480 msec (by Bazett formula) Adequate Neurologic Function Defined as:

• Patients with neurological deficits should have deficits that are stable for aminimum of 1 week prior to enrollment.

• Patients with current seizure disorders may be enrolled if seizures arewell-controlled on antiepileptic therapies.

7. Informed Consent: All patients and/or their parents or legally authorizedrepresentatives must sign a written informed consent. Assent, when appropriate, willbe obtained according to institutional guidelines

Exclusion Criteria:

1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered onthis study due to unknown risks of fetal and teratogenic adverse events as seen inanimal/human studies. Pregnancy tests must be obtained in girls who arepost-menarchal. Males or females of reproductive potential may not participateunless they have agreed to use an effective contraceptive method for at least 90days after discontinuation of drug for females and at least 60 days for males. Forfemales of childbearing potential, agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods (bilateral tubal ligation,male sterilization, hormonal contraceptives that inhibit ovulation,hormone-releasing intrauterine devices, and copper intrauterine devices; hormonalcontraceptive methods must be supplemented by a barrier method) and agreement torefrain from donating eggs are required. For males of reproductive potential,agreement to remain abstinent (refrain from heterosexual intercourse) or use acondom, and agreement to refrain from donating sperm.

2. Gastrointestinal Disease:

• Patients with a history of serious gastrointestinal disease, includinginflammatory bowel disease or gastrointestinal perforation

• Patients who are unable to swallow, retain or absorb oral medications

3. Concomitant Medications

• Corticosteroids: Patients receiving corticosteroids who have not been on astable or decreasing dose of corticosteroid for at least 7 days prior toenrollment are not eligible.

• Investigational Drugs: Patients who are currently receiving anotherinvestigational drug are not eligible.

• Anti-cancer Agents: Patients who are currently receiving other anti-canceragents are not eligible.

4. Study Specific:

• Patients who have an uncontrolled infection are not eligible.

• Patients who have received any live or attenuated vaccinations within threemonths prior to start of therapy are not eligible.

• Any significant concurrent medical or surgical condition that would jeopardizethe patient's safety or ability to complete the study, including, but notlimited to, disease of the nervous, renal, hepatic, cardiac (such assymptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia), pulmonary, or endocrine system

• Patients who have a history of Human Immunodeficiency Virus, Hepatitis B Virus,Hepatitis C Virus or Tuberculosis infection are not eligible.

• Patients who have received a prior solid organ transplantation are noteligible.

• Patients who in the opinion of the investigator may not be able to comply withthe safety monitoring requirements of the study are not eligible.

• Patients who have a history of alcohol, drug, or chemical abuse within 6 monthsof screening.

• Patients who have had surgery within the last 6 weeks or who have concerns forpoor postsurgical wound healing.

• Patients who have a history of allergic reactions attributed to compounds ofsimilar chemical or biologic composition to tocilizumab and its excipients arenot eligible.