HUMC 1612: Optune NovoTTF-200A System

This phase I trial will utilize a standard 3+3 design to determine the safety and tolerability of the Optune NovoTTF-200A System in pediatric patients with recurrent high-grade glioma end ependemomas.

Patients will receive treatment with the Optune NovoTTF-200A System along with Temozolomide and Bevacizumab and will consist of children with recurrent high-grade gliomas and Ependamomas. Patients enrolled will receive treatment with the Optune NovoTTF-200A with 200kHz for a minimum of 18 hours per day in 28 day cycles as monotherapy. Phase I safety evaluation will take place over the initial two cycles (56 days) of treatment. Following the completion of the safety evaluation period, patients will continue to receive treatment in 28 day cycles, which may be repeated continuously without therapy interruption for 12 cycles or until clinical criteria for discontinuation are met. Patients how appear to benefit from this treatment may be allowed to continue treatment beyond 12 cycles if approved by the study Principle Investigator.

Inclusion criteria

• Patients must have a minimum head circumference of 44 cm
• Patients must have a histologically- or cytologically-confirmed supratentorial high-grade glioma or supratentorial ependemoma.
• Patients with metastatic disease involving the infratentorium or spinal cord are eligible providing that they have a supratentorial tumor that is able to be targeted with TTFields.
• Eligible pathologic diagnoses include:

High-grade Glioma (WHO Grade III or IV): Anaplastic Astrocytoma, Astroblastoma, Diffuse Midline Glioma, Glioblastoma, Gliosarcoma Ependymoma (WHO Grade II or III):Ependymoma, Anaplastic Ependymoma

• Patients with high-grade glioma must must have be newly-diagnosed or have a tumor that is progressive or recurrent following standard treatment. Patients with ependymoma must have a tumor that is progressive or recurrent following standard treatment.
• Patients must have received the maximal feasible resection of their tumor and radiation therapy (unless contraindicated due to patient age) as part of their initial treatment prior to study enrollment.
• Patients must be enrolled before treatment begins. Treatment must start within 14 days of study enrollment.
• All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated in the eligibility section.
• Newly-diagnosed patients must begin therapy within six weeks of the completion of radiotherapy, or within six weeks of surgical resection if radiotherapy is contraindicated.
• Recurrent high-grade glioma patients must begin therapy within four weeks of documented tumor progression by MRI scan.
• Patients must have a Lansky or Karnofsky performance status score of ≥ 50%, corresponding to ECOG categories of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.
• Able to undergo adequate tumor imaging, via magnetic resonance imaging (MRI) scan to evaluate disease evolution.
• Adequate hematologic, renal, liver function as demonstrated by laboratory values: ANC ≥ 1,000/ul Hemoglobin ≥8.0 gm/dl Platelet count ≥ 100,000/ul

Adequate Liver Function Defined As:

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
• SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. Adequate Renal Function Defined As Either
• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2
• or a serum creatinine less than or equal to the institutional normal for age

• Negative pregnancy test in women of childbearing potential within 7 days of initiating investigational therapy
• Recent mothers must agree not to breast feed while receiving medications on study
• Patient or legal guardian must give written, informed consent or assent (when applicable).
• Able to swallow and ingest oral medication or have a NG or G-tube for drug administration
• Urine protein should be screened by urine analysis. If protein ≥ 2+ on urinalysis, then Urine Protein Creatinine (UPC) ratio should be calculated. If UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment.

Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1000 mg. UPC ratio is calculated using one of the following formula:

• [urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/dL
• [(urine protein) x0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L
• Adequate Coagulation Defined As: PT/INR ≤ 1.5 x upper limit of normal

Exclusion criteria

• Age less than 5 or greater than or equal to 18 years
• Head circumference < 44 cm
• Absence of supratentorial tumor
• Use of any other investigational drug within five half-lives of that drug prior to the initiation of protocol therapy
• Anti-cancer therapy within 4 weeks prior to the initiation of protocol therapy (6 weeks for mitomycin and nitrosureas, 4 weeks for curative-intent radiotherapy, and 2 weeks for palliative radiotherapy)
• Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE version 4.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy that could impact on safety outcome assessment
• Any surgery within 14 days prior to initiation of protocol therapy (excluding shunt or line insertion)
• Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
• Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness) Patients receiving escalating doses of corticosteroids to control symptoms of increased intracranial pressure (e.g., require a stable or decreasing dose of corticosteroids for at least 7 days prior to enrollment) will also be excluded.
• Known > Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scan within the last 1 month. Patients with resolving hemorrhage changes, punctuate hemorrhage or hemosiderin may enter the study
• Pregnant female patients, Pregnancy tests with a negative result must be obtained in all post-menarchal females.
• Lactating females must agree they will not breastfeed a child while on this study.
• Males and females of reproductive potential may not participate unless they agree to use an effective contraceptive method and continue to do so for at least 6 months after the completion of therapy.
• Any serious and/or unstable pre-existing medical, psychiatric or other condition which in the Investigator's opinion could interfere with subject safety, obtaining written informed consent, or compliance with the study protocol
• Known hypersensitivity to temozolomide or bevacizumab
• Patients who are unable to take oral medications because of significant uncontrolled vomiting will be excluded.
• Patients must not have a history of myocardial infarction, severe or unstable angina, clinically significant peripheral vascular disease, Grade 2 or greater heart failure, or serious and inadequately controlled cardiac arrhythmia.
• Patients must not have a known clinically significant bleeding diathesis or coagulopathy
• Patients who have experienced arterial thromboembolic events, including transient ischemic attacks or cerebrovascular accidents are excluded from participation.
• Patients must not have been previously diagnosed with a deep venous thrombosis (including pulmonary embolism), and must not have a known thrombophilic condition (e.g., protein S, protein C, antithrombin III deficiency, Factor V Leiden or Factor II G202'0A mutation, homocysteinemia, or antiphospholipid antibody syndrome).
• Patients must not have a history of an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the last 6 months prior to study entry.
• Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible for this study.
• Patients with a history of allergic reaction to Chinese hamster ovary cell products, or other recombinant human antibodies are ineligible.