Phase I Study of APX005M in Pediatric Central Nervous System Tumors

Inclusion Criteria

• •Diagnosis -- Stratum 1: Recurrent or refractory primary malignant CNS tumor patients Patients with a histologically confirmed diagnosis of a primary malignant non-brainstem CNS tumor (excluding DIPG patients) that is recurrent, progressive, or refractory. All tumors must have histologic verification at either the time of diagnosis or recurrence except patients with marker (+) CNS germ cell tumors.
• •Available Pre-trial Tumor Tissue -- Stratum 1: Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or FFPE tumor material (minimum of 10 unstained slides) available for use in the tumor mutation burden studies (section 9.1.5).
• •Stratum 2: Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility.
• •Age -- Patient must be ≥ 1 and ≤ 21 years of age at the time of enrollment.
• •Prior Therapy -- Newly Diagnosed DIPG patients Patients must have not received any prior therapy for treatment of their current CNS malignancy other than radiation therapy.
• •Refractory/Recurrent patients Patients must have recovered from the acute treatment related toxicities (defined as \< grade 1) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study.
• •Myelosuppressive 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.
• •Biological agent: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the 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 antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.
• •Radiation --
• •Patients must have had their last fraction of:
• •Craniospinal irradiation (\>24Gy) or total body irradiation or radiation to greater than 50% of pelvis \> 3 months prior to enrollment.
• •Focal irradiation \>6 weeks prior to enrollment Local palliative irradiation (small port) ≥4 weeks
• •Autologous Stem Cell Transplant -- Patient must be ≥ 6 months since autologous bone marrow/stem cell transplant prior to enrollment and have CD4 counts above 200/mm3.
• •Surgery -- Patients must be at least 4 weeks (28 days) from major surgery and fully recovered from all acute effects of prior surgical intervention.
• •Inclusion of Women and Minorities -- Both males and females of all races and ethnic groups are eligible for this study
• •Neurologic Status -- Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.
• •Patients with seizure disorders may be enrolled if seizures are well controlled.
• •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 ≥ 60. 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.
• •Organ Function --
• •Patients must have adequate organ and bone marrow function as defined below:
• •Absolute Neutrophil Count (ANC) ≥ 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) Total bilirubin ≤1.5 times institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 3 x institutional upper limit of normal (ULN) Albumin ≥ 3 g/dl Serum creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24 hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.
• •Age Maximum Serum Creatinine (mg/dL) 1 to \< 2 years 0.6, 0.6 (M, F); 2 to \< 6 years 0.8, 0.8 (M, F); 6 to \< 10 years 1, 1 (M, F); 10 to \< 13 years 1.2, 1.2 (M, F); 13 to \< 16 years 1.5, 1.4 (M, F); ≥ 16 years 1.7, 1.4 (M, F).
• •Cardiac Function: Left Ventricular Ejection Fraction (LVEF) \> 50% ECG QTc ≤ 450 msec
• •Pulmonary Function: Oxygen saturation as measured by pulse oximetry is \> 93% on room air and no evidence of dyspnea at rest
• •Growth Factors -- Patients must be off all colony- forming growth factor(s) for at least 1 week prior to enrollment (i.e., filgrastim, sargramostim or erythropoietin). 2 weeks must have elapsed if patients received PEG formulations.
• •Pregnancy Status -- Female patients of childbearing potential must have a negative serum or urine pregnancy test.
• •Pregnancy Prevention -- Female subjects with childbearing potential and male subjects should use effective contraception methods (or abstain from sexual activity) while being treated with APX005M and for 30 days following treatment.
• •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.