A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors

Inclusion Criteria

• •Age:
• •Patients must be less than or equal to 21 years of age at the time of study enrollment. At the time the MTD or the dose to be recommended for future trials is identified, up to 12 additional patients will be enrolled at that dose level to further define the toxicity profile. Six of these patients will be less than 12 years of age and the other half will be greater than or equal to 12 years.
• •Tumor:
• •Patients with a diagnosis of a primary CNS malignancy (including low-grade glioma) that is recurrent or refractory to standard therapy and for which there is no known curative therapy. All patients must have had histological verification of malignancy at initial diagnosis or relapse, excluding patients with diffuse intrinsic brain stem tumors, optic pathway tumors or CNS germ cell tumors with elevations of reliable serum or CSF tumor markers (alpha-fetoprotein or beta-HCG). Patients with intrinsic pontine gliomas or optic pathway tumors do not require histological confirmation of disease but should have clinical and/or radiographic evidence of progression.
• •Performance Status:
• •Patients must have Karnofsky Performance Score (for patients greater than 16 years of age) or Lansky Performance Score (for patients less than or equal to 16 years of age) greater than or equal to 50% assessed within two weeks of study enrollment.
• •Neurological Status:
• •Patients must be able to take oral medications (either capsules or liquid). Patients with neurologic deficits must have been stable for a minimum of 1 week prior to study entry. 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.
• •Prior/Concurrent Therapy:
• •Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Recovery is defined as all AE s, attributable to prior therapy, having improved to grade 2 or better or as outlined below.
• •Myelosuppressive chemotherapy:
• •* Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study registration.
• •* Patients must have received their last dose of nitrosourea (including Gliadel) at least six (6) weeks prior to study registration.
• •Biologic agent (anti-neoplastic): Patient must have received their last dose of other biologic agent greater than or equal to 7 days prior to study registration.
• •--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. The duration of this interval must be discussed with the study chair.
• •Monoclonal antibody treatment: Patient must have received their last dose of monoclonal antibody greater than or equal to 4 weeks prior to registration.
• •Radiation - Patients who have had prior radiation must have had their last fraction of:
• •* Craniospinal irradiation or total body irradiation greater than 3 months prior to registration
• •* Local irradiation to the primary tumors or other sites (cumulative dose greater than or equal to 40Gy) greater than 3 months prior to registration
• •* Palliative irradiation delivered to symptomatic metastatic sites greater than 4 weeks prior to registration.
• •Stem Cell Transplant: Patient must be:
• •* greater than or equal to 6 months since allogeneic stem cell transplant prior to registration
• •* greater than or equal to 3 months since autologous stem cell transplant prior to registration.
• •Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
• •Growth factors:
• •* Off all colony forming growth factor(s) that support platelet or white blood cell count, number or function for at least 1 week prior to registration (filgrastim, sargramostim, erythropoietin).
• •* Off Pegylated G-CSF and/or Erythropoiesis Stimulating Protein for at least 14 days prior to registration.
• •Prior CNS ischemia and/or infarction:
• •Patients with documented CNS ischemia and/or infarction, whether symptomatic or discovered incidentally without clinical symptoms, will be excluded from study participation.
• •Inability to Participate:
• •Patients with an inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.