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. Atthe time the MTD or the dose to be recommended for future trials is identified, up to 12additional patients will be enrolled at that dose level to further define the toxicityprofile. Six of these patients will be less than 12 years of age and the other half will begreater than or equal to 12 years. Tumor: Patients with a diagnosis of a primary CNS malignancy (including low-grade glioma) that isrecurrent or refractory to standard therapy and for which there is no known curativetherapy. All patients must have had histological verification of malignancy at initialdiagnosis or relapse, excluding patients with diffuse intrinsic brain stem tumors, opticpathway tumors or CNS germ cell tumors with elevations of reliable serum or CSF tumormarkers (alpha-fetoprotein or beta-HCG). Patients with intrinsic pontine gliomas or opticpathway tumors do not require histological confirmation of disease but should have clinicaland/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) greaterthan 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 withneurologic 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, willbe 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 AEs, attributable to prior therapy, having improved to grade 2 or better or as outlinedbelow.

• Myelosuppressive chemotherapy:

• Patients must have received their last dose of known myelosuppressive anticancerchemotherapy at least three (3) weeks prior to study registration.

• Patients must have received their last dose of nitrosourea (including Gliadel) atleast six (6) weeks prior to study registration.

• Biologic agent (anti-neoplastic): Patient must have received their last dose of otherbiologic agent greater than or equal to 7 days prior to study registration.

--For agents that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during which adverseevents are known to occur. The duration of this interval must be discussed with thestudy chair.

• Monoclonal antibody treatment: Patient must have received their last dose ofmonoclonal antibody greater than or equal to 4 weeks prior to registration.

• Radiation - Patients who have had prior radiation must have had their last fractionof:

• Craniospinal irradiation or total body irradiation greater than 3 months prior toregistration

• Local irradiation to the primary tumors or other sites (cumulative dose greaterthan or equal to 40Gy) greater than 3 months prior to registration

• Palliative irradiation delivered to symptomatic metastatic sites greater than 4weeks prior to registration.

• Stem Cell Transplant: Patient must be:

• greater than or equal to 6 months since allogeneic stem cell transplant prior toregistration

• greater than or equal to 3 months since autologous stem cell transplant prior toregistration.

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

• Growth factors:

• Off all colony forming growth factor(s) that support platelet or white blood cellcount, 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 14days prior to registration.

• Temozolomide: Patients who have received temozolomide previously are eligible for thisstudy if they meet all other inclusion and exclusion criteria. Organ Function: Documented within 14 days of registration and within 7 days of startingtreatment.

• Bone Marrow:

• Hgb greater than 8 gm/dL (transfusion independent)

• Platelet count greater than 100,000/mm(3) (transfusion independent)

• Absolute neutrophil count (ANC) greater than 1,500/mm(3)

• Hepatic:

• Total Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5times institutional upper limit of normal (ULN) for age

• SGPT (ALT) less than or equal to 2.5 times institutional ULN for age

• Serum albumin greater than or equal to 2 g/dL

• Renal:

--Creatinine clearance or radioisotope GFR greater than or equal to 70 ml/min/1.73m(2)or a serum creatinine based on age as follows:

• Age less than 5 (years): a Maximum Serum Creatinine (mg/dL) of 0.8

• Age greater than 5 (years) but less than 10: a Maximum Serum Creatinine (mg/dL) of 1

• Age greater than 10 (years) but less than 15: a Maximum Serum Creatinine (mg/dL) of 1.2

• Age greater than 15 (years): a Maximum Serum Creatinine (mg/dL) of 1.5 Pregnancy or Breast-feeding: Patients must not be pregnant or breast-feeding. Females of reproductive potential musthave a negative serum or urine pregnancy test (within 72 hours prior to enrollment). Malesor females of reproductive potential may not participate unless they have agreed to use aneffective contraceptive method, which includes abstinence. Signed informed consent which includes consent to participate in the requiredpharmacokinetic and pharmacodynamic studies prior to registration.

EXCLUSION CRITERIA: Concomitant Medications: Patients receiving any of the following medications are not eligible for study entry:

• Anti-cancer therapy

• Investigational agents Concurrent Illness: Patients with any clinically significant, unrelated systemic illness (serious infections orsignificant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromisethe patient s ability to tolerate protocol therapy or would likely interfere with the studyprocedures or results. Seizures: Patients with uncontrolled seizures are not eligible for study entry. Hypertension:

• Patients with inadequately controlled systemic hypertension (SBP and/or DBP greaterthan 95th percentile for age and height

• Patients with a prior history of hypertensive crisis and/or hypertensiveencephalopathy If a BP measurement prior to registration is greater than 95th percentile for age andheight, it must be rechecked and documented to be less than 95th percentile for age andheight prior to registration. If a patient falls between the height or weight percentiles,site should average the value as appropriate. For patients greater than or equal to 18years the normal blood pressure should be less than 140/90 mm of Hg. Patients withhypertension are eligible if their blood pressures become less than 95th percentile for ageand height after anti-hypertensive medications. Prior CNS ischemia and/or infarction: Patients with documented CNS ischemia and/or infarction, whether symptomatic or discoveredincidentally 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 studiesrequired to assess toxicity to therapy.