Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas
Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas
This phase I/II trial studies the side effects and the best dose of veliparib when given
 together with radiation therapy and temozolomide and to see how well they work in treating
 younger patients newly diagnosed with diffuse pontine gliomas. Veliparib may stop the growth
 of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses
 high-energy x rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide,
 work in different ways to stop the growth of tumor cells either by killing the cells or by
 stopping them from dividing. Giving veliparib with radiation therapy and temozolomide may
 kill more tumor cells.
PRIMARY OBJECTIVES:

 I. To identify the maximum-tolerated dose or recommended Phase II dose of ABT-888 (veliparib)
 which can be safely administered concurrently with radiation therapy, followed by maintenance
 therapy with ABT-888 and temozolomide (TMZ), in patients with newly diagnosed diffuse pontine
 gliomas (DIPG). (Phase I) II. To study the plasma pharmacokinetics (PK) of ABT-888 during
 ABT-888 and radiation therapy. (Phase I) III. To study the feasibility of intra-patient dose
 escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase I) IV. To describe
 the toxicities associated with administering ABT-888 and radiation therapy, followed by
 ABT-888 and TMZ, in patients with newly diagnosed DIPG. (Phase I) V. To estimate the
 proportion of newly diagnosed DIPG patients treated on protocol that are determined to have
 experienced pseudo progression. (Phase I) VI. To estimate the overall survival distribution
 for newly diagnosed patients with DIPG treated with the combination of ABT-888 and radiation
 therapy, followed by ABT-888 and TMZ, and compare to Pediatric Brain Tumor Consortium (PBTC)
 historical controls. (Phase II) VII. To study the feasibility of intra-patient dose
 escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase II) VIII. To
 estimate the proportion of newly diagnosed DIPG patients treated on protocol that are
 determined to have experienced pseudo progression. (Phase II)

 SECONDARY OBJECTIVES:

 I. To estimate the progression-free survival (PFS) distribution and to summarize the best
 tumor responses observed prior to progression or recurrence.

 II. To explore the plasma PK of ABT-888 during ABT-888 and radiation therapy. III. To explore
 peripheral blood mononuclear cell (PBMC) poly (ADP-ribose) polymerase 1(PARP) activity before
 and after treatment with ABT-888.

 IV. To explore quantifying non-homologous end-joining (NHEJ) activity or gamma-H2A histone
 family, member X (H2AX) levels (as surrogate markers of unrepaired double-strand breaks
 (DSBs)) in PBMC before and after treatment with ABT-888.

 V. To explore quantifying PARP activity and deoxyribonucleic acid (DNA)-repair protein levels
 in biopsied atypical pontine gliomas, if available.

 VI. To explore associations of molecular parameters from secondary aims III, IV, and V with
 PFS and overall survival (OS) after conclusion of clinical trial.

 VII. To explore the quantitative magnetic resonance (MR) measures of relative cerebral blood
 volume (rCBV), vascular permeability (Ktrans, fractional plasma volume [vp], and
 extravascular extracellular space volume fraction [ve] values), and apparent diffusion
 coefficient (ADC) within the first six months of initiating protocol treatment to correlate
 with disease outcome and determine whether such metrics differentiate patients with pseudo
 progression from those with true early progressive disease.

 VIII. To explore the potential utility of urine biomarkers as a novel, non-invasive method of
 detecting and tracking changes in the status of pediatric brain stem gliomas.

 OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study.

 DOSE-ESCALATION: Patients receive veliparib orally (PO) twice daily (BID) 5 days a week for
 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiotherapy (3D-CRT) or
 intensity-modulated radiotherapy (IMRT) once daily (QD) 5 days a week for 6-7 weeks.

 MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5
 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in
 the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up periodically for up to 3 years.
Inclusion Criteria:

 -  Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as
 tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, are
 eligible without histologic confirmation; patients with brainstem tumors that do not
 meet these criteria or not considered to be typical intrinsic pontine gliomas will
 only be eligible if the tumors are biopsied and proven to be an anaplastic
 astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma, or
 fibrillary astrocytoma

 -  Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, fibrillary
 astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not
 eligible;

 -  Patients with disseminated disease are not eligible, and magnetic resonance
 imaging (MRI) of spine must be performed if disseminated disease is suspected by
 the treating physician

 -  Patient must be able to swallow oral medications to be eligible for study enrollment

 -  Karnofsky >= 50% for patients > 16 years of age or Lansky >= 50% 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

 -  Patients must have not received any prior therapy other than surgery and/or steroids

 -  Absolute neutrophil count >= 1,000/mm^3

 -  Platelets >= 100,000/mm^3 (unsupported)

 -  Hemoglobin >= 10 g/dL (unsupported)

 -  Total bilirubin =< 1.5 times upper limit of normal (ULN) for age

 -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 5 x
 institutional upper limit of normal for age

 -  Albumin >= 2 g/dL

 -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

 -  0.6 mg/dL (1 to < 2 years of age)

 -  0.8 mg/dL (2 to < 6 years of age)

 -  1.0 mg/dL (6 to < 10 years of age)

 -  1.2 mg/dL (10 to < 13 years of age)

 -  1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

 -  1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)

 -  Female patients of childbearing potential must not be pregnant or breast-feeding;
 female patients of childbearing potential must have a negative serum or urine
 pregnancy test

 -  Patients of childbearing or child-fathering potential must be willing to use a
 medically acceptable form of birth control, which includes abstinence, while being
 treated on this study

 -  Signed informed consent according to institutional guidelines must be obtained;
 assent, when appropriate, will be obtained according to institutional guidelines

 Exclusion Criteria:

 -  Patients with any clinically significant unrelated systemic illness (serious
 infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
 that would compromise the patient's ability to tolerate protocol therapy or would
 likely interfere with the study procedures or results

 -  Patients with inability to return for follow-up visits or obtain follow-up studies
 required to assess toxicity to therapy

 -  Patients with active seizures or a history of seizure are not eligible for study
 entry, with the exception of patients with documented febrile seizure