Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

• Maximum-tolerated dose (MTD) of veliparib based on the incidence of dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: 7 weeks ] [ Designated as safety issue: Yes ]
  
• Feasibility of intra-patient dose escalation of temozolomide during maintenance therapy with veliparib (Phase I and II) [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  
• Overall survival (phase II) [ Time Frame: Time from initiation of therapy to the date of death from any cause or to the date patient was known to be alive for surviving patients, assessed to up to 1 year ] [ Designated as safety issue: No ]
  Patients who have not failed (died) at the time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.
  
  

• PFS (Phase II) [ Time Frame: Time from initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second malignancy), assessed up to 1 year ] [ Designated as safety issue: No ]
  Patients who start other anti-cancer therapy prior to disease progression will be censored in the Kaplan-Meier estimate of PFS as of the date the alternative therapy began. Patients who have not failed (died) at the time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.
  
  
• Number of pseudoprogression [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  To differentiate pseudoprogression from true early progressive disease, quantitative MR measures of relative cerebral blood volume (rCBV), permeability (Ktrans, vp, and ve values), and apparent diffusion coefficient (ADC) will be obtained of these parameters via descriptive statistics and plots. Providing 95% confidence interval estimates of the proportion of patients determined to have experienced pseudoprogression.
  
  
• Pharmacokinetics of veliparib (Phase I) [ Time Frame: At baseline, at 0.5, 1, 2 and 6-8 hours of day 1, and at day 4 ] [ Designated as safety issue: No ]
  

PRIMARY OBJECTIVES:

I. To identify the maximum-tolerated dose or recommended Phase II dose of veliparib (ABT-888) 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 pseudoprogression. (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 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 pseudoprogression. (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) polymerase (PARP) activity before and after treatment with ABT-888.

IV. To explore quantifying non-homologous end-joining (NHEJ) activity or γ-H2AX levels (as surrogate markers of unrepaired DSBs) in PBMC before and after treatment with ABT-888.

V. To explore quantifying PARP activity and 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, vp, and 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 pseudoprogression 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 dose-escalation, phase I 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.