A Phase I/ II Study of ABT-888, an Oral Poly( ADP-ribose) Polymerase Inhibitor, and Concurrent Radiation Therapy, Followed by ABT-888 and Temozolomide, in Children With Newly Diagnosed Diffuse Pontine Gliomas (DIPG)
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)
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
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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)
Pediatric Brain Tumor Consortium
United States: Food and Drug Administration
|Children's Hospital of Philadelphia||Philadelphia, Pennsylvania 19104|
|Children's National Medical Center||Washington, District of Columbia 20010-2970|
|St. Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Children's Hospital of Pittsburgh of UPMC||Pittsburgh, Pennsylvania 15213|
|Duke University Medical Center||Durham, North Carolina 27710|
|Texas Children's Hospital||Houston, Texas|
|Childrens Memorial Hospital||Chicago, Illinois 60614|
|National Cancer Institute Pediatric Oncology Branch||Bethesda, Maryland 20892|