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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)


Phase 1/Phase 2
N/A
21 Years
Open (Enrolling)
Both
Childhood Mixed Glioma, Untreated Childhood Anaplastic Astrocytoma, Untreated Childhood Brain Stem Glioma, Untreated Childhood Giant Cell Glioblastoma, Untreated Childhood Glioblastoma, Untreated Childhood Gliosarcoma

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Trial Information

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)


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.


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, or anaplastic mixed glioma

- 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 and 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)

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

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

- Hemoglobin >= 10 g/dL (unsupported)

- 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)

- Total bilirubin (sum of conjugated and unconjugated) =< 1.5 times upper limit of
normal (ULN)

- Serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5
times institutional ULN

- Albumin >= 2 g/dL

- 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

- No 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

- No 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

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

- Other concurrent anticancer or experimental agents or therapies are not permitted

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Time Frame:

7 weeks

Safety Issue:

Yes

Principal Investigator

Patricia Baxter

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-00082

NCT ID:

NCT01514201

Start Date:

November 2011

Completion Date:

Related Keywords:

  • Childhood Mixed Glioma
  • Untreated Childhood Anaplastic Astrocytoma
  • Untreated Childhood Brain Stem Glioma
  • Untreated Childhood Giant Cell Glioblastoma
  • Untreated Childhood Glioblastoma
  • Untreated Childhood Gliosarcoma
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Gliosarcoma
  • Pontine Glioma

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Children's National Medical CenterWashington, District of Columbia  20010-2970
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Duke University Medical CenterDurham, North Carolina  27710
Texas Children's HospitalHouston, Texas  
Childrens Memorial HospitalChicago, Illinois  60614
National Cancer Institute Pediatric Oncology BranchBethesda, Maryland  20892