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



Status:Completed
Conditions:Brain Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:Any - 21
Updated:10/5/2018
Start Date:November 17, 2011
End Date:March 28, 2018

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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)

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 TMZ (temozolomide), 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 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
We found this trial at
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sites
3333 Burnet Avenue # Mlc3008
Cincinnati, Ohio 45229
 1-513-636-4200 
Cincinnati Children's Hospital Medical Center Patients and families from across the region and around the...
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4650 Sunset Blvd
Los Angeles, California 90027
 (323) 660-2450
Childrens Hospital Los Angeles Children's Hospital Los Angeles is a 501(c)(3) nonprofit hospital for pediatric...
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Los Angeles, CA
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262 Danny Thomas Pl
Memphis, Tennessee 38105
(901) 495-3300
St. Jude Children's Research Hospital St. Jude is unlike any other pediatric treatment and research...
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Memphis, TN
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4401 Penn Avenue
Pittsburgh, Pennsylvania 15224
412-692-5325
Children's Hospital of Pittsburgh of UPMC UPMC is one of the leading nonprofit health systems...
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Pittsburgh, PA
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9000 Rockville Pike
Bethesda, Maryland 20892
301-496-2563
National Institutes of Health Clinical Center The National Institutes of Health (NIH) Clinical Center in...
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Chicago, Illinois 60614
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Chicago, IL
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2301 Erwin Rd
Durham, North Carolina 27710
919-684-8111
Duke Univ Med Ctr As a world-class academic and health care system, Duke Medicine strives...
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Durham, NC
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6621 Fannin St
Houston, Texas 77030
(832) 824-1000
Texas Children's Hospital Texas Children's Hospital, located in Houston, Texas, is a not-for-profit organization whose...
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Houston, TX
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Memphis, Tennessee 38105
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Memphis, TN
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1275 York Ave
New York, New York 10021
(212) 639-2000
Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Cancer Center — the world's oldest and...
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New York, NY
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725 Welch Rd
Palo Alto, California 94304
(650) 497-8000
Lucile Packard Children's Hospital Stanford University Stanford Children's Health is the only network in the...
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111 Michigan Ave NW
Washington, District of Columbia
(202) 476-5000
Childrens National Medical Center As the nation’s children’s hospital, the mission of Children’s National Medical...
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Washington,
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