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

National Cancer Institute (NCI)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Untreated Childhood Giant Cell Glioblastoma

Glioblastoma

Untreated Childhood Anaplastic Astrocytoma

Fibrillary Astrocytoma

Brain Stem Glioma

Untreated Childhood Gliosarcoma

Childhood Mixed Glioma

Untreated Childhood Glioblastoma

Untreated Childhood Brain Stem Glioma

Anaplastic Astrocytoma

Giant Cell Glioblastoma

Untreated Childhood Fibrillary Astrocytoma

Gliosarcoma

Treatments

Drug: Temozolomide

Radiation: Intensity-Modulated Radiation Therapy

Other: Laboratory Biomarker Analysis

Radiation: 3-Dimensional Conformal Radiation Therapy

Other: Pharmacological Study

Drug: Veliparib

Study type

Interventional

Funder types

NIH

Identifiers

NCT01514201

12-C-0213

U01CA081457 (U.S. NIH Grant/Contract)

PBTC-033

P12978

NCI-2012-00082 (Registry Identifier)

UM1CA081457 (U.S. NIH Grant/Contract)

CDR0000717423

Details and patient eligibility

About

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.

Full description

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.

Enrollment

66 patients

Sex

All

Ages

Under 21 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

66 participants in 1 patient group

Treatment (veliparib, temozolomide, 3D-CRT, IMRT)

Experimental group

Description:

DOSE-ESCALATION: Patients receive veliparib PO BID 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D-CRT or IMRT 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.