Overview

This trial is active, not recruiting.

Conditions childhood mixed glioma, untreated childhood anaplastic astrocytoma, untreated childhood brain stem glioma, untreated childhood fibrillary astrocytoma, untreated childhood giant cell glioblastoma, untreated childhood glioblastoma, untreated childhood gliosarcoma
Treatments 3-dimensional conformal radiation therapy, intensity-modulated radiation therapy, laboratory biomarker analysis, pharmacological study, temozolomide, veliparib
Phase phase 1/phase 2
Target PARP
Sponsor National Cancer Institute (NCI)
Start date November 2011
End date August 2019
Trial size 66 participants
Trial identifier NCT01514201, 12-C-0213, CDR0000717423, NCI-2012-00082, NCT01507324, P12978, PBTC-033, U01CA081457

Summary

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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.
3-dimensional conformal radiation therapy 3-dimensional radiation therapy
Undergo 3D-CRT
intensity-modulated radiation therapy IMRT
Undergo IMRT
laboratory biomarker analysis
Optional correlative studies
pharmacological study
Correlative studies
temozolomide CCRG-81045
Given PO
veliparib ABT-888
Given PO

Primary Outcomes

Measure
Feasibility of intra-patient dose escalation of temozolomide during maintenance therapy with veliparib (Phase I and II)
time frame: 28 days
Maximum-tolerated dose of veliparib defined as highest dose level with fewer than 2 dose limiting toxicities in 6 patients as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)
time frame: 10 weeks
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 3 years

Secondary Outcomes

Measure
Number of pseudo progression
time frame: Up to 6 months
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 3 years
Pharmacokinetic parameters of veliparib
time frame: At baseline, at 0.5, 1, 2 and 6-8 hours of day 1, and at day 4

Eligibility Criteria

Male or female participants up to 21 years old.

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

Additional Information

Official title 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)
Principal investigator Patricia Baxter
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 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.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).