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

NCT ID: NCT01514201

Last Updated: 2019-08-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-01
• Study Completion Date: 2018-03-28

Brief 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.

Detailed 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.

Conditions

Anaplastic Astrocytoma; Brain Stem Glioma; Childhood Mixed Glioma; Fibrillary Astrocytoma; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

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.

Group Type: EXPERIMENTAL

3-Dimensional Conformal Radiation Therapy

Intervention Type: RADIATION

Undergo 3D-CRT

Intensity-Modulated Radiation Therapy

Intervention Type: RADIATION

Undergo IMRT

Laboratory Biomarker Analysis

Intervention Type: OTHER

Optional correlative studies

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Temozolomide

Intervention Type: DRUG

Given PO

Veliparib

Intervention Type: DRUG

Given PO

Interventions

3-Dimensional Conformal Radiation Therapy

Undergo 3D-CRT

Intervention Type: RADIATION

Intensity-Modulated Radiation Therapy

Undergo IMRT

Intervention Type: RADIATION

Laboratory Biomarker Analysis

Optional correlative studies

Intervention Type: OTHER

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Temozolomide

Given PO

Intervention Type: DRUG

Veliparib

Given PO

Intervention Type: DRUG

Other Intervention Names

3-dimensional radiation therapy; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac; ABT-888; PARP-1 inhibitor ABT-888

Eligibility Criteria

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

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patricia Baxter

Role: PRINCIPAL_INVESTIGATOR

Pediatric Brain Tumor Consortium

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Pediatric Brain Tumor Consortium

Memphis, Tennessee, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Texas Children's Hospital

Houston, Texas, United States

Countries

United States

References

Sesen J, Driscoll J, Shah N, Moses-Gardner A, Luiselli G, Alexandrescu S, Zurakowski D, Baxter PA, Su JM, Pricola Fehnel K, Smith ER. Neogenin is highly expressed in diffuse intrinsic pontine glioma and influences tumor invasion. Brain Res. 2021 Jul 1;1762:147348. doi: 10.1016/j.brainres.2021.147348. Epub 2021 Feb 9. No abstract available.

Reference Type: DERIVED

PMID: 33571520 (View on PubMed)

Baxter PA, Su JM, Onar-Thomas A, Billups CA, Li XN, Poussaint TY, Smith ER, Thompson P, Adesina A, Ansell P, Giranda V, Paulino A, Kilburn L, Quaddoumi I, Broniscer A, Blaney SM, Dunkel IJ, Fouladi M. A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study. Neuro Oncol. 2020 Jun 9;22(6):875-885. doi: 10.1093/neuonc/noaa016.

Reference Type: DERIVED

PMID: 32009149 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2012-00082

Identifier Type: REGISTRY

Identifier Source: secondary_id

PBTC-033

Identifier Type: -

Identifier Source: secondary_id

12-C-0213

Identifier Type: -

Identifier Source: secondary_id

CDR0000717423

Identifier Type: -

Identifier Source: secondary_id

P12978

Identifier Type: -

Identifier Source: secondary_id

PBTC-033

Identifier Type: OTHER

Identifier Source: secondary_id

PBTC-033

Identifier Type: OTHER

Identifier Source: secondary_id

U01CA081457

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UM1CA081457

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2012-00082

Identifier Type: -

Identifier Source: org_study_id

NCT01507324

Identifier Type: -

Identifier Source: nct_alias