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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01514201
First received: January 16, 2012
Last updated: July 18, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
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
Drug: veliparib
Drug: temozolomide
Radiation: 3-dimensional conformal radiation therapy
Radiation: intensity-modulated radiation therapy
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • Feasibility of intra-patient dose escalation of temozolomide during maintenance therapy with veliparib (Phase I and II) [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    Patients who have not failed (died) at the time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Patients who start other anti-cancer therapy prior to disease progression will be censored in the Kaplan-Meier estimate of PFS as of the date the alternative therapy began. Patients who have not failed (died) at the time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.

  • Number of pseudo progression [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
    To differentiate pseudo progression from true early progressive disease, quantitative MR measures of relative cerebral blood volume (rCBV), permeability (Ktrans, vp, and ve values), and apparent diffusion coefficient (ADC) will be obtained of these parameters via descriptive statistics and plots. Providing 95% confidence interval estimates of the proportion of patients determined to have experienced pseudo progression.

  • Pharmacokinetic parameters of veliparib [ Time Frame: At baseline, at 0.5, 1, 2 and 6-8 hours of day 1, and at day 4 ] [ Designated as safety issue: No ]
    Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central compartment, elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance on dose-normalized parameters.


Other Outcome Measures:
  • Change in level PARP activity measured in PBMCs [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Cox models to explore associations between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ activity or gamma-H2AX levels and PFS and OS. Associations between these parameters and objective response may also be explored provided a large enough number of responses are observed. Otherwise correlations between PARP and NHEJ activity or gamma-H2AX levels with radiographic response and clinical outcome will be summarized descriptively.

  • Change in level NHEJ activity measured in PBMCs [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Cox models to explore associations between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ activity or gamma-H2AX levels and PFS and OS. Associations between these parameters and objective response may also be explored provided a large enough number of responses are observed. Otherwise correlations between PARP and NHEJ activity or gamma-H2AX levels with radiographic response and clinical outcome will be summarized descriptively.

  • Change in level gamma-H2AX measured in PBMCs [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Cox models to explore associations between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ activity or gamma-H2AX levels and PFS and OS. Associations between these parameters and objective response may also be explored provided a large enough number of responses are observed. Otherwise correlations between PARP and NHEJ activity or gamma-H2AX levels with radiographic response and clinical outcome will be summarized descriptively.

  • Change in levels of urinary biomarkers [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]
    Median levels for tumor patients will be compared to levels in healthy age- and gender-matched controls using the Mann-Whitney U-test. Multivariable logistic regression models coupled with receiver operating characteristic analyses will be used to select a combination of these biomarkers in an attempt to improve their collective performance as a classifier.


Estimated Enrollment: 66
Study Start Date: November 2011
Estimated Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.

Drug: veliparib
Given PO
Other Name: ABT-888
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Radiation: 3-dimensional conformal radiation therapy
Undergo 3D-CRT
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: intensity-modulated radiation therapy
Undergo IMRT
Other Name: IMRT
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Optional correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01514201

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Girish Dhall    323-361-4629    gdhall@chla.usc.edu   
Principal Investigator: Girish Dhall         
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Paul G. Fisher    650-721-5889    pfisher@stanford.edu   
Principal Investigator: Paul G. Fisher         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Roger J. Packer    202-884-2120    rpacker@cnmc.org   
Principal Investigator: Roger J. Packer         
United States, Illinois
Lurie Children's Hospital-Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Stewart Goldman    773-880-4562    sgoldman@northwestern.edu   
Principal Investigator: Stewart Goldman         
United States, Maryland
Mark O Hatfield-Warren Grant Magnuson Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: Katherine E. Warren    301-435-4683    warrenk@mail.nih.gov   
Principal Investigator: Katherine E. Warren         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ira J. Dunkel    212-639-2153    dunkeli@mskcc.org   
Principal Investigator: Ira J. Dunkel         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Sridharan Gururangan    919-684-3506    gurur002@mc.duke.edu   
Principal Investigator: Sridharan Gururangan         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maryam Fouladi    513-803-0721    maryam.fouladi@cchmc.org   
Principal Investigator: Maryam Fouladi         
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Ian F. Pollack    412-692-5881    Pollaci@chp.edu   
Principal Investigator: Ian F. Pollack         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Larry E. Kun    901-595-3565    larry.kun@stjude.org   
Principal Investigator: Larry E. Kun         
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Patricia A. Baxter    832-824-4681    pabaxter@txch.org   
Principal Investigator: Patricia A. Baxter         
Sponsors and Collaborators
Investigators
Principal Investigator: Patricia Baxter Pediatric Brain Tumor Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01514201     History of Changes
Obsolete Identifiers: NCT01507324
Other Study ID Numbers: NCI-2012-00082, NCI-2012-00082, 12-C-0213, CDR0000717423, P12978, PBTC-033, PBTC-033, U01CA081457
Study First Received: January 16, 2012
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioma
Pontine Glioma
Astrocytoma
Glioblastoma
Gliosarcoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 26, 2014