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

January 16, 2012
July 18, 2014
November 2011
August 2019   (final data collection date for primary outcome measure)
  • 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.
  • Maximum-tolerated dose or recommended Phase II dose of ABT-888 that can safely be delivered with radiotherapy (Phase I) [ Designated as safety issue: No ]
  • Feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 (Phase I and II) [ Designated as safety issue: No ]
  • Overall survival (phase II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01514201 on ClinicalTrials.gov Archive Site
  • 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.
  • Progression-free survival (Phase II) [ Designated as safety issue: No ]
  • Assessment of true vs pseudoprogression [ Designated as safety issue: No ]
  • Pharmacokinetics of ABT-888 (Phase I) [ Designated as safety issue: No ]
  • 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.
Not Provided
 
Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas
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.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
    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
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.

Interventions:
  • Drug: veliparib
  • Drug: temozolomide
  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: intensity-modulated radiation therapy
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
66
Not Provided
August 2019   (final data collection date for primary outcome measure)

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
Both
up to 21 Years
No
United States
 
NCT01514201
NCI-2012-00082, NCI-2012-00082, 12-C-0213, CDR0000717423, P12978, PBTC-033, PBTC-033, U01CA081457
No
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Patricia Baxter Pediatric Brain Tumor Consortium
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP