Vorinostat and Radiation Therapy Followed by Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01189266
First received: August 25, 2010
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

This phase I/II trial studies the side effects and best dose of vorinostat and to see how well it works when given together with radiation therapy followed by maintenance therapy with vorinostat in treating younger patients with newly diagnosed diffuse intrinsic pontine glioma (a brainstem tumor). Vorinostat 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. Giving vorinostat together with radiation therapy may kill more tumor cells.


Condition Intervention Phase
Childhood Glioblastoma
Untreated Childhood Anaplastic Astrocytoma
Untreated Childhood Anaplastic Oligoastrocytoma
Untreated Childhood Brain Stem Glioma
Untreated Childhood Giant Cell Glioblastoma
Untreated Childhood Gliosarcoma
Drug: vorinostat
Radiation: 3-dimensional conformal radiation therapy
Radiation: intensity-modulated radiation therapy
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 1/2 Study of Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat) and Local Irradiation, Followed by Maintenance SAHA in Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas (DIPG)

Resource links provided by NLM:


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

Primary Outcome Measures:
  • MTD of vorinostat, defined as the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT) during chemoradiation, graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase I) [ Time Frame: Up to 7 weeks ] [ Designated as safety issue: Yes ]
    Categorical measures will be described by percentages with binary confidence intervals and frequency tables.

  • EFS (Phase II) [ Time Frame: Time to disease progression, disease relapse, occurrence of a second neoplasm, or death from any cause, or date of last follow-up measured from time of study enrollment, assessed up to 60 months ] [ Designated as safety issue: No ]
    Mean and standard deviation will be used to summarize continuous measures; log transformation may be considered when appropriate. Log rank tests will be used to explore the prognostic significance of a categorical factor on EFS. Cox proportional hazards models will be used to explore the effect of a continuous marker on EFS, and will be used for exploratory multivariate analysis examining the effect of the predictor of interest with adjustments for other patient characteristics or risk factors.

  • Incidence of toxicities (Phase II) [ Time Frame: Up to 60 months ] [ Designated as safety issue: Yes ]
    The analysis of toxicity will focus on estimates of the rates of chemoradiotherapy-phase DLT and rates of maintenance phase toxicities. Estimates will be obtained using life-table methods, with an event defined as the first occurrence of a primary toxicity. Patients who have progression or recurrence of disease will be censored in these analyses. Appropriate adjustment will be made to the rates estimates to account for potential effects of the initial vorinostat dose selection. Categorical measures will be described by percentages with binary confidence intervals and frequency tables.


Secondary Outcome Measures:
  • OS (Phase II) [ Time Frame: Time to death from any cause, assessed up to 60 months ] [ Designated as safety issue: No ]
    Mean and standard deviation will be used to summarize continuous measures; log transformation may be considered when appropriate. Log rank tests will be used to explore the prognostic significance of a categorical factor on OS. Cox proportional hazards models will be used to explore the effect of a continuous marker on OS, and will be used for exploratory multivariate analysis examining the effect of the predictor of interest with adjustments for other patient characteristics or risk factors.

  • Change in H3 and H4 acetylation levels in PBMCs [ Time Frame: Baseline to up to 7 weeks ] [ Designated as safety issue: No ]
    Degree of acetylation in peripheral blood monocytes will be divided into quartiles and coded as none, mild, moderation or marked. Descriptive statistics will be used to summarize the biological/laboratory measures and the changes in these measures across time-points. Exploratory analyses to correlate the biological/laboratory measures with disease outcome will be performed.

  • Change in NHEJ activity in PBMCs [ Time Frame: Baseline to up to 7 weeks ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to summarize the biological/laboratory measures and the changes in these measures across time-points. Exploratory analyses to correlate the biological/laboratory measures with disease outcome will be performed.

  • Levels of DNA repair proteins in paraffin-embedded blocks, measured via immunohistochemistry or Western analysis [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    For immunohistochemistry from tumor blocks, the intensity will be graded from 1 to 3; for Western analysis, a percentage of the intensity relative to the tumor with the highest level will be measured. Descriptive statistics will be used to summarize the biological/laboratory measures. Exploratory analyses to correlate the biological/laboratory measures with disease outcome will be performed.


Estimated Enrollment: 80
Study Start Date: August 2010
Estimated Primary Completion Date: November 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, radiation therapy)
Patients receive vorinostat PO on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients undergo 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. Patients then receive maintenance therapy comprising vorinostat PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Radiation: 3-dimensional conformal radiation therapy
Undergo 3D conformal radiation therapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: intensity-modulated radiation therapy
Undergo intensity-modulated radiation therapy
Other Name: IMRT
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

l. To estimate the maximum tolerated dose (MTD) or recommend a phase 2 dose of vorinostat given concurrently with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

II. To define and describe the toxicities of vorinostat given concurrently with radiation in children with newly diagnosed DIPG.

III. To determine, in the context of this phase I/II trial, the anti-tumor activity of combining vorinostat with radiation, followed by maintenance vorinostat for twelve courses, in children with newly diagnosed DIPG, as measured by 12-month event-free survival (EFS) and overall survival (OS).

IV. To determine the toxicities of vorinostat for 12 additional courses after completion of vorinostat and radiation.

SECONDARY OBJECTIVES:

I. To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMCs) before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation.

II. To measure histone deacetylase 2 (HDAC2) levels and assess histone acetylation in PBMCs before treatment, at 2 weeks after starting vorinostat and radiation, and at the end of radiation.

III. To quantify deoxyribonucleic acid (DNA) repair proteins from the NHEJ and homologous recombination repair (HHR) pathways in tumors by either Western analysis or immunohistochemistry, if paraffin-embedded tumor is available.

OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients receive vorinostat orally (PO) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients undergo 3-dimensional (3D) conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. Patients then receive maintenance therapy comprising vorinostat PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.

  Eligibility

Ages Eligible for Study:   37 Months 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 involvement of at least 2/3 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, or anaplastic mixed glioma; patients with juvenile pilocytic 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
  • Karnofsky >= 50% for patients > 16 years of age and 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 not have received any prior treatment except dexamethasone and/or surgery
  • Peripheral absolute neutrophil count (ANC) >= 1000/uL
  • Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
  • Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • 0.8 mg/dL (3 to < 6 years of age)
    • 1 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)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT (ALT) is 45 U/L
  • Serum albumin >= 2 g/dL
  • Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants (with the exception of valproic acid) and seizures are well controlled
  • Patients must be able to swallow capsules or liquids; patients dependent on nasogastric (NG) tube feeding are not permitted to receive protocol therapy
  • Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
  • Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients must not currently be receiving enzyme inducing anticonvulsants
  • Patients on valproic acid must discontinue valproic acid for at least 2 weeks before starting protocol therapy
  • Patients receiving coumadin, heparin, low-molecular weight heparin, or any other anti-coagulants are not eligible for study entry
  • Patients receiving acetylsalicylic acid (ASA) (> 81 mg/day), non-steroidal anti-inflammatory drugs, clopidogrel (Plavix), dipyridamole (Persantine), or any other drug that inhibits platelet function are not eligible for study entry
  • Patients who have an uncontrolled infection are not eligible
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
  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: NCT01189266

  Show 176 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Jack Su Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01189266     History of Changes
Other Study ID Numbers: NCI-2011-02600, NCI-2011-02600, CDR0000683459, COG-ACNS0927, ACNS0927, ACNS0927, U10CA180886, UM1CA097452, U10CA098543
Study First Received: August 25, 2010
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on September 18, 2014