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

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ClinicalTrials.gov Identifier: NCT01189266
Recruitment Status : Active, not recruiting
First Posted : August 26, 2010
Last Update Posted : April 9, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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 or disease Intervention/treatment Phase
Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Brain Stem Glioma Childhood Glioblastoma Giant Cell Glioblastoma Gliosarcoma Untreated Childhood Anaplastic Astrocytoma Untreated Childhood Anaplastic Oligoastrocytoma Untreated Childhood Brain Stem Glioma Untreated Childhood Giant Cell Glioblastoma Untreated Childhood Gliosarcoma Radiation: 3-Dimensional Conformal Radiation Therapy Radiation: Intensity-Modulated Radiation Therapy Other: Laboratory Biomarker Analysis Drug: Vorinostat Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Intervention Model: Single Group Assignment
Masking: None (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)
Actual Study Start Date : August 9, 2010
Estimated Primary Completion Date : November 30, 2020


Arm Intervention/treatment
Experimental: Arm 1 Phase I Vorinostat 180 mg/m^2
Patients in phase I received vorinostat at 180 mg/m^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m^2/day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D conformal radiation therapy
Other Names:
  • 3-dimensional radiation therapy
  • 3D CONFORMAL RADIATION THERAPY
  • 3D CRT
  • 3D-CRT
  • Conformal Therapy
  • Radiation Conformal Therapy

Radiation: Intensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Vorinostat
Given PO
Other Names:
  • L-001079038
  • MSK-390
  • SAHA
  • Suberanilohydroxamic Acid
  • Suberoylanilide Hydroxamic Acid
  • Zolinza

Experimental: Arm 2 Phase 1 Vorinostat 230 mg/m^2
Patients received a higher dose of vorinostat at 230 mg/m^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m^2/day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D conformal radiation therapy
Other Names:
  • 3-dimensional radiation therapy
  • 3D CONFORMAL RADIATION THERAPY
  • 3D CRT
  • 3D-CRT
  • Conformal Therapy
  • Radiation Conformal Therapy

Radiation: Intensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Vorinostat
Given PO
Other Names:
  • L-001079038
  • MSK-390
  • SAHA
  • Suberanilohydroxamic Acid
  • Suberoylanilide Hydroxamic Acid
  • Zolinza

Experimental: Arm 3 Phase II Evaluation Vorinostat 230 mg/m^2
Patients received a higher dose of vorinostat at 230 mg/m^2/day PO on Monday through Friday weekly for the duration of radiation therapy (6-7 weeks). Patients underwent 3D conformal or intensity-modulated radiation therapy 5 days per week for 6 weeks. After completing concurrent vorinostat and radiation therapy, patients then received maintenance therapy comprising of vorinostat at 230 mg/m^2/ day PO on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D conformal radiation therapy
Other Names:
  • 3-dimensional radiation therapy
  • 3D CONFORMAL RADIATION THERAPY
  • 3D CRT
  • 3D-CRT
  • Conformal Therapy
  • Radiation Conformal Therapy

Radiation: Intensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Vorinostat
Given PO
Other Names:
  • L-001079038
  • MSK-390
  • SAHA
  • Suberanilohydroxamic Acid
  • Suberoylanilide Hydroxamic Acid
  • Zolinza




Primary Outcome Measures :
  1. MTD of vorinostat [ Time Frame: Up to 7 weeks ]
    The dose of vorinostat in mg/m^2/day to be administered in combination with radiation therapy.

  2. Event-free survival [ Time Frame: Up to 2 years ]
    Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first.

  3. Incidence of toxicities [ Time Frame: Through 6-7 weeks of vorinostat and radiation therapy, and also during maintenance therapy (up to 12 months) ]

Secondary Outcome Measures :
  1. OS [ Time Frame: Up to 2 years ]
    Time from enrollment to death or last follow-up, whichever occurs first.

  2. Change in H3 and H4 acetylation levels in PBMCs [ Time Frame: Baseline to up to 7 weeks ]
    Degree of acetylation in peripheral blood monocytes will be divided into quartiles and coded as none, mild, moderation or marked.

  3. Change in NHEJ activity in PBMCs [ Time Frame: Baseline to up to 7 weeks ]
    Descriptive statistics will be used to summarize the biological/laboratory measures and the changes in these measures across time-points.

  4. Levels of DNA repair proteins in paraffin-embedded blocks, measured via immunohistochemistry or Western analysis [ Time Frame: Baseline ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   37 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01189266


  Show 180 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jack M Su Children's Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01189266     History of Changes
Other Study ID Numbers: NCI-2011-02600
NCI-2011-02600 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000683459
COG-ACNS0927
ACNS0927
S12-02793
ACNS0927 ( Other Identifier: Childrens Oncology Group )
ACNS0927 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
UM1CA097452 ( U.S. NIH Grant/Contract )
First Posted: August 26, 2010    Key Record Dates
Last Update Posted: April 9, 2019
Last Verified: December 2018
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Gliosarcoma
Oligodendroglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Vorinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action