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Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma

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ClinicalTrials.gov Identifier: NCT01236560
Recruitment Status : Completed
First Posted : November 8, 2010
Last Update Posted : January 25, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 5, 2010
First Posted Date  ICMJE November 8, 2010
Last Update Posted Date January 25, 2019
Actual Study Start Date  ICMJE November 15, 2010
Actual Primary Completion Date September 27, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2019)
  • Maximum tolerated dose (MTD) of vorinostat [ Time Frame: 10 weeks ]
    The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy.
  • Event-free survival [ Time Frame: 1 year after enrollment ]
    Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first.
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2010)
  • Dose-limiting toxicity of vorinostat when given with radiotherapy (feasibility study)
  • Toxicity of vorinostat, bevacizumab, or temozolomide when given in combination with radiotherapy
Change History Complete list of historical versions of study NCT01236560 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2019)
  • Overall survival [ Time Frame: 1 year after enrollment ]
    Time from enrollment to death or last follow-up, whichever occurs first.
  • Cumulative incidence of disease progression in each treatment arm [ Time Frame: 1 year after enrollment ]
    Cumulative incidence of progression where death from any cause prior to progression and diagnosis of a second malignant neoplasm prior to progression are considered competing events.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2010)
  • Event-free survival of patients in each treatment arm
  • Overall survival of patients in each treatment arm
  • Progression-free survival of patients in each treatment arm
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma
Official Title  ICMJE A Randomized Phase II/III Study of Vorinostat and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas
Brief Summary This randomized phase II/III trial is studying vorinostat, temozolomide, or bevacizumab to see how well they work compared with each other when given together with radiation therapy followed by bevacizumab and temozolomide in treating young patients with newly diagnosed high-grade glioma. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether giving vorinostat is more effective then temozolomide or bevacizumab when given together with radiation therapy in treating glioma.
Detailed Description

PRIMARY OBJECTIVES:

I. To identify the dose of vorinostat that is feasible when given in combination with radiotherapy (RT) in patients with newly diagnosed high-grade gliomas (HGG). II. To compare 1-year event-free survival of patients with newly diagnosed HGG treated with vorinostat (using MTD) versus bevacizumab versus temozolomide when given in combination with RT followed by maintenance therapy with bevacizumab and temozolomide. (Phase II) III. To compare the event-free survival of patients with newly diagnosed HGG treated with the superior chemoradiotherapy (from phase II portion) versus temozolomide given in combination with RT followed by maintenance chemotherapy with bevacizumab and temozolomide. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate the anti-tumor activity, as measured by event-free survival (EFS), progression-free survival (PFS), and overall survival (OS), of patients with newly diagnosed HGG treated with vorinostat, bevacizumab, or temozolomide when given in combination with RT followed by maintenance chemotherapy with bevacizumab and temozolomide. II. To define and evaluate the toxicities of each of the treatment arms of the study.

III. To conduct gene expression profiling and SNP arrays in patients with newly diagnosed HGG.

IV. To assess telomerase activity, hTert expression, and telomere length in patients with newly diagnosed HGG. V. To document changes in perfusion and diffusion using MR imaging at baseline, prior to, during (prior to course 3), and after maintenance therapy with bevacizumab and temozolomide.

VI. To correlate functional changes in tumor with responses to bevacizumab treatment using MR diffusion/perfusion imaging. VII. To correlate the results of the bevacizumab biology studies in serum or tumor with EFS.

VIII. To explore the prognostic significance of MGMT status for patients newly diagnosed with HGG treated with combined surgery, radiation, chemotherapy, and anti-angiogenic therapy.

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

FEASIBILITY STUDY: Patients undergo 3-D conformal radiotherapy (RT) or intensity-modulated RT 5 days a week for 6 weeks. Patients also receive vorinostat orally (PO) once daily on days 1-5. Courses repeat every week for 6 weeks in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and temozolomide PO on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

PHASE II STUDY: Patients are stratified according to extent of resection (near total resection or gross total resection vs other) and histology (glioblastoma multiforme vs other). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study.

ARM II: Patients undergo RT as in arm I and receive temozolomide PO once daily for 42 days beginning on day 5 of RT.

ARM III: Patients undergo RT as in arm I and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients in all arms receive maintenance therapy as in the feasibility study.

PHASE III study: Patients are randomized to 1 of 2 treatment arms.

ARM IV: Patients receive RT and temozolomide as in phase II, arm II.

ARM V: Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as the superior chemoradiotherapy arm in phase II. Patients in all arms receive maintenance therapy as in the feasibility study. Some patients undergo blood and tumor tissue sample (from surgery) collection for telomerase activity, hTert expression, telomere length, and gene expression profiling and SNP arrays analysis.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Brain Stem Glioma
  • Cerebral Astrocytoma
  • Childhood Cerebellar Anaplastic Astrocytoma
  • Childhood Cerebral Anaplastic Astrocytoma
  • Childhood Spinal Cord Neoplasm
  • Untreated Childhood Brain Stem Glioma
  • Untreated Childhood Cerebral Astrocytoma
Intervention  ICMJE
  • Biological: Bevacizumab
    Given IV
    Other Names:
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF rhuMAb
    • Avastin
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Bevacizumab Biosimilar CBT 124
    • Bevacizumab Biosimilar FKB238
    • Bevacizumab Biosimilar MIL60
    • Bevacizumab Biosimilar QL 1101
    • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
  • Drug: Temozolomide
    Given PO
    Other Names:
    • 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
  • Drug: Vorinostat
    Given PO
    Other Names:
    • L-001079038
    • MSK-390
    • SAHA
    • Suberanilohydroxamic Acid
    • Suberoylanilide Hydroxamic Acid
    • Zolinza
Study Arms  ICMJE
  • Experimental: Arm I (vorinostat)
    Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study.
    Intervention: Drug: Vorinostat
  • Experimental: Arm II (vorinostat and temozolomide)
    Patients undergo RT as in arm I and receive temozolomide PO once daily for 42 days beginning on day 5 of RT.
    Interventions:
    • Drug: Temozolomide
    • Drug: Vorinostat
  • Experimental: Arm III (vorinostat and bevacizumab)
    Patients undergo RT as in arm I and receive bevacizumab IV over 30-90 minutes on days 22 and 36.
    Interventions:
    • Biological: Bevacizumab
    • Drug: Vorinostat
  • Experimental: Arm IV (vorinostat and temozolomide)
    Patients receive RT and temozolomide as in phase II, arm II.
    Interventions:
    • Drug: Temozolomide
    • Drug: Vorinostat
  • Experimental: Arm V (vorinostat, bevacizumab, temozolomide)
    Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as the superior chemoradiotherapy arm in phase II.
    Interventions:
    • Biological: Bevacizumab
    • Drug: Temozolomide
    • Drug: Vorinostat
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 11, 2017)
101
Original Estimated Enrollment  ICMJE
 (submitted: November 5, 2010)
248
Actual Study Completion Date  ICMJE September 27, 2016
Actual Primary Completion Date September 27, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Newly diagnosed high-grade glioma

    • Anaplastic astrocytoma
    • Glioblastomamultiforme
    • Gliosarcoma
    • Primary spinal cord malignant glioma allowed
    • No oligodendroglioma oroligoastrocytoma
  • Patient must have histological verification of diagnosis

    • No M+ disease (defined as evidence of neuraxis dissemination)
    • No positive CSF cytology
  • ECOG performance status (PS) 0-2

    • Karnofsky PS 50-100% (patients > 16 years of age)
    • Lansky PS 50-100% (patients ? 16 years of age)
  • ANC ? 1,000/?L
  • Platelet count ? 100,000/?L
  • Hemoglobin ? 8.0 mg/dL (transfusion independent)
  • Creatinine clearance or radioisotope GFR ? 70 mL/min OR serum creatinine based on age and/or gender as follows:

    • 0.4 mg/dL (1 month to < 6 months of age)
    • 0.5 mg/dL (6 months to < 1 year of age)
    • 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)
  • Proteinuria < 2+ OR urine; protein ratio (UPC) ? 0.5

    • If UPC > 0.5, a 24-hour urine protein should be obtained and level should be < 1,000 mg of protein
  • Total bilirubin ? 1.5 times upper limit of normal (ULN)
  • ALT < 2.5 times ULN
  • Serum albumin ? 2 g/dL
  • PT INR ? 1.5 times ULN
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during all study therapy and for ? 6 months after completion of bevacizumab
  • Hypertension well controlled (? 95^th percentile for age and height if patient is ? 17years) by stable doses of medication allowed

    • For patients > 17 years, systolic blood pressure (BP) ? 150 mm Hg or diastolic BP ? 100 mm Hg)
  • Seizure disorder allowed provided patient is well-controlled and on nonenzyme-inducing anticonvulsants
  • No history of myocardial infarction, severe or unstable angina, clinically significant peripheral vascular disease, ? grade 2 heart failure, or serious and inadequately controlled cardiac arrhythmia
  • No known bleeding diathesis or coagulopathy
  • No prior arterial thromboembolic events, including transient ischemic attacks orcerebrovascular accidents
  • No prior diagnosis of a deep venous thrombosis, including pulmonary embolism, and no known thrombophilic condition (e.g., protein S, protein C, antithrombin III deficiency, Factor V Leiden or Factor II G202`0A mutation, homocysteinemia, or antiphospholipid antibody syndrome)
  • No history of an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
  • No serious or non-healing wound, ulcer, or bone fracture
  • No evidence of significant postoperative intracranial hemorrhage, defined as > 1 cm of blood on postoperative MRI scan (potentially in addition to the postoperative scan) obtained within the past 14days
  • No history of allergic reaction to Chinese hamster ovary cell products or other recombinanthuman antibodies
  • No more than 31 days since definitive surgery
  • Must not have received any prior chemotherapy, radiotherapy, immunotherapy, or bone marrow transplant
  • More than 7 days since major surgical procedure and recovered

    • For patients scheduled to receive bevacizumab:

      • More than 28 days since major procedure
      • More than 14 days since intermediate procedure
      • More than 7 days since minor procedure (lumbar picture or placement of PICC lines are not considered minor procedures)
  • No other current anti-cancer agents
  • No concurrent nonsteroidal anti-inflammatory medications known to inhibit platelet function or known to selectively inhibit cyclooxygenase activity
  • No concurrent enzyme inducing anticonvulsants
  • No concurrent HDAC inhibitors (e.g., valproic acid)
  • No concurrent anticoagulants including systemic thrombolytic agents, heparin, low molecular weight heparins, or warfarin except as required to maintain patency of pre-existing permanent vascular catheters or for prevention of thrombosis in the post-operative period
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries Australia
 
Administrative Information
NCT Number  ICMJE NCT01236560
Other Study ID Numbers  ICMJE NCI-2011-02616
NCI-2011-02616 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
11-00910
CDR0000688443
ACNS0822
ACNS0822 ( Other Identifier: Childrens Oncology Group )
ACNS0822 ( Other Identifier: CTEP )
U10CA098543 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Maryam Fouladi Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date January 2019

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