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A Randomized Phase II/III Study of Vorinostat (IND# 71976) and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab (IND# 7921) and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas

Phase 2/Phase 3
3 Years
21 Years
Open (Enrolling)
Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Childhood Spinal Cord Neoplasm, Untreated Childhood Brain Stem Glioma, Untreated Childhood Cerebral Astrocytoma

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Trial Information

A Randomized Phase II/III Study of Vorinostat (IND# 71976) and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab (IND# 7921) and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas


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)


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

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

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

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.

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/μL

- Platelet count ≥ 100,000/μL

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of vorinostat when given concurrently with radiation therapy determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (feasability study)

Outcome Time Frame:

10 weeks

Safety Issue:


Principal Investigator

Maryam Fouladi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

November 2010

Completion Date:

Related Keywords:

  • Childhood High-grade Cerebellar Astrocytoma
  • Childhood High-grade Cerebral Astrocytoma
  • Childhood Spinal Cord Neoplasm
  • Untreated Childhood Brain Stem Glioma
  • Untreated Childhood Cerebral Astrocytoma
  • Astrocytoma
  • Neoplasms
  • Glioma
  • Spinal Cord Neoplasms



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