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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)
Both
Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Childhood Spinal Cord Neoplasm, Untreated Childhood Brain Stem Glioma, Untreated Childhood Cerebral Astrocytoma

Thank you

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


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.


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:

Interventional

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:

Yes

Principal Investigator

Maryam Fouladi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02616

NCT ID:

NCT01236560

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

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Bronson Methodist HospitalKalamazoo, Michigan  49007
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Marshfield ClinicMarshfield, Wisconsin  54449
Loma Linda University Medical CenterLoma Linda, California  92354
New York Medical CollegeValhalla, New York  10595
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Cedars-Sinai Medical CenterLos Angeles, California  90048
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Brooke Army Medical CenterFort Sam Houston, Texas  78234-6200
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
Miami Children's HospitalMiami, Florida  33155-4069
All Children's HospitalSt. Petersburg, Florida  33701
Saint Jude Midwest AffiliatePeoria, Illinois  61637
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Scott and White Memorial HospitalTemple, Texas  76508
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Naval Medical Center - PortsmouthPortsmouth, Virginia  23708-2197
Montefiore Medical CenterBronx, New York  10467-2490
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Lee Memorial Health SystemFort Myers, Florida  33902
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
Vanderbilt UniversityNashville, Tennessee  37232-6305
University of North CarolinaChapel Hill, North Carolina  27599
University of RochesterRochester, New York  14642
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
Albany Medical CenterAlbany, New York  12208
University of KentuckyLexington, Kentucky  40536-0098
Oregon Health and Science UniversityPortland, Oregon  97201
Virginia Commonwealth UniversityRichmond, Virginia  
Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Seattle Children's HospitalSeattle, Washington  98105
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
University of HawaiiHonolulu, Hawaii  96813
Saint Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
University of IllinoisChicago, Illinois  60612
Cook Children's Medical CenterFort Worth, Texas  76104
West Virginia University CharlestonCharleston, West Virginia  25304
The Children's Medical Center of DaytonDayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
Children's Oncology GroupArcadia, California  91006-3776
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Cardinal Glennon Children's Medical CenterSt. Louis, Missouri  63104
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Sanford Medical Center-FargoFargo, North Dakota  58122
Floating Hospital for Children at Tufts Medical CenterBoston, Massachusetts  02111
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Raymond Blank Children's HospitalDes Moines, Iowa  50309
The Toledo Hospital/Toledo Children's HospitalToledo, Ohio  43606
Greenville Cancer Treatment CenterGreenville, South Carolina  29605
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204
The Steven and Alexandra Cohen Children's Medical Center of New YorkNew Hyde Park, New York  11040
Mattel Children's Hospital UCLALos Angeles, California  90095