Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors

Temozolomide With Irinotecan Versus Temozolomide, Irinotecan Plus Bevacizumab (NSC# 704865) for Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, a COG Randomized Phase II Screening Trial

This randomized phase II trial studies how well giving temozolomide and irinotecan hydrochloride together with or without bevacizumab works in treating young patients with recurrent or refractory medulloblastoma or central nervous system (CNS) primitive neuroectodermal tumors. Drugs used in chemotherapy, such as temozolomide and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. 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. It is not yet known whether temozolomide and irinotecan hydrochloride are more effective with or without bevacizumab in treating medulloblastoma or CNS primitive neuroectodermal tumors.

Study Overview

• Status: Completed
• Conditions: Pineoblastoma; Recurrent Medulloblastoma; Refractory Medulloblastoma; Refractory Peripheral Primitive Neuroectodermal Tumor; Central Nervous System Neoplasm; Recurrent Primitive Neuroectodermal Tumor
• Intervention / Treatment: Biological: Bevacizumab; Drug: Temozolomide; Drug: Irinotecan Hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

l. To compare the overall survival (OS) of subjects receiving the combination of temozolomide and irinotecan with that of subjects receiving temozolomide, irinotecan (irinotecan hydrochloride), and bevacizumab for recurrent medulloblastoma (MB)/primitive neuroectodermal tumor (PNET) of childhood.

SECONDARY OBJECTIVES:

I. To assess the response rate for each treatment arm amongst patients who are enrolled with measurable disease.

II. To determine event-free survival (EFS) for each patient compared across regimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive temozolomide orally (PO) and irinotecan hydrochloride IV over 90 minutes on days 1-5.

ARM II: Patients receive temozolomide PO and irinotecan hydrochloride IV as in arm I and bevacizumab IV over 30-90 minutes on days 1 and 15.

In both arms, 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 for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Hunter Regional Mail Centre, New South Wales, Australia, 2310
      • John Hunter Children's Hospital
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
    • Westmead, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Children's Hospital-Brisbane
    • South Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • The Montreal Children's Hospital of the MUHC
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• New Zealand
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1145
      • Starship Children's Hospital
• Puerto Rico
  • San Juan, Puerto Rico, 00926
    • University Pediatric Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Kaiser Permanente Downey Medical Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's and Women's Hospital Long Beach
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Madera, California, United States, 93636
      • Valley Children's Hospital
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • Sacramento, California, United States, 95816
      • Sutter Medical Center Sacramento
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
    • San Francisco, California, United States, 94143
      • UCSF Medical Center-Parnassus
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Fort Myers, Florida, United States, 33908
      • Golisano Children's Hospital of Southwest Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Memorial Health System
    • Gainesville, Florida, United States, 32610
      • University of Florida Health Science Center - Gainesville
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Orlando, Florida, United States, 32806
      • Orlando Health Cancer Institute
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic - Orlando
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
    • Tampa, Florida, United States, 33607
      • Saint Joseph's Hospital/Children's Hospital-Tampa
    • West Palm Beach, Florida, United States, 33407
      • Saint Mary's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
    • Savannah, Georgia, United States, 31404
      • Memorial Health University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Cancer Institute - Boise
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Children's Hospital-Oak Lawn
    • Peoria, Illinois, United States, 61637
      • Saint Jude Midwest Affiliate
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Children's Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
    • Louisville, Kentucky, United States, 40202
      • Norton Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • East Lansing, Michigan, United States, 48824-7016
      • Michigan State University Clinical Center
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Columbia Regional
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89144
      • Summerlin Hospital Medical Center
    • Las Vegas, Nevada, United States, 89109
      • Sunrise Hospital and Medical Center
    • Las Vegas, Nevada, United States, 89135
      • Alliance for Childhood Diseases/Cure 4 the Kids Foundation
    • Las Vegas, Nevada, United States, 89102
      • University Medical Center of Southern Nevada
    • Las Vegas, Nevada, United States, 89169
      • Nevada Cancer Research Foundation NCORP
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center/Levine Cancer Institute
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Broadway Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Children's Hospital
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Prisma Health Richland Hospital
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Cancer Treatment Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Childrens Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • El Paso, Texas, United States, 79905
      • El Paso Children's Hospital
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont and State Agricultural College
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center and Children's Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center-Marshfield
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Medulloblastoma or PNET of childhood that has relapsed or become refractory to standard chemotherapy; patients with pineoblastoma are eligible
• Patients must have had histologic verification of the malignancy at original diagnosis or at the time of recurrence
• Patients must have clear residual disease, defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) OR diffuse leptomeningeal disease OR clear MRI evidence of disease that may not be measurable in two perpendicular diameters
• All patients must have a brain MRI with and without gadolinium and a spine MRI with gadolinium performed within 2 weeks prior to study enrollment
• Patients must have a Lansky or Karnofsky performance status score of >= 50%, corresponding to Eastern Cooperative Oncology Group (ECOG) categories of 0, 1, or 2 (use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age)
• Patients must have a life expectancy of >= 8 weeks
• Patients must have experienced at least one and at most two relapses prior to study enrollment; patients with primary refractory disease are eligible

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

  • Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this study (6 weeks if prior nitrosourea)
  • Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent; at least 3 weeks for biologic agents with a long half life, such as antibodies
  • External beam radiation therapy (XRT): Must not have received craniospinal radiotherapy within 24 weeks prior to study entry; the tumor designated as "measurable" for protocol purposes must not have received radiation within 12 weeks prior to study entry); focal radiation to areas of symptomatic metastatic disease must not be given within 14 days of study entry
  • Stem cell transplant (SCT): For autologous SCT, >= 3 months must have elapsed prior to study entry

  • Study specific limitations on prior therapy:

    • Patients must not have previously received bevacizumab, irinotecan, temozolomide or other anti-vascular endothelial growth factor (VEGF) inhibitor
    • Patients must not be taking enzyme-inducing antiepileptic medicines within 1 week of study entry

• Patients must have recovered from any surgical procedure before enrolling on this study:

  • Patients with a major surgical procedure within 28 days prior to enrollment should be excluded
  • Patients with an intermediate surgical procedure within 14 days prior to enrollment should be excluded
  • For minor surgical procedures (including Broviac line or infusaport placement), patients should not receive the first planned dose of bevacizumab until the wound is healed and at least 7 days have elapsed

  • There should be no anticipation of need for major surgical procedures during the course of the study

    • Examples of major, intermediate, or minor surgical procedures:

      • Major procedures: Major craniotomy for tumor resection; organ resection; bowel wall anastomosis; arteriovenous grafts; exploratory laparotomy; thoracotomy
      • Intermediate procedures: Ventriculoperitoneal (VP)-shunt placement; stereotactic brain biopsy
      • Minor procedures: Incision and drainage of superficial skin abscesses; punch biopsy of skin lesions; superficial skin wound suturing; bone marrow aspirate and/or biopsy; fine needle aspirations; Broviac line or infusaport placement; paracentesis or thoracocentesis
  • Please note: Lumbar punctures or placement of peripherally inserted central catheter (PICC) lines are not considered minor procedures and may occur at any time prior to or during therapy
• Hypertension must be well controlled (=< 95th percentile for age and height if patient is =< 17 years) on stable doses of medication

• Concomitant medications restrictions:

  • Growth factor(s): Must not have received within 7 days of entry onto this study
  • Steroids: Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 7 days
  • Study Specific: Patients must not be currently taking nonsteroidal anti-inflammatory drugs (NSAIDs), clopidrogel, dipyridamole or aspirin therapy > 81 mg/day
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (must not have received filgrastim [G-CSF] within the prior 7 days)
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 8.0 gm/dL (may receive packed red blood cell [PRBC] transfusions)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR a serum creatinine based on age/gender as follows:

  • =< 0.4 mg/dL (for patients aged 1 month to < 6 months)
  • =< 0.5 mg/dL (for patients aged 6 months to < 1 year)
  • =< 0.6 mg/dL (for patients aged 1 to < 2 years)
  • =< 0.8 mg/dL (for patients aged 2 to < 6 years)
  • =< 1 mg/dL (for patients aged 6 to < 10 years)
  • =< 1.2 mg/dL (for patients aged 10 to < 13 years)
  • =< 1.4 mg/dL (for female patients aged >= 13 years)
  • =< 1.5 mg/dL (for male patients aged 13 to < 16 years)
  • =< 1.7 mg/dL (for male patients aged >= 16 years)
• Urine protein should be screened by dipstick analysis; if protein >= 2+ on dipstick, then urine protein creatinine (UPC) ratio should be calculated; if UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg/24 hours for patient enrollment
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) for age

• Central nervous system function defined as

  • Patients with a seizure disorder may be enrolled if well-controlled and on non-enzyme inducing anticonvulsants

• Adequate coagulation defined as

  • International normalized ratio (INR)/prothrombin time (PT) =< 1.5 x upper limit of normal

Exclusion Criteria:

• Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible for this study
• Patients must not have a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to study entry
• Patients must not have a known bleeding diathesis or coagulopathy
• Patients must not have had significant vascular disease (eg, aortic aneurysm requiring surgical repair, deep venous or arterial thrombosis) within the last 6 months prior to study entry
• Patients must not have a known thrombophilic condition (i.e. protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia or antiphospholipid antibody syndrome); testing is not required in patients without thrombophilic history
• Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained within 14 days prior to study enrollment
• Patients with a history of stroke, myocardial infarction, transient ischemic attack (TIA), severe or unstable angina, peripheral vascular disease, or grade II or greater congestive heart failure within the past 6 months are not eligible
• Patients must not have serious and inadequately controlled cardiac arrhythmia
• Female patients who are pregnant are not eligible for this study
• Female patients who are breastfeeding are not eligible for this study unless they agree not to breastfeed
• Female patients of childbearing potential must have a negative pregnancy test
• Sexually active patients of childbearing potential must agree to use an effective method of contraception during the study and for at least 6 months after the completion of bevacizumab therapy
• Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (temozolomide, irinotecan hydrochloride); Patients receive temozolomide PO and irinotecan hydrochloride IV over 90 minutes on days 1-5.	Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; 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; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; U-101440E; CPT-11; Camptothecin 11; Camptothecin-11; CPT 11; Irinomedac; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate
Experimental: Arm II (temozolomide, irinotecan hydrochloride, bevacizumab); Patients receive temozolomide PO and irinotecan hydrochloride IV as in arm I and bevacizumab IV over 30-90 minutes on days 1 and 15.	Biological: Bevacizumab; Given IV; Other Names: Avastin; ABP 215; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; Bevacizumab awwb; Bevacizumab Biosimilar ABP 215; Bevacizumab Biosimilar BEVZ92; Bevacizumab Biosimilar BI 695502; Bevacizumab Biosimilar CBT 124; Bevacizumab Biosimilar CT-P16; Bevacizumab Biosimilar FKB238; Bevacizumab Biosimilar GB-222; Bevacizumab Biosimilar HD204; Bevacizumab Biosimilar HLX04; Bevacizumab Biosimilar IBI305; Bevacizumab Biosimilar LY01008; Bevacizumab Biosimilar MIL60; Bevacizumab Biosimilar Mvasi; Bevacizumab Biosimilar MYL-1402O; Bevacizumab Biosimilar QL 1101; Bevacizumab Biosimilar RPH-001; Bevacizumab Biosimilar SCT501; Bevacizumab Biosimilar Zirabev; Bevacizumab-awwb; Bevacizumab-bvzr; BP102; BP102 Biosimilar; HD204; 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; Mvasi; MYL-1402O; Recombinant Humanized Anti-VEGF Monoclonal Antibody; rhuMab-VEGF; SCT501; Zirabev; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; 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; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; U-101440E; CPT-11; Camptothecin 11; Camptothecin-11; CPT 11; Irinomedac; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Percentage Probability of remaining alive 5 years after enrollment estimated by the method of Kaplan and Meier	Up to 5 years after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response	Patient's best response during protocol therapy coded as complete response, partial response or no response.	Up to 12 cycles of therapy (11 months)
Event-free Survival	Percentage Probability of remaining event-free 5 years after enrollment estimated by the method of Kaplan and Meier	Up to 5 years after enrollment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Adam S Levy, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2010
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: October 7, 2010
• First Submitted That Met QC Criteria: October 7, 2010
• First Posted (Estimate): October 8, 2010

Study Record Updates

• Last Update Posted (Actual): July 23, 2021
• Last Update Submitted That Met QC Criteria: July 1, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Glioma; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Neoplasms; Recurrence; Sarcoma, Ewing; Nervous System Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Pinealoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Topoisomerase I Inhibitors; Antibodies; Temozolomide; Immunoglobulins; Bevacizumab; Irinotecan; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Immunoglobulin G; Endothelial Growth Factors; Camptothecin
• Other Study ID Numbers: NCI-2011-02605 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180886 (U.S. NIH Grant/Contract); U10CA098543 (U.S. NIH Grant/Contract); 11-00909; CDR0000686608; COG-ACNS0821; ACNS0821 (Other Identifier: CTEP)