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Temozolomide With Irinotecan Versus Temozolomide, Irinotecan Plus Bevacizumab (NSC# 704865, BB-IND# 7921) for Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, A COG Randomized Phase II Screening Trial

Phase 2
21 Years
Open (Enrolling)
Recurrent Childhood Medulloblastoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

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Trial Information

Temozolomide With Irinotecan Versus Temozolomide, Irinotecan Plus Bevacizumab (NSC# 704865, BB-IND# 7921) for Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, A COG Randomized Phase II Screening Trial


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


I. To assess the response rate for each treatment arm. II. To determine event-free survival
(EFS) for each patient compared across regimens.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral temozolomide and irinotecan hydrochloride IV over 90 minutes on
days 1-5.

ARM II: Patients receive oral temozolomide 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.

Inclusion Criteria:

- Diagnosis of medulloblastoma or PNET of childhood that has relapsed or become
refractory to standard chemotherapy; patients with pineoblastoma are eligible

- Patients must have experienced at least one and at most two relapses prior to study

- Patients with primary refractory disease are eligible

- Patients must have had histologic verification of the malignancy at original
diagnosis or at the time of recurrence

- Patients must have measurable residual disease, defined as tumor that is measurable
in two perpendicular diameters on MRI

- Diffuse leptomeningeal disease is not considered measurable

- 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 not have evidence of new CNS hemorrhage on baseline MRI

- Patients must have a Lansky or Karnofsky performance status score of ≥ 50%,
corresponding to ECOG categories of 0, 1, or 2 (Karnofsky for patients > 16 years of
age and Lansky for patients ≤ 16 years ofage)

- Patients must have a life expectancy of ≥ 8 weeks

- Peripheral absolute neutrophil count (ANC) ≥ 1000/μL (must not have received
G-CSFwithin the prior 7 days)

- Platelet count ≥ 100,000/μL (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (may receive PRBC transfusions)

- Creatinine clearance or radioisotope 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

- If UPC ratio > 0.5, 24-hour urine protein should be obtained and the level
should be < 1,000 mg/24 hours for patient enrollment

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

- SGPT (ALT) ≤ 3 x ULN for age

- INR/PT ≤ 1.5 x ULN

- 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

- Hypertension must be well controlled (≤ 95th percentile for age and height if patient
is≤ 17 years) on stable doses of medication

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

- 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 (e.g., 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 IIIdeficiency, Factor V Leiden, Factor II G20210A mutation,
homocysteinemia, or antiphospholipidantibody syndrome)

- Testing is not required in patients without thrombophilic history

- 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

- No patients with known hypersensitivity to Chinese hamster ovary cell products or
other recombinant human antibodies

- No concurrent radiotherapy

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

- No myelosuppressive chemotherapy within 3 weeks of entry onto this study (6 weeks if
prior nitrosourea)

- At least 7 days since the completion of therapy with abiologic agent; at least 3
weeks for biologic agents with a long half life, such as antibodies

- 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

- For autologous stem cell transplant, ≥ 3 months must have elapsed prior to study

- Patients must not have previously received bevacizumab, irinotecan, temozolomide, or
other anti-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

- 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

- No growth factors within 7 days of entry onto this study

- Patients who are receiving corticosteroids must be on a stable or decreasing dose for
at least 7 days

- Patients must not be currently taking NSAIDs, clopidogrel, dipyridamole,or aspirin
therapy > 81 mg/day

- No other cancer chemotherapy or immunomodulating agents are permitted (the use of
alternative or complementary therapies is discouraged)

Type of Study:


Study Design:

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

Outcome Measure:

Overall survival for each treatment arm

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Adam Levy

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:

  • Recurrent Childhood Medulloblastoma
  • Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
  • Medulloblastoma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive



Baylor College of Medicine Houston, Texas  77030
Johns Hopkins University Baltimore, Maryland  21205
Memorial Sloan Kettering Cancer Center New York, New York  10021
Cleveland Clinic Foundation Cleveland, Ohio  44195
Mayo Clinic Rochester, Minnesota  55905
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Washington University School of Medicine Saint Louis, Missouri  63110
Rhode Island Hospital Providence, Rhode Island  02903
Medical City Dallas Hospital Dallas, Texas  75230
Midwest Children's Cancer Center Milwaukee, Wisconsin  53226
Morristown Memorial Hospital Morristown, New Jersey  07962-1956
Loma Linda University Medical Center Loma Linda, California  92354
Newark Beth Israel Medical Center Newark, New Jersey  07112
Dana-Farber Cancer Institute Boston, Massachusetts  02115
Cedars-Sinai Medical Center Los Angeles, California  90048
University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Hackensack University Medical Center Hackensack, New Jersey  07601
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's National Medical Center Washington, District of Columbia  20010-2970
All Children's Hospital St. Petersburg, Florida  33701
Advocate Hope Children's Hospital Oak Lawn, Illinois  60453
Saint Jude Midwest Affiliate Peoria, Illinois  61637
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health Center Portland, Oregon  97227
Driscoll Children's Hospital Corpus Christi, Texas  78466
Southern California Permanente Medical Group Downey, California  90242
Children's Hospital Central California Madera, California  93638-8762
Kosair Children's Hospital Louisville, Kentucky  40202-3830
Children's Hospital Medical Center of Akron Akron, Ohio  44308
Covenant Children's Hospital Lubbock, Texas  79410
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Overlook Hospital Summit, New Jersey  07902-0220
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Primary Children's Medical Center Salt Lake City, Utah  84113-1100
Montefiore Medical Center Bronx, New York  10467-2490
Rady Children's Hospital - San Diego San Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis, Minnesota  55404
University of New Mexico Cancer Center Albuquerque, New Mexico  87131-5636
Nationwide Children's Hospital Columbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central Texas Austin, Texas  78723
Presbyterian Hospital Charlotte, North Carolina  28233-3549
Lee Memorial Health System Fort Myers, Florida  33902
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Children's Hospital of Alabama Birmingham, Alabama  35233
Connecticut Children's Medical Center Hartford, Connecticut  06106
Vanderbilt University Nashville, Tennessee  37232-6305
University of North Carolina Chapel Hill, North Carolina  27599
Nemours Children's Clinic - Pensacola Pensacola, Florida  32504
Wayne State University Detroit, Michigan  48202
Legacy Emanuel Children's Hospital Portland, Oregon  97227
BI-LO Charities Children's Cancer Center Greenville, South Carolina  29605
University Of Vermont Burlington,, Vermont  05403
Albany Medical Center Albany, New York  12208
University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer Center Sacramento, California  95817
Oregon Health and Science University Portland, Oregon  97201
Virginia Commonwealth University Richmond, Virginia  
Florida Hospital Orlando, Florida  32803
Memorial Health University Medical Center Savannah, Georgia  31404
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470
Seattle Children's Hospital Seattle, Washington  98105
Childrens Memorial Hospital Chicago, Illinois  60614
Kaiser Permanente-Oakland Oakland, California  94611
Lombardi Comprehensive Cancer Center at Georgetown University Washington, District of Columbia  20057
M D Anderson Cancer Center- Orlando Orlando, Florida  32806
University of Hawaii Honolulu, Hawaii  96813
Saint Luke's Mountain States Tumor Institute Boise, Idaho  83712
Michigan State University - Breslin Cancer Center East Lansing, Michigan  48824-1313
Saint John's Mercy Medical Center Saint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOP Las Vegas, Nevada  89106
Saint Barnabas Medical Center Livingston, New Jersey  07039
New York University Langone Medical Center New York, New York  10016
Columbia University Medical Center New York, New York  10032
State University of New York Upstate Medical University Syracuse, New York  13210
Cook Children's Medical Center Fort Worth, Texas  76104
The Children's Medical Center of Dayton Dayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer Center Miami, Florida  33136
C S Mott Children's Hospital Ann Arbor, Michigan  48109
Riley Hospital for Children Indianapolis, Indiana  46202
Cardinal Glennon Children's Medical Center St. Louis, Missouri  63104
Miller Children's Hospital Long Beach, California  90806
Childrens Hospital of Orange County Orange, California  92868-3874
Alfred I duPont Hospital for Children Wilmington, Delaware  19803
Nemours Children's Clinic - Jacksonville Jacksonville, Florida  32207-8426
Nemours Childrens Clinic - Orlando Orlando, Florida  32806
Saint Joseph Children's Hospital of Tampa Tampa, Florida  33607
Children's Healthcare of Atlanta - Egleston Atlanta, Georgia  30322
The Childrens Mercy Hospital Kansas City, Missouri  64108
Rainbow Babies and Childrens Hospital Cleveland, Ohio  44106
Penn State Hershey Children's Hospital Hershey, Pennsylvania  17033
Palmetto Health Richland Columbia, South Carolina  29203
East Tennessee Childrens Hospital Knoxville, Tennessee  37916
Childrens Hospital-King's Daughters Norfolk, Virginia  23507
Lucile Packard Children's Hospital Stanford University Palo Alto, California  94304
University of California San Francisco Medical Center-Parnassus San Francisco, California  94143
Raymond Blank Children's Hospital Des Moines, Iowa  50309
Greenville Cancer Treatment Center Greenville, South Carolina  29605
Providence Sacred Heart Medical Center and Children's Hospital Spokane, Washington  99204