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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



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University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
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All Children's HospitalSt. Petersburg, Florida  33701
Advocate Hope Children's HospitalOak Lawn, Illinois  60453
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Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Covenant Children's HospitalLubbock, Texas  79410
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
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
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Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Wayne State UniversityDetroit, Michigan  48202
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
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Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
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Seattle Children's HospitalSeattle, Washington  98105
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Saint Luke's Mountain States Tumor InstituteBoise, Idaho  83712
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Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
Saint Barnabas Medical CenterLivingston, New Jersey  07039
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Cook Children's Medical CenterFort Worth, Texas  76104
The Children's Medical Center of DaytonDayton, Ohio  45404
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C S Mott Children's HospitalAnn Arbor, Michigan  48109
Riley Hospital for ChildrenIndianapolis, Indiana  46202
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Saint Joseph Children's Hospital of TampaTampa, Florida  33607
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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
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