Clinical trial NCT00058370
Conditions: Brain and Central Nervous System Tumors
Keywords: adult medulloblastoma untreated childhood medulloblastoma
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2003-02-01; Completion date: 2019-06-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Radioimmunotherapy uses radiolabeled monoclonal antibodies to locate tumor cells and deliver radioactive tumor-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining intrathecal radioimmunotherapy and radiation therapy with combination chemotherapy may kill any tumor cells remaining after surgery.

PURPOSE: Phase II trial to study the effectiveness of combining intrathecal radioimmunotherapy and radiation therapy with combination chemotherapy in treating patients who have undergone surgery for medulloblastoma.

Detailed description:
OBJECTIVES:

* Determine the feasibility of combining post-operative intrathecal radioimmunotherapy, craniospinal radiotherapy with intensity-modulated radiotherapy boost, and chemotherapy in patients with standard-risk medulloblastoma.
* Determine whether this regimen can maintain or exceed the current progression-free survival rate while decreasing long-term serious morbidity in these patients.
* Determine the long-term morbidities, most specifically neuropsychological, neuroendocrine, audiometric, and growth outcomes, in patients treated with this regimen.

OUTLINE:

* Radioimmunotherapy: Patients receive intrathecal iodine I 131 monoclonal antibody 3F8 on days 1 and 8.
* Radiotherapy: Beginning as soon as possible after radioimmunotherapy, patients undergo external-beam and intensity-modulated radiotherapy 5 days a week for 6 weeks.
* Chemotherapy: Patients receive vincristine IV once weekly for 8 weeks concurrently with radiotherapy. Beginning about 6 weeks after completion of radiotherapy (4 weeks after vincristine), patients receive cisplatin IV over 6 hours and oral lomustine on day 0 and vincristine IV on days 0, 7, and 14. Treatment repeats every 6 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 6-20 patients will be accrued for this study within 3.2 years.

Arms: arm 1: This is a single-arm study of post-operative radioimmunotherapy (intrathecal 131-I-3F8), reduced-dose craniospinal radiation therapy (1800 cGy), primary site boost (to 5400 cGy) via IMRT and standard chemotherapy.
Interventions: intervention 1: cisplatin intervention 2: lomustine intervention 3: vincristine sulfate intervention 4: adjuvant therapy intervention 5: iodine I 131 monoclonal antibody 3F8 intervention 6: radiation therapy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center
IRB Protocol 
IRB#: 02-088A(5)
Amended: 2/26/08
 
 
 
 
 
 
A trial of radioimmunotherapy, reduced-dose external beam craniospinal radiation 
therapy with IMRT boost, and chemotherapy for patients with standard-risk 
medulloblastoma 
 
THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal Investigator: 
Ira Dunkel, M.D. 
Pediatrics: Pediatrics 
639-2153 
 
Co-Principal Investigator(s): Kim Kramer, M.D. 
Pediatrics: Pediatrics 
Suzanne L. Wolden, M.D. 
Radiation Oncology: Brachytherapy 


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Investigator(s): 
Oren Becher, M.D. 
Pediatrics: Pediatrics 
Nai-Kong V. Cheung, M.D., Ph.D. 
Pediatrics: Pediatrics 
Sofia Cooperman, M.D. 
Radiology: Neuroradiology 
Mark Edgar, M.D. 
Pathology: Neuropathology 
Ronald D. Finn, Ph.D. 
Radiology: Radiopharmaceutical Chemistry 
Timothy Gershon, M.D., Ph.D. 
Pediatrics: Pediatrics 
Stephen Gilheeney, M.D. 
Pediatrics: Pediatrics 
John L. Humm, Ph.D. 
Medical Physics: Clinical Physics 
Yasmin Khakoo, M.D. 
Pediatrics: Pediatrics 
Steven M. Larson, M.D. 
Radiology: Nuclear Medicine 
Eric Lis, M.D. 
Radiology: Neuroradiology 
David Lyden, M.D., Ph.D. 
Pediatrics: Pediatrics 
Marc Rosenblum, M.D. 
Pathology: Neuropathology and Autopsy 
Charles A. Sklar, M.D. 
Pediatrics: Pediatrics 
Mark Souweidane, M.D. 
Surgery: Neurosurgery 
Howard T. Thaler, Ph.D. 
Epidemiology and Biostatistics: Biostatistics 


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Consenting Professional(s): Oren Becher Ira 
Dunkel Timothy 
Gershon 
Stephen Gilheeney 
Yasmin Khakoo 
Kim Kramer 
David Lyden 
Mark Souweidane 
Suzanne Wolden 
 
 
 
 
 
Collaborating Institution (s):  Columbia University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, N.Y.  10021 


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A trial of radioimmunotherapy, reduced-dose external beam craniospinal radiation 
therapy with IMRT boost, and chemotherapy for patients with standard-risk 
medulloblastoma 
 
Table Of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..........................................................................1 
3.0 
BACKGROUND AND RATIONALE ...............................................................................1 
4.0 
STUDY DESIGN ................................................................................................................5 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................5 
6.0 
CRITERIA FOR PATIENT/SUBJECT ELIGIBILITY .....................................................7 
6.1 
PATIENT/SUBJECT INCLUSION CRITERIA .....................................................7 
6.2 
PATIENT/SUBJECT EXCLUSION CRITERIA....................................................7 
7.0 
RECRUITMENT PLAN .....................................................................................................8 
8.0 
PRETREATMENT EVALUATION ..................................................................................8 
9.0 
TREATMENT/INTERVENTION PLAN ..........................................................................9 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION  .......................................13 
11.0 
TOXICITIES/SIDE EFFECTS .........................................................................................14 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUT COME ASSESSMENT ..............15 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................15 
14.0 
BIOSTATISTICS .............................................................................................................15 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES .....................16 
15.1 
PATIENT/SUBJECT REGISTRATION ..............................................................16 
15.2 
RANDOMIZATION .............................................................................................16 
16.0 
DATA MANAGEMENT ISSUES ...................................................................................16 
16.1 
QUALITY ASSURANCE .....................................................................................16 
17.0 
PROTECTION OF HUMAN SUBJECTS .......................................................................17 
18.0 
INFORMED CONSENT PROCEDURES .......................................................................17 
19.0 
REFERENCE(S)................................................................................................................18 
20.0 
APPENDICE(S) 
APPENDIX A: MODEL ORDER SHEET FOR DAY 0 CHEMOTHERAPY ................22 
APPENDIX B: SUMMARY OF TIMING OF REQUIRED OBSERVATIONS……….23 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
In this pilot study, 20 patients with standard-risk medulloblastoma will be treated post- 
operatively with intrathecal 131-I-3F8, reduced-dose external beam radiation therapy 
(1800 cGy craniospinal + primary site boost to 5400 cGy via IMRT), and standard 
chemotherapy (vincristine, lomustine, cisplatin). 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
To assess the feasibility of combining intrathecal radioimmunotherapy with 
external beam radiation therapy and chemotherapy. 
 
• 
To maintain or exceed the current progression-free survival rate for patients with 
standard-risk medulloblastoma while using the protocol-prescribed regimen that is 
hypothesized to have less long-term serious morbidity. 
 
• 
To evaluate the long-term morbidities in patients treated with this regimen, with 
specific attention to neuropsychological, neuroendocrine, audiometric and growth 
outcomes. 
 
3.0 
BACKGROUND AND RATIONALE 
 
Brain tumors are a significant cause of mortality and severe morbidity in the pediatric age 
range. They are the most common type of solid tumor in children and recent data have 
suggested that their incidence has exceeded that of acute lymphoblastic leukemia to 
represent the most common type of cancer in children. About 3,000 cases are estimated to 
occur per year in the United States and 30,000 to 40,000 cases are estimated to occur per 
year worldwide. 
 
Medulloblastoma and other central nervous system primitive neuroectodermal tumors 
have been estimated to represent 20 to 25% of pediatric brain tumors. SEER data have 
suggested that approximately 317 cases of medulloblastoma are diagnosed in patients 
aged 0 to 24 years in the United States per year, with approximately 218 in the group 3 to 
24 years old. Approximately 1/2 of these patients are thought to have standard- risk 
disease, leading to an estimate of 110 patients per year potentially eligible for this study. 
 
Patients with medulloblastoma are divided into 3 groups for clinical trials. Patients older 
than 3 years of age are divided into standard-risk and high-risk groups. Standard-risk (the 
group of subjects to be involved in this study) is defined as the absence of metastatic 
disease (disease beyond the primary site) and the lack of post-operative residual tumor at 
the primary site greater than 1.5 cm2. High-risk disease is defined by the presence of either 
or both of those criteria. Patients less than 3 years of age are usually treated with protocols 
that attempt to avoid the use of RT due to the high risk of severe 


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neuropsychological damage associated with its use in these patients with immature 
brains. 
 
Medulloblastomas are highly malignant tumors that are very unlikely to be cured by 
surgery alone due to either recurrence at the primary site or dissemination through the 
cerebrospinal fluid (CSF) to distant leptomeningeal sites. The use of post-operative RT 
can be curative. The historical approach was to use RT without chemotherapy, with doses 
of 3600 cGy craniospinal, with a boost to 5400 cGy to the posterior fossa. Several recent 
studies have indicated that this approach produces an approximate 5-year event-free 
survival rate of 60% in patients with standard-risk disease. However, these doses of RT 
are associated with a significant risk of severe chronic neuropsychological and 
neuroendocrine morbidities, and growth retardation, as will be described below. These 
problems can be ascribed both to the craniospinal component of the radiation treatment 
and also to the temporal lobe and auditory apparatus inadvertently receiving a significant 
proportion of the boost dose when conventional treatment techniques are utilized. An 
attempt to reduce the craniospinal dose to 2340 cGy without the addition of 
chemotherapy in patients with standard-risk disease resulted an increased risk of early 
relapse, early isolated neuraxis relapse and a strong trend towards lower 5-year event-free 
survival (p=0.080).1 
 
However, in single-arm studies, the addition of chemotherapy appears to both improve 
event-free survival and to allow the use of reduced-dose craniospinal RT. The Children's 
Cancer Group treated 65 children between 3 and 10 years of age with non-metastatic 
medulloblastoma with reduced-dose craniospinal RT (2340 cGy) and a boost to the 
posterior fossa to 5580 cGy. Patients also received weekly vincristine during the RT and 
beginning 6 weeks after completion of RT began a planned eight cycles of vincristine, 
cisplatin and lomustine chemotherapy. Progression-free survival was 86% +/- 4% at 3 
years and 79% +/- 7% at 5 years. Hearing loss (presumably due to both cisplatin and RT 
to the auditory apparatus) occurred in 32%. Neuropsychological outcome was not 
described.2 This regimen has been explored on a larger scale in CCG-9961. The study 
completed accrual in December 2000, but results are not yet available. 
 
Only very limited data exist regarding the use of even lower craniospinal radiation doses. 
Investigators at the Children's Hospital of Philadelphia treated 10 children between 18 and 
60 months of age with non-metastatic medulloblastoma with very reduced-dose 
craniospinal RT (1800 cGy) and a boost to the posterior fossa to 5040 to 5580 cGy. 
Patients also received weekly vincristine during the RT and beginning 6 weeks after 
completion of RT began a planned eight cycles of vincristine, cisplatin and lomustine 
chemotherapy. Actuarial survival at over 6 years was 70% +/- 20%. Of the 3 patients 
whose tumor recurred, in 1 recurrence was simultaneously appreciated in the primary site 
and distantly and 2 at distant sites only. IQ testing of the survivors suggested minimal 
neurocognitive damage.3 


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Neuropsychological outcome of children treated for medulloblastoma was assessed by 
investigators at St. Jude. They described 22 patients who were treated with RT only and 
whose craniospinal dose was randomly assigned to 3600 versus 2340 cGy. They noted 
that the patients that received the lower dose suffered less severe neuropsychological 
toxicity.4 
 
Poor linear growth and adult short stature are extremely common in survivors of 
medulloblastoma and result from a combination of inadequate production of essential 
hormones such as growth hormone and thyroxine, and impaired spinal growth. In 
general, these abnormalities are directly correlated with the dose of radiation. Doses 
>3500 cGy to the hypothalamus result in growth hormone deficiency in 80-100% of 
subjects within 5 years.5-7 Similar doses administered to the whole spine are associated 
with a 60% incidence of primary hypothyroidism8 and an estimated loss in height in the 
range of 5 to 9 cm.9 Limited data suggest that reducing the dose of craniospinal RT from 
2340 cGy to 1800 cGy would result in an improvement in growth and final height,10 as 
well as reduce the risks of neurocognitive dysfunction.11 
 
Preliminary Data 
 
Radioimmunotherapy 
 
3F8 is an IgG3 murine monoclonal antibody directed against the ganglioside GD2 that is 
expressed on many human neural tumors, including 20 of 21 medulloblastoma tumors that 
we have tested (unpublished data). The 3F8 antibody localizes to GD2+ tumors in 
humans,12 mediates tumor cell lysis in vitro via interactions with human complement and 
leukocytes, can be conjugated to 131-I for targeted radioimmunotherapy, and has been 
effective intravenously in patients with metastatic neuroblastoma.13 Intrathecal 
administration of radiolabeled 3F8 to nude rats with GD2+ leptomeningeal neoplastic 
xenografts demonstrated a tumor dose of 1870 cGy/mCi versus only 40 cGy/mCi using a 
radiolabeled control antibody. Area under the curve values in tumor tissue were 14-fold 
greater than in blood.14 A trial of intrathecal 131-I-3F8 was performed in 8 cynomolgus 
monkeys at MSKCC. The therapy was tolerable and therapeutically relevant doses of 
radiation (1900 to 8200 cGy) were delivered to the CSF space.15 No long-term toxicity 
was observed with more than 4.5 years of follow-up from treatment. 
 
Intrathecal 131-I-3F8 is currently the subject of a phase I clinical trial at our institution 
(MSKCC 97-021) in patients with GD2+ leptomeningeal tumors. Ten patients (including 
4 with medulloblastoma or PNET), aged 1 to 61 years, have received 22 intrathecal 
injections of 131-I-3F8. They first received 1 to 2 mCi of intrathecal 131-I-3F8 via 
Ommaya reservoir, were imaged to obtain dosimetry, and then 7 patients received a 
second dose of 7.8 to 12 mCi.16 
 
Side effects for the 10 patients receiving the dosimetry dose were all transient and < 
grade 2 including fever (n=5), headache (n=5), emesis (n=4), and leg pain (n=2). One 


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patient had raised intracranial pressure above his baseline for 48 hours, associated with a 
headache. He was observed without treatment. Three patients had no toxicity. 
 
Seven of the above patients received single therapeutic injections of 7.8 to 12 mCi of 
intrathecal 131-I-3F8. Pharmacokinetics, dosimetry, imaging and clinical evaluation were 
carried out in an identical manner and compared to that obtained in the dosimetry doses. 
Acute toxicities included grade 1 or 2 fever, headache and emesis. One patient with a pre- 
existing seizure disorder had a generalized seizure 4 days after treatment requiring 
treatment and hospitalization. This patient was found to have sub-therapeutic anti- 
convulsant medications and progressive tumor on MRI imaging. One patient with pre- 
existing communicating hydrocephalus was treated with more than one therapeutic 
injection; symptoms of raised intracranial pressure occurred after the 4th injection, and 
required the placement of a ventriculo-peritoneal shunt. No long-term toxicity has been 
observed in one patient surviving 14 months. 
 
Dosimetry to CSF and marrow appears favorable: the estimated dose received to the CSF 
was 14.9 to 56.7 cGy/mCi (test doses) and 15 to 78.9 cGy/mCi (therapy doses), with little 
intra-patient variability. Dose to blood and other organs outside the central nervous 
system was < 2 cGy/mCi. Radioactivity was detected in the thecal sac by 4 hours and 
over the convexity by 24 hours. Focal uptake consistent with tumor was seen along the 
craniospinal axis in most patients; in the 1 patient with a normal MRI, clearance was 
rapid with no focal uptake. There was close agreement in CSF clearance in patients who 
received 2 injections, ranging from 6 to 14 hours. 
 
Given the selective tumor uptake, tumor dose is expected to be 5 to 10 fold the CSF dose, 
and thus we hypothesize that this agent may have clinical utility in the treatment of GD2+ 
cancers with a high-risk of leptomeningeal dissemination such as medulloblastoma. Only 
minimal doses of radiation are delivered to the brain and spinal cord parenchyma due to 
the short path length (~1 mm) of the 131-I isotope. This is potentially advantageous to 
these patients since parenchymal disease is rare. 
 
The MSKCC neurosurgical staff reviewed the recent institutional experience of placing 
Ommaya reservoirs in patients for the treatment of prophylaxis of leptomeningeal 
metastases.17 Between January 1995 and June 1998, Ommaya reservoirs were placed in 
107 patients. Complications occurred in 10 patients (9.3%) and included 2 infections, 5 
catheter malpositions, and 3 intracranial hemorrhages. Two deaths occurred secondary to 
intracranial hemorrhage, but both had risk factors that should not apply to our patients. 
One was receiving anti-coagulation therapy for a mechanical heart valve and the other 
had thrombocytopenia secondary to other treatment. 
 
Intensity modulated radiation therapy (IMRT) 
 
IMRT is a new technology for the planning and delivery of RT. It represents a significant 
improvement over traditional 3-dimensional (3D) planning. IMRT features sophisticated 


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computer-optimized intensity distributions within a number of radiation beams. This is 
achieved by using an inverse-planning algorithm with dose and volume constraints for 
every target and critical tissue in the treatment field. Penalties are set for each constraint 
in order to set priorities among the various volumes. Treatment is delivered using 
dynamic multileaf collimators (tiny strips of metal shielding) whose movements 
throughout each field during the treatment are controlled by a computer. The result is a 
dramatically higher degree of conformality of dose to the target and significant sparing of 
adjacent healthy tissues. 
 
IMRT is currently available in only a limited number of centers. There is only 1 
publication that we are aware of reporting its use for patients with medulloblastoma. The 
authors noted that the auditory apparatus received lower doses of radiation when 
compared to historical patients treated with conventional techniques.18 
 
We have treated 10 patients with newly-diagnosed medulloblastoma from July 1999 to 
the present with IMRT boosts and have shown a significant improvement in dose 
distributions for every patient compared to 2D and traditional 3D planning. In all cases, 
the dose conformality to the tumor target volume is improved while doses to the inner 
ears and other critical tissues are minimized. This decrease is expected to result in 
improved long-term hearing and a lower risk of endocrine dysfunction and 
neurocognitive delay, but this has not yet been proven. All 10 patients are currently event- 
free survivors, suggesting that the smaller boost volume does not adversely effect local 
control, but follow-up has been short (4 to 34 months, median 20 months, as of 5-31-02) 
and continued surveillance necessary. 
 
4.0 
STUDY DESIGN 
 
This is a single-arm study of post-operative radioimmunotherapy (intrathecal 131-I-3F8), 
reduced-dose craniospinal radiation therapy (1800 cGy), primary site boost (to 5400 cGy) 
via IMRT and standard chemotherapy. Statistical stopping rules are defined to minimize 
the risk of excessive failures. Long-term neuropsychological, neuroendocrine, 
audiometric and growth parameters will be closely followed to assess long-term 
morbidities that are hypothesized to be reduced with this regimen. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
131-I-3F8 
 
Source and pharmacology: Monoclonal antibody 3F8 is a murine IgG3 antibody. It is 
raised in BALB/c mice and specifically recognizes the ganglioside GD2. Formulation and 
stability: 3F8 is stored as 2 mg/ml in pH 4.2 citrate phosphate buffer. Vials are stored at - 
80 C. 
 
Route of administration: Intrathecal. 


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Supplier: 3F8 is produced using FDA guidelines for good laboratory practice within the 
premises of Memorial Sloan-Kettering Cancer Center. All lots have to pass sterility, 
safety, pyrogen, murine viruses, and DNA testing before human use. 131-I-3F8 is 
prepared by the Radiochem istry/Cyclotron Core Facility under the supervision of Dr. R. 
Finn. It is approved for human use via IND BB-IND-2299. 
 
5.2 
Vincristine 
 
Roue of administration: Intravenous 
 
Supplier: Commercially available. NSC-67574. 
Formulation: Clear liquid, 1 mg, 2 mg, and 5 mg vials. 
Storage: Refrigerate. Protect from light. 
Stability: Multiple-dose containers with preservatives are stable 30 days after opening if 
refrigerated. 
 
5.3 
Lomustine 
 
Route of administration: Oral 
 
Supplier: Commercially available.NSC-79037. 
Formulation: 10 mg, 40 mg, and 100 mg capsules. 
Storage: Room temperature. 
5.4 
Cisplatin 
 
Route of administration: Intravenous 
 
Supplier: Commercially available. NSC-119875. 
Formulation: 50 mg vials. 
Storage: Room temperature. Protect from light. 
 
Reconstitution: Reconstitute each vial with sterile water to achieve a final concentration 
of 1 mg/ml. Cisplatin is compatible with KC1, mannitol, and magnesium but NOT 
NaHCO3. 
 
Stability: Reconstituted solution is stable for 20 hours at room temperature. May 
precipitate if refrigerated after reconstitution. Aluminum reacts with cisplatin causing 


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precipitate formation and loss of potency. Therefore, needles or intravenous sets 
containing aluminum parts that may come in contact with the drug must not be used for 
the preparation or administration of cisplatin. 
 
6.0 
CRITERIA FOR PATIENT/SUBJECT ELIGIBILITY 
 
6.1 
PATIENT/SUBJECT INCLUSION CRITERIA 
 
• 
Patients must have histologic proof of medulloblastoma reviewed by the 
Department of Pathology at the Memorial Sloan-Kettering Cancer Center. 
 
• 
Patients must begin study prescribed therapy within 42 days of 
neurosurgical resection of the tumor 
 
• 
Age ≥ 3-years-old. 
 
• 
Post-operative head MRI must confirm ≤ 1.5 cm2 of residual tumor is 
present. 
 
• 
Head and spine MRI and lumbar CSF cytology must not show any 
definitive evidence of leptomeningeal dissemination (Chang stage M-0). 
 
• 
Examinations evaluating extra-neural sites will not be mandated, but any 
performed for clinical indications must be free of metastatic disease. 
 
• 
No prior RT or chemotherapy for the medulloblastoma is permitted. 
 
• 
Patients must have adequate CSF flow (defined as lack of 
compartmentalization) on an 111-Indium DTPA flow study. 
 
• 
Patients must have adequate organ function as defined by: 
 
• 
Hepatic: total bilirubin < 2.0 mg/dl, AST < 3 x the upper limit of 
normal. 
 
• 
 
Renal: Calculated creatinine clearance or nuclear GFR ≥ 70 
ml/min/1.73 m2. 
 
• 
The patient, or for minors, a parent or legal guardian, must give informed 
written consent indicating they are aware of the investigational nature of 
this study. 


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6.2 
PATIENT/SUBJECT EXCLUSION CRITERIA 
 
• 
Unable to start study prescribed therapy within 42 days of neurosurgical 
resection of the tumor 
 
• 
Age less than 3 years 
 
• 
> 1.5 cm2 residual tumor on post-operative head MRI 
 
• 
Evidence of leptomeningeal dissemination on head or spine MRI or CSF 
cytology positivity 
 
• 
Evidence of extra-neural metastases 
 
• 
Prior radiation therapy or chemotherapy for the medulloblastoma 
 
• 
Inadequate CSF flow on 111-Indium DTPA flow study 
 
• 
Patients with signs or symptoms suggestive of increased intracranial 
pressure (headache, emesis, ocular paresis) will not be eligible until they 
are cleared by neurology and/or neurosurgery. 
 
• 
Pregnancy 
 
• 
Total bilirubin ≥ 2.0 mg/dl 
 
• 
AST ≥ 3 x the upper limit of normal 
 
• 
Creatinine clearance and GFR < 70 ml/min/1.73 m2 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be offered the opportunity to participate in this trial if they meet the 
eligibility criteria. There will be no discrimination against females or minorities. Informed 
consent will be obtained from the patient, or if they are non-emancipated minors, their 
parent or legal guardian. Consent will be obtained by an investigator authorized to obtain 
consent. Patients will not receive any payment for their participation in this study. 
 
8.0 
PRETREATMENT EVALUATION 
 
• 
Review of the pathology by the Memorial Sloan-Kettering Cancer Center 
Department of Pathology 


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• 
Post-operative head MRI 
 
• 
Spine MRI 
 
• 
CSF cytology obtained via lumbar puncture 
 
• 
111-Indium DTPA CSF flow study 
 
• 
Liver function tests: Total bilirubin, AST 
 
• 
Renal function tests: Creatinine clearance or nuclear GFR study 
 
• 
For females ≥ 12-years-old, pregnancy test 
 
• 
All of these pre-treatment evaluations (other than pathology review) should have 
been performed ≤ 30 days before registration onto study 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Patients will receive 3 components of therapy, as described below. 
 
9.1 
Intrathecal 131-I-3F8 
 
Treatment will be given via an Ommaya reservoir that will be placed by neurosurgery if 
not already present. If the patient has a ventriculoperitoneal shunt, and CSF flow study 
using the shunt tubing has confirmed acceptable CSF flow, the shunt may be used for the 
administration of 131-I-3F8. 
 
9.1.1 
Premedications for 131-I-3F8 
 
The following pre-medication guidelines are strongly suggested, but may be altered based 
on the clinical judgment of the investigators without being considered a protocol 
violation. 
 
To start about 2 weeks prior to injection: 
 
Levetiracetam (Keppra): Start at 10-20 mg/kg divided BID about 2 weeks prior to 
injection, after one week increase by 10 mg/kg. The pills come in 250 and 500 mg 
strength and no liquid preparation is currently available. For patients unable to tolerate 
oral tablets, phenytoin may be substituted. Taper of the anti-convulsant is recommended 
(decrease dose by about 50% 2 weeks post-injection, then discontinue medication 3 days 
later) rather than abrupt discontinuation. 
 
To start about 5 days prior to injection: 


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SSKI: 7 drops daily (to begin 5 days pre-injection and to continue for 2 weeks post- 
injection) 
 
Liothyronine (Cytomel): 25 mcg/day if weight less than 25 kg, 50 mcg/day if weight 
greater or equal to 25 kg (to begin 5 days pre-injection and to continue for 2 weeks post- 
injection) 
 
To start 1-2 days prior to injection: 
 
 
 
 
Dexamethasone (for those patients not already on a higher dose of dexamethasone): 0.5 
mg po bid if weight less than 15 kg, 1 mg po bid if weight greater than or equal to 15 kg 
(to begin about 24 hours pre-injection and to be tapered over 1 to 2 weeks) 
 
To be started about 1 to 2 hours before injection: 
 
Hydroxyzine (Vistaril): 1 mg/kg IV, then Q 4 hours x 24 hours post-injection 
 
Acetaminophen (Tylenol): 10 mg/kg po before injection and then Q4 hours x 24 hours 
post-injection 
 
Lorazepam (Ativan): 0.05 mg/kg IV x 1 
 
Hydromorphone (Dilaudid): 0.015 mg/kg/dose x 1, then PRN 
 
9.1.2 
Treatment and dosimetry 
 
Patients will receive an intrathecal dose of 2 mCi of 131-I-3F8 via the Ommaya reservoir. 
Distribution throughout the thecal sac will be confirmed via whole body imaging at 
approximately 24 hours post-injection. Patients will have CSF and blood (2 ml/sample) 
obtained for radioactivity levels at approximately 5, 15, and 30 minutes, and 1, 2, 4, 18, 
and 44 hours post-injection. Pharmacokinetic data obtained from whole body and SPECT 
imaging will be used in conjunction with direct counting of CSF and blood samples in a 
well scintillation counter, and combined with MRI anatomical imaging to estimate the 
absorbed dose to brain, spinal column, blood and visible tumor nodules. 
 
About 1 week after the initial dose, patients will receive a therapeutic dose of 10 mCi. 
They will have the same CSF and blood monitoring specified in the previous paragraph, 
but will not have the SPECT imaging. 
 
Patients will be hospitalized overnight for supportive care after each of the 2 131-I-3F8 
injections. 
 
9.2 
External beam radiation therapy 


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Dose: A dose of 1800 cGy will be delivered to the craniospinal axis using external beam 
photons. The posterior fossa tumor bed boost will be treated to a total dose of 5400 cGy 
(1800 cGy craniospinal + 3600 cGy focal). The whole brain dose is calculated at 
midplane while the spine dose is calculated at the average anterior cord depth. The IMRT 
boost will be prescribed to the isodose line that includes at least 95% of the planning 
target volume (PTV). 
 
Radiation should begin as soon as possible after the patient has recovered from surgery 
and intrathecal 131-I-3F8. Treatment will be given according to standard fractionation at 
180 cGy per day, 5 days per week. All fields shall be treated daily. Days missed due to 
holidays or for other unavoidable reasons are acceptable but should be kept to a 
minimum. Holding radiation treatments is allowed at the discretion of the radiation 
oncologist, but interruptions in radiation therapy should be avoided whenever possible. 
There are no minimum blood count requirements for radiation therapy and radiation 
therapy may be given even if chemotherapy is held. 
 
Treatment volume: Radiation will be delivered to the entire craniospinal axis with an 
inferior border 1 to 2 cm below the thecal sack. Care will be taken to include the 
cribriform plate while shielding the lenses of the eyes. The clinical target volume (CTV) 
for the boost to the posterior fossa tumor bed will include the postoperative cavity and any 
residual disease plus a 1 cm margin in all dimensions. The only exception is that the CTV 
should not extend into bones (skull base, calvarium, vertebral bodies) and thus the margin 
may be less than 1 cm in these regions. The PTV is defined as the CTV plus a 0.5 cm 
margin in all dimensions. The PTV may extend into bones. The entire posterior fossa is 
NOT intended for treatment in the boost field. 
 
Technique: Patients will receive craniospinal radiation using standard techniques. They 
will be simulated in the prone position using immobilization casts as well as anesthesia 
when necessary. A treatment planning CT scan will be performed and images will be 
fused with a diagnostic MRI scan for better definition of anatomy. The brain will be 
treated with lateral or lateral oblique fields (depending upon the technique chosen for lens 
sparing) matched to posterior spine field(s). Appropriate gantry and collimator angles will 
be calculated to prevent overlapping fields. There will not be a gap between the cranial and 
spine fields but the match line will be shifted 1 cm half way through treatment, at 900 cGy. 
 
Intensity modulated radiation therapy will be used for focal treatment of the tumor bed 
boost. The number of fields and orientation of beams will be determined on an individual 
basis. The general goals of the optimization algorithm are to maximize coverage of the 
target volume (PTV as defined above) while minimizing heterogeneity within the target 
and sparing the cochlea to the extent possible. The maximum dose to any point in the 
brainstem must not exceed 6000 cGy and the maximum dose to any point in the cord must 
not exceed 5000 cGy in the composite plan (including the craniospinal portion of 


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treatment). Dose to the hypothalamic-pituitary axis should also be constrained as much as 
possible. The parotid glands and oral cavity should be contoured and the cumulative 
mean dose to each of these structures should not exceed 2600 cGy. 
 
All fields will be treated using 6MV photons. Initial and weekly portal films will be taken 
to ensure correct positioning. 
 
Evaluation on treatment: Patients will be evaluated by a radiation oncologist at least once 
per week. Complete blood counts will be drawn about weekly. 
 
9.3 
Chemotherapy 
 
Starting at about the onset of external beam RT, patients will receive 8 weekly doses of 
vincristine (1.5 mg/m2/dose, maximum 2 mg). 
 
Starting about 6 weeks after completion of the RT (about 4 weeks after the 8th dose of 
vincristine noted above), we will start 8 planned cycles of vincristine, cisplatin, and 
lomustine chemotherapy. Each cycle consists of: 
 
Vincristine (1.5 mg/m2/dose, maximum 2 mg) IV push on days 0, 7, & 14. 
 
Cisplatin (75 mg/m2/dose) IV over about 6 hours on day 0 with mannitol and hydration. A 
sample order set is included as an appendix. 
 
Lomustine (75 mg/m2/dose) po on day 0. Because the capsules only are available in 10, 
40, and 100 mg doses, the actual dose of lomustine will be rounded off to the closest 
possible dose. 
 
Cycles are intended to be repeated about every 6 weeks depending on the ANC and 
platelet count (see below). The post-RT chemotherapy may be given at another center if 
more convenient for the patient as long as adequate documentation is sent to the MSKCC 
PI in a timely fashion. 
 
9.4 
Chemotherapy dose modification rules: 
 
Hematopoietic toxicity: If the ANC is < 750 or platelet count < 75,000, a cycle should not 
be started. If the ANC is ≥ 750, but < 1000, or the platelet count is ≥ 75,000 but < 
100,000, the cycle may start, but the lomustine dose will be reduced by 50%. 
 
Neurotoxicity: For vincristine neurotoxicity grade 3 or 4 and/or for vincristine 
neuropathy: motor grade 2 to 4: hold vincristine. When toxicity resolves to less than 
grade 3 (less than grade 2 for vincristine neuropathy: motor), vincristine may be restarted 
at 50% dose (0.75 mg/m2). If the neurotoxicity completely resolves, increase to full 
dosage may be considered. 


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Hepatotoxicity: If total bilirubin is > 1.9 mg/dl, do not administer vincristine dose. If total 
bilirubin is 1.5 to 1.9 mg/dl, administer vincristine at 1 mg/m2 (1.5 mg maximum). 
 
Nephrotoxicity: If the creatinine clearance or GFR are > 60 ml/minute/1.73 m2, 
administer the full dose. If the creatinine clearance or GFR are 30-60 ml/minute/1.73 m2, 
administer 50% of the dose (37.5 mg/m2). If the creatinine clearance or GFR are < 30 
ml/minute/1.73 m2, do not administer cisplatin. 
 
Ototoxicity: For a decrease in auditory acuity of (1) ≥ 30 decibels at 4000 to 8000 Hz or 
(2) ≥ 20 decibels at 500 to 3000 Hz or (3) grade 3 ototoxicity (subjective loss correctable 
with hearing aid), a 50% reduction in cisplatin dosage will be made. For grade 4 
ototoxicity (deafness not correctable), cisplatin will be discontinued unless follow-up 
audiogram shows an improvement in hearing function. 
 
9.5 
Supportive care guidelines 
 
Clinical judgment may be used to alter the following guidelines without being a protocol 
violation. 
 
Patients should receive PCP prophylaxis. 
 
Filgrastim (G-CSF) is allowed to be used according to clinical judgment. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
A tabular summary of the timing of the mandated observations is included as an appendix 
to the protocol. 
 
Dosimetry studies during phase 1 of the protocol (see section 9.1). 
 
CBC will be obtained about weekly during external beam radiation therapy. 
 
CBC, total bilirubin, AST, creatinine clearance or GFR, and audiograms will be obtained 
at baseline and prior to each cycle of cisplatin-containing chemotherapy. 
 
Serum for anti-idiotype testing (order as Research test: 1 red top tube to be sent to Dr. 
Cheung’s laboratory, Z-1431) will be obtained about every 6 months. 
 
Neuropsychological battery will be performed at “baseline”, and at about 1 year and 4 
years post- completion of treatment. The “baseline” testing may be performed up to 4 
months post-completion of external beam radiation therapy. 
 
The tests in the assessment battery are presented in Table 1 below for parents and 
children by age and by functional domain assessed. The attending neuropsychologist may 


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make necessary modifications to the battery as indicated for an individual patient’s 
special circumstances without it being considered a protocol violation. 


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Table 1. Neuropsychological and Behavioral Battery 
Child’s Age 
Test 
> 3 & 
≤ 4 yrs 
>4 & 
≤ 6 yrs 
> 6 & 
≤ 12 yrs 
> 12 & 
≤ 16 yrs 
> 16 yrs 
Children 
Intelligence 
WPPSI-III (Vocabulary, Block Design) (15 min) 
X 
X 
WISC-IV (Vocabulary, Block Design) (15 min) 
X 
X 
WAIS-III (Vocabulary, Block Design) (15 min) 
X 
Processing Speed/Attention 
WPPSI-III (Symbol Search, Coding) (10 min) 
X 
X 
WISC-IV (Symbol Search, Coding) (10 min) 
X 
X 
WAIS-III (Symbol Search, Coding) (10 min) 
X 
Memory 
NEPSY (Story Memory) (5 min) 
X (3-5 yrs) 
CMS (15 min) 
X (≥ 5 yrs) 
CVLT-C (15 min) 
X (≥ 5 yrs) 
WISC-IV (Digit Span) (5 min) 
X 
X 
WAIS-III (Digit Span) (5 min) 
X 
WMS-III and CVLT-II (20 min) 
X 
Parents 
Attention and Behavior/Social/Em otional Function 
BASC-II (20 min) 
X 
Executive Function 
BRIEF(5 min) 
X 
X 
X 
X 
X 
Quality of Life 
PedsQL 4.0 (Generic Version) 
X 
X 
X 
X 
X 
 
 
Index of Test Abbreviations 
WPPSI-III 
Wechsler Preschool and Primary Scale of Intelligence – 3rd Edition 
WISC-IV 
Wechsler Intelligence Scales for Children – 4th Edition 
WAIS-III 
Wechsler Adult Intelligence Scales – 3rd Edition 
NEPSY 
NEPSY: A Developmental Neuropsychological Assessment 
CMS 
Children’s Memory Scale 
CVLT-C 
California Verbal Learning Test – Children’s Version 
WMS-III 
Wechsler Memory Scale – 3rd Edition 
CVLT-II 
California Verbal Learning Test – 2nd Edition 
BASC-II 
Behavior Assessment System for Children – 2nd Edition 
BRIEF 
Behavior Rating Inventory of Executive Function Scales 
PedsQL 4.0 
Pediatric Quality of Life Inventory Version 4 


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Neuropsychological Battery 
 
As indicated in Table 1 above, the tests that are administered depend on the child’s age at 
the time of the assessment. Procedural information for the tests in the neuropsychological 
and behavioral battery is provided by age group in Appendix II. General information about 
each of the measures in the Neuropsychological and Behavioral Battery is 
provided below. 
 
Wechsler Preschool and Primary Scale of Intelligence – 3rd Edition (WPPSI-III) 
 
The WPPSI-III is a test for assessment of intellectual function in individuals greater than 
2 years of age but less than 7 years of age. Four subtests from this measure will be used: 
1. Vocabulary will be utilized to assess verbal intellectual function; 2. Block Design will 
be utilized to assess nonverbal intellectual function; 3. Symbol Search and 4. Coding will 
be used to assess processing speed. Reliability for this measure has been reported to be 
between 0.83 and 0.95. Criterion and discriminant validity have been established for this 
measure. 
 
Wechsler Intelligence Scales for Children – 4th Edition (WISC-IV) 
 
The WISC-IV is a test for assessment of intellectual function in individuals 7-16 years of 
age. Five subtests from this measure will be used: 1. Vocabulary will be utilized to assess 
verbal intellectual function; 2. Block Design will be utilized to assess nonverbal 
intellectual function; 3. Symbol Search and 4. Coding will be used to assess processing 
speed; and 5. Digit Span will be used to assess short-term memory. Reliability has been 
reported between 0.79 and 0.97 for this measure. Construct validity has been established 
for this measure. 
 
Wechsler Adult Intelligence Scales – 3rd Edition (WAIS-III) 
 
The WAIS-III is a test for assessment of intellectual function in individuals greater than 
16 years of age. Five subtests from this measure will be used: 1. Vocabulary will be 
utilized to assess verbal intellectual function; 2. Block Design will be utilized to assess 
nonverbal intellectual function; 3. Symbol Search and 4. Coding will be used to assess 
processing speed; and 5. Digit Span will be used to assess short-term memory. Very good 
reliability as well as concurrent and criterion validity have been established for this 
measure. 
 
NEPSY: A Developmental Neuropsychological Assessment 
 
The NEPSY is a test for assessment of a wide range of children’s neuropsychological 
function. One subtest, Story Memory, will be utilized for assessing narrative memory in 
children 3 to 5 years of age. Reliability of this measure has been reported to be between 
0.77 and 0.85. Validity has also been established for this measure. 


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Children’s Memory Scale (CMS) 
 
The CMS is a test to assess verbal and visual memory in individuals 5-16 years of age. 
The following subtests will be utilized: Story Memory, Story Memory Recall, Faces, 
Faces Recall, Dot Location, and Dot Location Recall. Reliability and validity have been 
established for this measure. 
 
California Verbal Learning Test – Child (CVLT-C) or Adult 2nd Edition (CVLT-II) 
 
The CVLT-C and CVLT-II involve verbally presenting a list learning task over the course 
of 5 trials. The test measures multiple aspects of how verbal learning occurs, or fails to 
occur, as well as the amount of verbal material learned. The CVLT-C is for individuals 5- 
16 years of age while the CVLT-II is for individuals older than 16 years of age. Test-retest 
reliability of this measure has been reported to be between 0.80 and 0.84. 
 
Wechsler Memory Scale – 3rd Edition (WMS-III) 
 
The WMS-III is a test to assess verbal and visual memory in individuals greater than 16 
years of age. The following subtests will be utilized: Logical Memory I, Logical Memory 
II, Faces I, Faces II, and Spatial Span. Internal consistency reliability has been reported to 
be above 0.70 for this measure. Construct, convergent, and discriminant validity have been 
established for this measure. 
 
Behavior Assessment System for Children – 2nd Edition (BASC-II) 
 
The BASC-II describes the behaviors, thoughts, and emotions of children and adolescents. 
The parent rating scale will be utilized for individuals older than 2 years of age. The 
questionnaire yields composite and scale scores in the domains of externalizing, 
internalizing, school, and other problems as well as adaptive skills and behavioral 
symptoms. Internal consistency reliability has been reported to be between 0.80 and 0.95, 
test-retest reliability between 0.72 to 0.92, and interrater reliability between 0.53 and 
0.86. Content and construct validity have been established for this measure. 
Behavior Rating Inventory of Executive Function Scales (BRIEF) 
The 86-item parent-report version of the BRIEF will be used to assess executive function 
in individuals 6 years of age and older. This pertains to the following functional areas: 
inhibition and shifting of attention, emotional control, initiation, working memory, 
planning, organization and self-monitoring. Internal consistency of the BRIEF has been 
reported from 0.80 to 0.98 and test-retest reliability has been reported between 0.76 and 
0.85. The preschool version of the questionnaire will be utilized for individuals younger 


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than 6 years of age. Construct, content, convergent, and discriminant validity have also 
been established for this measure. 
 
 
 
 
Pediatric Quality of Life Inventory Version 4 (PedsQL 4.0) 
 
The PedsQL 4.0 is a modular approach to measuring health-related quality of life in 
healthy children and adolescents as well as in those with acute and chronic health 
conditions. The Generic Version consists of 23 items, with parent-report for ages 2-4, 5-7, 
8-12, and 13-18. The questionnaire yields domain scores for Physical, Emotional, Social, 
and School Functioning as well as summary scores for Total, Physical Health, and 
Psychosocial Health. Reliability and validity have been established for this measure. 
 
Neuroendocrine assessment performed at baseline will include standing and sitting 
height, Tanner staging of puberty, free thyroxine, TSH, and bone age x-ray. For patients > 
12-years-old or who have ≥ Tanner 2 puberty, LH/FSH, and testosterone or estradiol will 
be assessed. Follow-up examinations will be performed until 5 years post-diagnosis and 
will consist of standing and sitting height, Tanner staging, free thyroxine, and TSH every 
6 months. Growth hormone stimulation testing will be performed if yearly growth 
velocity post-treatment is < 4cm per year or at 2 years post-completion of all therapy, 
whichever occurs first. Bone age x-ray, and LH/FSH, and testosterone or estradiol for 
patients > 12 years or who have ≥ Tanner 2 puberty, will be performed annually. 
 
Assessment of tumor status via brain MRI will be performed about 4 weeks after 
completing RT (pre-cycle 1 chemotherapy), then about every 3 months while on therapy 
(prior to cycles 3, 5, and 7). After completion of therapy, brain MRI scans will be 
performed about every 3 months for 1 year, then every 6 months for 2 years, then every 
12 months for 1 year. Total spine MRI scans will be performed at about 1 year, 2 years, 
and 3 years post-completion of therapy. Subsequent scans will be performed at the 
clinician's discretion and are not mandated by this protocol, but brain MRI scans are 
recommended to be done about annually. 
 
Mandated evaluations including lab work, audiograms, and MRI scans may be performed 
at other (non-MSKCC) centers if deemed clinically indicated by an investigator. Outside 
MRI scans should be submitted to PACS, and reports submitted to medical records, as 
soon as possible. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Toxicities will be assessed via the NCI toxicity criteria. All toxicities will be recorded in 
CRDB until 30 days after the last dose of 131-I-3F8. Subsequently, only toxicities greater 
than or equal to grade 3 will be recorded in CRDB. 


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The most common side effects expected are alopecia (likely), nausea and vomiting due to 
RT and/or chemotherapy (likely), myelosuppression (blood product transfusions and need 
for hospitalization for fever and neutropenia both possible), ototoxicity (likely), 
nephrotoxicity (possible), infertility (possible), and second malignancies due to RT and/or 
chemotherapy (possible). Hospitalizations for therapy administration, fever and 
neutropenia, central venous catheter-associated bacteremia, possible septicemia, 
vomiting, or dehydration will not be considered serious adverse events (SAE) and will 
not be reported to the IRB or FDA. Non-life threatening grade 3 and 4 toxicities clearly 
due to the external beam radiation therapy and/or chemotherapy will not be reported as 
SAE’s. However, life-threatening infections or other life-threatening side effects will be 
considered SAE's and will be promptly reported. 
 
Possible risks include the possibility of unexpected side-effects from the addition of 
radioimmunotherapy to external beam radiation therapy and chemotherapy, and the 
possibility of increased failures from the reduced craniospinal radiation dose and reduced 
boost volume via IMRT. 
 
11.1 
131-I-3F8 
 
For patients who received one test dose and one therapeutic dose on MSKCC protocol 
97-21, no grade 3 or 4 side effects were seen at dose level 1, the dose to be used in this 
study. Among the first 7 patients, acute side effects seen included low-grade fever in 2, 
headache in 2, and emesis in 1. Two patients had no side effects. One patient had elevated 
opening CSF pressure that remained elevated for 36 to 48 hours post-injection of the test 
dose.16 He was observed without any intervention and complications ensued. 
 
11.2 
Radiation therapy 
 
Acute toxicities: Nausea with or without emesis is an anticipated side-effect and may be 
treated with antiemetic medications. Fatigue and a decrease in all blood counts are 
expected. Patients generally have transient complete alopecia and may have permanent 
epilation in some regions. Skin erythema is expected but is rarely severe when IMRT is 
used. Temporary xerostomia and dysphagia as well as diarrhea may occur. 
 
Late effects: The goal of this study is to reduce the incidence and severity of late effects 
of radiation therapy by reducing the dose of external beam radiation and by treating a 
focal boost volume using IMRT. Common late effects of radiation for medulloblastoma 
include neurocognitive dysfunction, growth impairment, hearing loss, and endocrine 
dysfunction (hypothalamic/pituitary, thyroid, and gonadal). Radiation dose to the gonads 
may increase the risk of infertility, especially in girls. Rare but severe late effects may 
include secondary malignancies (approximately 5%) and necrosis of central nervous 
system tissue, including brainstem and spinal cord (approximately 1-2%). 
 
11.3 
Vincristine 


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Neuromuscular effects, peripheral neuropathy, jaw pain, abdominal pain, mucositis, 
nausea and vomiting, hypersensitivity, urinary retention, optic atrophy (rare), blindness 
(rare), constipation, loss of deep tendon reflexes, foot and wrist drop, paresthesia, 
alopecia, convulsion (rare). Hyponatremia (SIADH). Severe soft tissue damage if 
extravasated. Vincristine is very irritating and must not be given intramuscularly, 
subcutaneously or intrathecally. Intrathecal administration of vincristine almost always 
has resulted in death. 
 
11.4 
Lomustine 
 
Myelosuppression. Anorexia, nausea and vomiting, mucosal ulceration. Alopecia. 
Transient liver function abnormalities. Pulmonary infiltrate and fibrosis. Decreased renal 
size, progressive azotemia, kidney failure. 
 
11.5 
Cisplatin 
 
Myelosuppression. Severe nausea and vomiting. Peripheral neuropathy, seizures, and 
high frequency hearing loss. Abnormalities in serum creatinine and creatine clearance, 
renal tubular necrosis, proteinuria, hypocalcemia, hypomagnesem ia. Anaphylactic 
hypersensitivity (tachycardia, wheezing, and hypotension). Optic neuritis, papilledema. 
Transient liver function abnormalities. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUT COME ASSESSMENT 
 
The study’s stopping rule (section 14.0) refers to failures. Failures are defined as 
unequivocal tumor progression or treatment-associated death. Unequivocal tumor 
progression may be determined via radiological studies (head or spine MRI) reviewed by 
the study radiologist or CSF cytology positivity reviewed by the study pathologist. If 
radiological studies suggest possible, but not unequivocal, progression, biopsy should be 
strongly considered. 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from the study if grade 4 toxicity due to the test dose of 131-I- 
3F8 occurs, tumor recurs or progresses post-external beam radiation therapy, if the 
patient is significantly non-compliant with the treatment plan, if they withdraw consent, 
or in the event of death. 
 
14.0 BIOSTATISTICS 
 
A total of 20 patients will be enrolled on this pilot study. We have recently seen 3 to 4 
patients per year potentially eligible for this study at MSKCC, but it is anticipated that the 
unique approach proposed in this protocol will allow accrual to be approximately 6 
patients per year. 


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Children with standard-risk medulloblastoma have been reported to achieve 3-year 
progression-free survival of 86%. Of those who failed, half failed within the first 2 years 
of diagnosis.2 CCG-9961 expanded the approach to a larger group of patients, but 
outcome data are not yet available. If they become available during the conduct of this 
trial, the statistical considerations described in this section will be revised if necessary. 
 
We will stop the trial if 6 or more patients fail before 3 years. The likelihood of stopping 
the trial is only 7% if the true 3-yr PFS is comparable to the control data (85%), and 
increases to 23% if the true PFS is 75% and to 76% if the true 3-yr PFS is only 65%. 
 
Neuropsychological test results will be reported in tabular format for each evaluation 
time (baseline, and annual post-treatment), using means and standard deviations or 
medians and ranges, as appropriate. They will be reported both as raw scores and as 
age/sex-adjusted "z-scores" and tracked for changes over time relative to baseline. Thus, 
given the relatively small sample size of 20 patients, the analysis of these scores for 
evidence of neurotoxicity, or lack thereof, will primarily be descriptive. 
 
Should the results of this trial be encouraging, future possibilities would include use of this 
strategy on a larger scale though the Children's Oncology Group, and/or additional 
institutional study of further decrease of the craniospinal RT dose, possibly in conjunction 
with the use of an increased radioimmunotherapy dose. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1   RESEARCH PARTICIPANT REGISTRATION 
The following person(s) can obtain informed consent: 
Oren Becher, MD 
Ira Dunkel, MD 
Timothy Gershon, MD, PhD 
Stephen Gilheeney, MD, MMS 
Yasmin Khakoo, MD 
Kim Kramer, MD 
David Lyden, MD 
Mark Souweidane, MD 
Suzanne Wolden, MD 
 
Confirm in the electronic medical record that the patient has received the Notice of 
Privacy Practice. This must be obtained before the eligibility confirmation and obtaining 
of the research informed consent. 


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Confirm eligibility as defined in the section entitled Criteria for Patient/Subject 
Eligibility. 
 
Obtain written informed consent, by following procedures defined in section entitled 
Informed Consent Procedures. 
 
All particpants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am - 5:30pm at (646) 735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003.  Registrations can be phoned in or faxed. The completed 
signature page of the informed consent form, the completed signature page of the 
Research Authorization and a completed Eligibility Checklist must be faxed to PPR. 
 
During the registration process registering individuals will be required to answer specific 
eligibility questions and provide the following information: 
 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 
Research Authorization 
[Date] 
MSKCC IRB Protocol# 
Attending of Record (if applicable)  
[Last, First Name] 
Consenting Professional 
[Last, First Name] 
Informed Consent Date 
Participant's Full Name 
[Last, First Name] 
Participant MRN 
 
 
 
15.2 
RANDOMIZATION 
 
Not applicable. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. His or her 
responsibilities will include data collection, abstraction and entry into CRDB, monitoring 
of compliance, and data reporting. 
 
16.1 
QUALITY ASSURANCE 
 
Registration reports will be generated by the RSA on a regular basis to monitor 
patient accruals and completeness of the registration data. Routine data quality 
reports will be generated to assess missing data and inconsistencies. Accrual rates 


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and extent and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study period. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Most patients on this study will be children, adolescents, and young adults, due to the 
nature of this tumor type. Patients of both sexes and all ethnic backgrounds are eligible 
for the study. Participation will be voluntary. Potential benefits include comparable 
event-free survival with hypothesized decreased risk of long-term side effects 
(neuropsychological, neuroendocrine, audiometric, growth). Alternatives include external 
beam radiation therapy alone (3600 cGy craniospinal with posterior fossa boost) or 
reduced-dose radiation therapy (2340 craniospinal with posterior fossa boost) with the 
same chemotherapy that will be prescribed in this study. 
 
Patients are responsible for all costs of their care including (but not limited to) physician 
visits, hospitalizations, medications (except for the 3F8 antibody), MRI scans, and 
laboratory work (except for dosimetry studies). 
 
Patient confidentiality will be protected, but records may be reviewed by appropriate staff 
of the Memorial Sloan-Kettering Cancer Center or the Food and Drug Administration 
(FDA). 
 
17.1 
Privacy 
 
It is the responsibility of the Research Staff to ensure that Memorial Sloan-Kettering 
Cancer Center has on file a written acknowledgment of receipt by the subject of the 
Center’s Notice of Privacy Practices. If the subject has not already done so, he/she must 
sign such an acknowledgment before participating in this study. 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use and 
disclosure of protected health information will be limited to the individuals described in 
the Research Authorization form. A Research Authorization form must be completed by 
the Principal Investigator and approved by the IRB and Privacy Board. 
17.2 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB as soon as possible but no later than 5 calendar 
days. The IRB requires a Clinical Research Database (CRDB) AE report to be delivered 
to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) containing the following 
information: 
Fields populated from the CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 


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• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE 
number written at the top of the report. The report will be forwarded to the FDA by the 
Institutional SAE Manager through the IND Office. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
All patients (or for unemancipated minors, their parents or guardians) will be required to 
sign an IRB-approved form documenting informed consent. The consent form is included 
as an appendix to this protocol. It is written in layman's language and includes 
 
The nature and purpose of this study, its objectives and possible benefits 
 
The length of the study and follow-up required 
 
Risks or discomforts involved 
 
Alternatives to the proposed study 
 
The names of the investigators responsible for the study 
 
The patient's rights to refuse participation and to withdraw from the study 
 
A statement that the patient's confidentiality will be maintained 


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18.1 
Research authorization 
 
Procedures for obtaining Research Authorization: Before any protocol-specific 
procedures are carried out, investigators and/or designated staff will fully explain the 
details of the protocol, study procedures, and the aspects of patient privacy concerning 
research specific information. In addition to signing the IRB Informed Consent, all 
patients must sign the Research Authorization component of the informed consent form. 
The Research Authorization requires a separate signature from the patient. The original 
signed documents will become part of the patient’s medical record, and each patient will 
receive a copy of the signed documents. 
 
19.0 REFERENCES 
 
1. Thomas PRM, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: final 
analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin 
Oncol 2000; 18:3004-3011. 
 
2. Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with 
medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant 
chemotherapy: a Children's Cancer Group study. J Clin Oncol 1999; 17:2127-2136. 
 
3. Goldwein JW, Radcliffe J, Johnson J, et al. Updated results of a pilot study of low dose 
craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive 
neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys 1996; 
34:899-904. 
 
4. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsychologic functioning of survivors 
of childhood medulloblastoma randomized to receive conventional or reduced-dose 
craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol 1998; 16:1723- 
1728. 
 
5. Clayton PE, Shalet SM. Dose dependency of time of onset of radiation-induced growth 
hormone deficiency. J Pediatr 1991; 118:226-228. 
 
6. Oberfield SE, Sklar C, Allen J, et al. Thyroid and gonadal function and growth of long- 
term survivors of medulloblastoma/PNET. In: Green DM, D'Angio GJ, editors. Late 
Effects of Treatment for Childhood Cancer. New York: Wiley-Liss, 1992:55-62. 
 
7. Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. 
Int J Radiat Oncol Biol Phys 1995; 31:1113-1121. 
 
8. Chin D, Sklar C, Donahue B, et al. Thyroid dysfunction as a late effect in survivors of 
pediatric medulloblastoma/prim itive neuroectodermal tumors. Cancer 1997; 80:798-804. 


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9. Shalet SM, Gibson B, Swindell R, Pearson D. Effect of spinal irradiation on growth. 
Arch Dis Child 1987; 62:461-464. 
 
10. Sklar C, Mertens A, Walter A, et al. Final height after treatment for childhood acute 
lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 
centigrays of cranial irradiation. J Pediatr 1993; 123:59-64. 
 
11. Silber JH, Radcliffe J, Peckham V, et al. Whole-brain irradiation and decline in 
intelligence: the influence of dose and age on IQ score. J Clin Oncol 1992; 10:1390-1396. 
 
12. Yeh SD, Larson SM, Burch L, et al. Radioimmunodetection of neuroblastoma with 
iodine-131-3F8: correlation with biopsy, iodine-131-metaiodobenzylguanidine and 
standard diagnostic modalities. J Nucl Med 1991; 32:769-776. 
 
13. Cheung NKV, Kushner BH, Cheung IY, et al. Anti-G(D2) antibody treatment of 
minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin 
Oncol 1998; 16:3053-3060. 
 
14. Bergman I, Pohl CR, Venkataramanan R, et al. Intrathecal administration of an anti- 
ganglioside antibody results in specific accumulation within meningeal neoplastic 
xenografts in nude rats. J Immunotherapy 1999; 22:114-123. 
 
15. Kramer K, Cheung NK, Humm J, et al. Pharmacokinetics and acute toxicology of 
intraventricular 131 I-monoclonal antibody targeting disialoganglioside in non-human 
primates. J Neurooncol 1997; 35:101-111. Update with unpublished data. 
 
16. Kramer K, Cheung NKV, Humm JL, et al. Targeted radioimmunotherapy for 
leptomeningeal cancer using 131-I-3F8. Med Pediatr Oncol 2000; 35:716-718, updated 
with unpublished data 
 
17. Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH. Ommaya reservoirs 
for the treatment of leptomeningeal metastases. Neurosurgery 2000; 47:49-54. 
 
18. Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for 
pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol 
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20.0 APPENDICES 
 
Appendix A: Model order sheet for Day 0 chemotherapy 
 
Appendix B: Summary of timing of required observations