Phase II Study of Intrathecal I-3F8 in Patients With GD2-Expressing Central Nervous System and Leptomeningeal Neoplasms
Phase: PHASE2
Conditions: Brain and Central Nervous System Tumors, Intraocular Melanoma, Lung Cancer, Melanoma (Skin), Metastatic Cancer, Neuroblastoma, Ovarian Cancer, Retinoblastoma, Sarcoma, Small Intestine Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 1 of 23 
 
 
 
 
 
Title:  Phase II study of intrathecal 131I-3F8 in patients with GD2-expressing central 
nervous system and leptomeningeal neoplasms 
Therapeutic /Diagnostic Protocol 
Principal Investigator: 
Kim Kramer, M.D. 
Pediatrics 
(212) 639-6410 
 
Co-Principal Investigator:   Shakeel Modak, MD 
Pediatrics 
(212) 639-7623 
 
Investigator(s): 
ELLEN BASU, M.D., PhD. 
MARK BILSKY, M.D. 
JORGE CARASQUILLO, M.D. 
KEVIN DE BRAGANCA, MD 
IRA J. DUNKEL, M.D. 
JASON LEWIS, PhD. 
STEPHEN ROBERTS, MD 
STEPHEN GILHEENEY, MD, MMS 
ANDREW VICKERS, PhD. 
JOHN HUMM, Ph.D. 
YASMIN KHAKOO, M.D. 
BRIAN H. KUSHNER, M.D. 
STEVEN LARSON, M.D. 
SHAKEEL MODAK, M.D. 
MARK M. SOUWEIDANE M.D. 
SUZANNE WOLDEN, M.D. 
NEETA PANDIT-TASKAR, M.D. 
PAT ZANZONICO, Ph. D 
SATISH TICKOO, M.D. 
 
 
Consenting Professional(s): KIM KRAMER, MD 
SHAKEEL MODAK, MD 
BRIAN H. KUSHNER, MD 
ELLEN BASU, MD, PHD 
STEPHEN GILHEENEY, MD, MMS 
STEPHEN ROBERTS, MD 
 
 
 
 
1. 
PROTOCOL SUMMARY………………………………………………….. 
3 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 2 of 23 
 
 
2. 
OBJECTIVES……………………………………………………………….. 
3 
3. 
BACKGROUND AND RATIONALE……………………………………… 
3 
4. 
STUDY DESIGN OVERVIEW…………………………………………….. 
7 
5. 
DRUG INFORMATION ..........................................................................…. 
8 
6. 
CRITERIA FOR PATIENT ELIGIBILITY………………………………. . 
8 
6.1 INCLUSION CRITERIA 
6.2 EXCLUSION CRITERIA 
7. 
RECRUITMENT PLAN…………………………………………………… 
9 
8. 
PRE-TREATMENT EVALUATION............................................................ 
10 
9. 
TREATMENT PLAN .................................................................................... 
10 
10. 
EVALUATION DURING TREATMENT.................................................... 
11 
11 
ASSESSMENT OF TOXICITY .................................................................... 
12 
12. 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME…………… .. 
12 
13. 
CRITERIA FOR REMOVAL…………………………………………….... 
13 
14. 
BIOSTATISTICAL CONSIDERATIONS.................................................... 
14 
15 
SUBJECT REGISTRATION/RANDOMIZATION……………………… . 
14 
15.1 REGISTRATION 
15.2 
RANDOMIZATION 
16. 
DATA MANAGEMENT ISSUES………………………………………… 
15 
17. 
PROTECTION OF HUMAN SUBJECTS .................................................... 
16 
18. 
INFORMED CONSENT PROCEDURES……………………………….. .. 
16 
19 
REFERENCES .............................................................................................. 
18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0 
Protocol Summary and/or Schema 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 3 of 23 
 
 
 
 
 
 
This study is designed to test the efficacy and the cumulative toxicity of intrathecal (administered 
through Ommaya reservoir) 131I-3F8 in children and adult patients with GD2-expressing central 
nervous system/leptomeningeal neoplasms.  Survival is extremely poor in these patients, with 
median survival of only a few months. In a prior phase I trial, 2 of 13  patients had negative 
remain alive and in complete remission after 4 years. Patients in this protocol will receive 
intrathecal 131I-3F8  weekly for a total of four treatment cycles. About 130 patients will be 
accrued on this study. The primary endpoint is overall survival at six months. 
 
2.1 
Objectives and Scientific Aims 
 
• To determine whether, in patients with GD2-expressing central nervous 
system/leptomeningeal neoplasms, the activity of intrathecal 131I-3F8  is sufficiently 
promising to warrant further study. Promising activity is defined as a 6 month overall 
survival rate of 25% or more. 
 
• To determine the response rate to 131I-3F8 in this population. 
• To determine the cumulative toxicities of serial injections of intrathecal 131I-3F8. 
 
• To describe the effects of HAMA (human-anti- mouse antibody) on cerebrospinal fluid 
(CSF) and serum pharmacokinetics following multiple injections of 131I-3F8 
 
3.1 
Background and Rationale 
 
3.2 
Disease background 
 
With the central nervous system as a sanctuary site, it is increasingly recognized that 
improved treatment of systemic cancers is associated with a higher incidence of central 
nervous system relapse and neoplastic meningitis1-3. By the time neuraxis metastases are 
clinically evident, limited palliative options exist;   median survival time for most 
malignancies is 4-14 months2,4,5.  Stereotactic radiosurgery for small, single metastases 
(<4cm diameter), surgery for solitary metastases and radiotherapy are used for palliation. 
New techniques including preoperative functional imaging, image-guided neurosurgery, 
intraoperative ultrasound and cortical mapping have improved the success of aggressive 
surgical resection, and lowered the associated surgical morbidity and mortality6,7. 
However, novel therapeutic agents that may prevent or delay the progression of disease 
are needed to improve overall outcome. 
 
 
 
 
 
 
3.3 
Rationale for targeted immunotherapy 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 4 of 23 
 
 
 
 
Tumor-selective radioimmunotherapeutic strategies may have potential in inhibiting 
leptomeningeal tumor growth8-10. The systemic administration of tumor specific 
monoclonal antibodies has proven useful in the detection and targeted treatment of ma ny 
human tumors11,12. GD2 expression has been demonstrated in neuroblastoma, small cell 
lung cancer, retinoblastoma, melanoma, high grade astrocytoma, medulloblastoma, 
osteosarcoma, desmoplastic small round blue cell tumor, and other sarcomas. Expression 
in normal human tissue is limited to nervous tissue. 3F8 is a murine IgG3 antibody 
against GD2. The intravenous administration of 3F8 has proven anti-tumor effects and 
has been incorporated into treatment strategies improving the disease-free survival for 
patients with metastatic neuroblastoma since 198913. Acute side effects including pain 
and urticaria are manageable. No long-term side effects have been observed over a 15 
year period.  3F8 is easily labeled with 131-I, enabling sensitive and accurate imaging14. 
 
3.4 
Results of Phase I Intraventricular 131 -I-3F8 
 
3.4.1 Dosimetry 
 
We studied the radiation dose to the CSF following intraventricular injection of 131I-3F8 
in patients diagnosed with GD2-positive LM disease, compared radiation dose estimates 
by CSF sampling and ROI (regions of interest) analyses, and monitored acute and chronic 
toxicities following drug administration in a phase I study. Fifteen patients (ages 1-61) 
received a tracer dose (37-74 MBq, 1-2 mCi) and a second therapeutic injection (370-740 
MBq, 10-20 mCi).   Dosimetry was evaluated by whole-body gamma camera scanning  
(4, 24, 48 hours), serial CSF and blood sampling. Pre- and post- treatment clinical, 
radiographic and cytologic status were evaluated.  Total absorbed dose to the CSF was 
1.12 – 13.0 Gy, 3.2 – 41.5 Gy to the ventricles and 1.0 – 13.7 Gy to the spinal column. 
Clearance half- life was 12.5 hr (3.5 - 44 hr). Average ratio of the therapy/tracer 
administration (Gy/MBq), was 0.88 (±0.58) and 1.08 (±0.66) by CSF counting and ROI 
analysis, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
Tumor Type 
Acti vi ty (mCi) 
administered 
Dose to 
Blood 
Dose to 
CSF 
Dose ratio: 
CSF:Blood 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 5 of 23 
 
 
 
 
 
(c Gy) 
(c Gy) 
#1 
melanoma 
11.5 
26 
472 
18 
#2 
ependymoma 
9.5 
14 
141 
10 
#3 
rhabdoid 
9.7 
15 
114 
7.6 
#4 
retinoblastoma 
1.1 
1 
62 
44 
#5 
rhabdoid 
10.4 
19 
771 
40 
#6 
PNET 
11.5 
12 
610 
50 
#7 
medulloblastoma 
14.3 
28 
319 
11.4 
#8 
medulloblastoma 
14.3 
87 
338 
4 
#9 
neuroblastoma 
22.6 
38 
362 
9.5 
#10 
medulloblastoma 
10.7 
35 
441 
12.6 
#11 
neuroblastoma 
22.2 
30 
1301 
44 
#12 
medulloblastoma 
21.4 
33 
315 
9.5 
#13 
PNET 
19.7 
10 
396 
38 
#14 
neuroblastoma 
21.8 
112 
908 
8.1 
#15 
ependymoma 
20.1 
98 
1338 
13.6 
 
3.4.2 Pharmacokinetics 
 
Peak CSF radioactivity was generally achieved within the first hour of injection. After an initial 
antibody redistribution phase within the CSF compartment, the CSF biological half- life was 3- 
12.9 hours by direct CSF samples, and was in close agreement with the CSF gamma camera 
estimates derived from region of interest data (7.2-13.1 hours). The average radiation dose to 
the blood was 0.48 Gy (0.14-1.3). Activity levels in the blood remained low (<0.01% injected 
dose/cc), peaking 12-48 hours. The activity in the CSF fell much more rapidly than the physical 
half- life of 8 days; the concentration of the activity (uCi/cc) dropped by two orders of magnitude 
within 2-3 days after administration. The dose contribution for the time interval 72 hours to 
infinity was less than 10 %. 
 
3.3.3 Acute toxicities 
 
No toxic deaths were associated with treatment. Acute toxicity including headache, fever, 
vomiting were self- limited are generally observed in the first 24-48 hours after therapy. At the 
higher dose levels, transient elevations in intracranial pressure (n=1), asymptomatic bradycardia 
(n=1) and chemical meningitis (n=1) were seen. All symptoms resolved within the first 2-7 days 
post therapy. No long term toxicities have been seen 19 months post- injection. 
 
Patient 
Tumor Type 
Total Dose 131-I- Acute Toxicity*† 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 6 of 23 
 
 
 
 
 
3F8 Administered 
#1 
melanoma 
11.5 
h/n/ v/f after dose 1; exacerbation of pre-existing 
communicating hydrocephalus after dose 2 
#2 
ependymoma 
9.5 
h/n/ v/f 
#3 
rhabdoid 
9.7 
h/n/ v/f 
#4 
retinoblastoma 
1.1 
Gr 2 h- exacerbation of pre-existing 
communicating  hydrocephalus 
#5 
rhabdoid 
10.4 
v/ h 
#6 
PNET 
11.5 
h/n/ v/f 
#7 
medulloblastoma 
14.3 
h/n/ v/f, leg pain 
#8 
medulloblastoma 
14.1 
h/n/ v/f 
#9 
neuroblastoma 
22.6 
h/n/ v/f 
#10 
medulloblastoma 
10.7 
h/ v, bone pain 
#11 
neuroblastoma 
22.2 
Gr 4 h/n/ v/ f, back pain, hyponatremia 
#12 
medulloblastoma 
21.4 
h 
#13 
PNET 
19.7 
Grade 3 h-exacerbation of pre-existing headache 
and leg pain/n/ v/f, bradycardia 
#14 
neuroblastoma 
21.8 
h/f 
#15 
ependymoma 
20.1 
Gr 3 h/n/ v/ f, chemical meningitis 
*toxic ities were grade 1 or 2 unless otherwise indicated. 
†h=headache, n=nausea, v=vomiting, f=fever 
 
 
3.3.4 Response 
 
Although not the primary objective of this study, of 13 evaluable patients, clinical improvement 
(n=2, patient #1, patient #6), radiographic improvement (n=2, patient #1, patient #13), and 
cytology clearing of malignant cells (n=2 patient #11, patient # 13) was observed. 
Patient #11 cleared CSF of malignant cells after therapy administration, but was observed to 
have a new spinal metastasis 1 month after treatment. She is alive with disease now 19 months 
since treatment. 
 
 
Patient #14 cleared the CSF of malignant cells immediately after injection and has remained off 
further therapy with negative CSF cytology by Ommaya and lumbar puncture sampling on 
multiple samplings over a 14 month period; resolution of 3 areas of enhancement on MR 
imaging was also noted. Patient #14 had an isolated CNS relapse of neuroblastoma. He was 
treated with surgery, chemotherapy, cranio-spinal radiation therapy, intraventricular 131-I-3F8 
and intravenous 3F8. He remains in complete remission now 28 months since relapse and >1.5 
years post-131I-3F8. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 7 of 23 
 
 
 
 
Although all patients had CSF flow throughout the subarachnoid space, variability in CSF flow 
dynamics were noted on baseline Indium –DTPA studies. Such variability may be attributed to 
prior therapies, the presence of bulk and microscopic disease, or the presence of an indwelling 
shunt all affecting CSF flow and reabsorption. This may in part account for the interpatient 
variability in CSF dosimetry and clearance is this diverse patient population. Although no 
patient in this study had measurable serum human-anti- mouse antibody (HAMA) titers at the 
time of treatment, this would contribute to faster clearance in the systemic circulation and 
decreased dose to the blood. Previous experiments have shown that, because of the blood-brain 
barrier, systemic production of HAMA is associated with low titers in the CSF, namely a 14-22 
fold difference of HAMA in the CSF versus the blood. In the presence of systemic HAMA, serial 
injections of intrathecal 131I-3F8are expected to deliver comparable doses of radiation to the CSF 
space, but with even more rapid systemic clearance. This observation is critical since 
myelosuppression has been the dose- limiting toxicity of most radioimmunotherapy trials to date. 
We concluded from the phase I study that intraventricular administration of 131I-3F8 targeting 
disialoganglioside GD2 achieves a favorable CSF to blood ratio, is associated with significant 
but manageable acute toxicities, and may have clinical utility in the treatment of some patients 
with GD2-positive LM cancers. 
 
There are few other therapeutic options to offer this patient population. This study fills an unmet 
need at this institution for both pediatric and adult patients and capitalizes on Memorial Sloan- 
Kettering‟s Cancer Center‟s unique contribution to the field of targeted immunotherapy. 
 
3.4      Preliminary Results of phase II study: initial cohort of patients 
8 of 10 patients treated with 4 injections of  131I-3F8 as a consolidative therapy following 
various chemotherapy or external beam radiotherap y doses remain alive and in cytologic and 
radiographic remission (3 mo+, 8 mo+, 10 mo+, 12 mo+, 12 mo+, 12 mo+, 18 mo+, 22 mo+). 3 
of these patients had CNS neuroblastoma, and remain alive and in remission 11 mo, 15 mo and 
24 mo since detection of CNS disease. This is significant in that the median time to death from 
the onset of CNS disease was 5.4 months in our previously published non- intra-Ommaya therapy 
experience. 3 patients with active disease progression at the time of study enrollment all had 
radiographic progression of disease after 1 injection. Toxicities included self- limited headache, 
fever, and vomiting generally resolved within 24-48 hours. No late toxicities have been seen in 
the 5 patients who remain in remission off therapy for >1 year since 131I-3F8 injections. Accrual 
is ongoing. These results support the need to continue this study in a larger cohort of patients, 
with the goal of decreasing the time between injections and further decreasing the toxicity profile 
by increasing the specific activity. 
 
 
 
4.1 
Overview of Study/Design Intervention 
 
4.2 
Design 
This is a phase II single-arm open- label study that will define responses to therapy with 
weekly intrathecal 131I-3F8 in patients with central nervous system/leptomeningeal GD2- 
expressing disease. Dosimetry at plaques of disease and surrounding normal tissues will be 
determined by a pre-treatment 131I-3F8 (2 mCi) scintigraphy. Pharmacokinetics of the dosimetry 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 8 of 23 
 
 
 
 
dose of intrathecal 131I-3F8 will be determined by measurements of counts per minute (cpm) of 
serial CSF and serum samples. 
Patients will then receive intrathecal 131I-3F8 treatment cycle (10 mCi/cycle) approximately 
weekly for a total of 4 cycles.  A total dose of 40 mCi 131I-3F8 will be administered. Since the 
phase I study demonstrated a CSF dose of 15-60 cGy/mCi to the CSF, maximum total anticipated 
CSF dose of 4 x 10 mCi of 131I-3F8 injections would be 600-2400 cGy; dose to the spinal cord and 
normal brain is negligible given the short range path length of 131I.  At an estimated tumor to CSF 
dose ratio of 5:1, tumor dose could be as high as 3000-12000 cGy.  Myelosuppression is not 
anticipated at this dose level. The chosen 40 mCi maximum 131I dose is considerably lower than 
the MTD reported using other intrathecal  131I-monoclonal antibodies for neoplastic meningitis on 
other phase I studies.10   To avoid the risk of radiation toxicity in patients who have had previous 
craniospinal radiation,  the CSF radiation dose delivered by 131I-3F8 therapy injections will not 
exceed  2400 cGy based on the CSF dosimetry estimates from pre-treatment 131I-3F8 / 
scintigraphy scans. This may require the elimination and/or dose reduction of the 3rd or 4th  
injection for patients who have had previous craniospinal radiation. There will be no dose 
modifications for patients who have not had craniospinal radiation. 
Response to therapy will be 
assessed by neurologic examination, radiographic imaging and CSF cytology analysis. Other aims 
will be met by monitoring patients clinically and biochemically for toxicity and by serum 
assessment of HAMA. 
 
It is quite possible that 131I-3F8 may lead to disease stabilization without complete or 
partial responses in this population with advanced disease. We therefore propose overall survival 
at six months as the primary endpoint of this study. Leptomeningeal disease is rapidly fatal. 
Though some prior studies have reported survival at six months of around 15% these included 
patients receiving chemotherapy. Patients receiving 131I-3F8 at MSKCC have completed all 
chemotherapy and are not anticipated to have further oncologic treatment after progressing on 
this protocol. If 131I-3F8 has zero effect, we would therefore expect no more than 5% of patients 
to survive for six months. We will therefore use 5% overall survival at six months as the null 
hypothesis with 25% overall survival at six months as the alternative hypothesis. 
 
Roadmap for the imaging dose of 131I-3F8 
Day -5: 
Start SSKI and Liothyronine orally 
Day -1: 
Start Dexamethasone (start ~24 hrs pre- injection and tapered over ~1-2 
days) orally 
Day 0: 
Injection of  131I-3F8 (2 mCi) intrathecally or by Ommaya 
 
Road map for eac h week ly tre atme nt c yc le o f 131I-3F8 
Day -5: 
Start SSKI and Liothyronine orally 
Day -1: 
Start Dexamethasone (start ~24 hrs pre- injection and tapered over ~1-2 
days) orally 
Day 0: 
Injection of  131I-3F8 (10mCi) intrathecally or by Ommaya 
 
* Dose adjustments for age <3 years based on CSF volume: 
< 1year: 50% dose reduction/injection 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 9 of 23 
 
 
 
 
1-3 years: 33% dose reduction/injection 
>3 years: Full dose 10 mCi 131I-3F8 per injection 
* Dose adjustments for patients with previous craniospinal radiation: The total maximum target 
CSF dose will be 2400 Gy. This may require a decrease or elimination of the 4th injection to 
prevent the risk of radiation toxicity for these patients. No dose adjustment will be made for 
patients who have not received prior craniospinal radiation. 
 
4.3 
Intervention 
Patients will receive 10mCi intrathecal 131I-3F8 per week. Patients will be pre- medicated 
with dexamethasone to prevent possible meningeal inflammatory reaction, Liothyronine and 
SSKI to prevent thyroid accumulation, and acetaminophen and diphenhydramine in anticipation 
of possible allergic reaction and fever. 
4.2.1 Clinical Evaluation 
Patients will have pre- and post-treatment clinical assessment including neurologic examination, 
hematology and serum chemistries, and CSF analysis. Patients without objective disease 
progression and without unexpected grade 4 toxicity (controllable fever, headache, nausea, 
vomiting not included) will be eligible for a total of 4 treatment cycles. No patient will receive 
more than 4 treatment cycles. 
4.2.2 Response 
MRI studies will be obtained at baseline and after the last injection. Stable disease may be an 
indicator of response, since most patients with leptomeningeal cancers (especially those with 
visible disease) historically die within a short time (4 weeks). 
4.2.3 Dosimetry 
Pharmacokinetics and dosimetry of the dosimetry dose of intrathecal 131I-3F8 will be determined 
by measurements of counts per minute (cpm) of serial CSF and serum samples and serial 
scintigraphy images obtained at approximately 4, 24 and 48 hours after injection. Dosimetry 
estimates will be calculated by Medical Physics physicists in the Dept of Nuclear Medicine. 
 
5.0      Therapeutic/Diagnostic Agents 
5.1       131-I-3F8: IND # - BB-IND-2299 
5.2 
Source and pharmacology: Monoclonal antibody 3F8 is a murine IgG3 antibody. It is 
raised in BALB/c mice and specifically recognizes the ganglioside GD2. 
5.3 
Formulation and stability: 3F8 is stored as 2 mg/ml in pH 4.2 citrate phosphate buffer. 
Vials are stored at -80 C. 3F8 is stable at –80oC, and at –20oC for at least 2 years. For intrathecal 
administration, 131I-3F8 is diluted into 5% human serum albumin and millipore (0.2 um) filtered 
before use. Total anticipated amount to be infused per injection is 2-10 mCi, and about 2 mg of 
total (cold + hot) 3F8. . 
 
5.4 
Route of administration: A volume of ~1.0-4.0 ml will be administered intraventricularly 
via Ommaya catheter at a rate of ~1.0ml over 3-4 minutes using sterile technique. . 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 10 of 23 
 
 
 
 
5.5 
Supplier: 3F8 is commercially prepared by GBI as an investigational agent under cGMP 
conditions as required by the US FDA, and purified by column chromatography. All lots have to 
pass sterility, safety, pyrogen, murine viruses, and DNA testing before human use. 131I-3F8 is 
prepared by the Radiochemistry and Molecular Imaging Probes Core Facility under the direction 
of Dr. Jason Lewis. It is approved for human use via IND BB-IND-2299. Radiolabeling is 
performed either on the day of patient  infusion or one day prior.  Administration to patients 
occurs within 24 hours of the end-of-synthesis time.. 
 
6.0      Criteria for Subject Eligibility 
 
6.1 
Patient/subject Inclusion Criteria 
6.1.1 Patients must have a histologically confirmed diagnosis of a malignancy known to express 
GD2. Such tumors include medulloblastoma/primitive neuroectodermal tumor of the CNS, high 
grade astrocytomas, malignant glioma, neuroblastoma, retinoblastoma, ependymoma, rhabdoid 
tumors, sarcomas, melanoma or small cell lung carcinoma. For patients with other tumor types, 
GD2 expression must be confirmed by immunohistochemical staining and assessed by the 
Department of Pathology using prior frozen tissue, bone marrow or CSF cytology (send to 
Research Lab). 
6.1.2 Patients must have CNS/ leptomeningeal disease including high risk medulloblastoma, 
or a CNS/leptomeningeal malignancy which is refractory to conventional therapies, or for which 
no conventional therapy exists, OR a recurrent brain tumors with a predilection for 
leptomeningeal dissemination (medulloblastoma, PNET, rhabdoid tumor). 
6.1.3 Patients must have an absolute neutrophil count (ANC) > 1000/ul and a platelet count > 
50,000/ul. 
6.1.4 Patients may have active malignancy outside the central nervous system. 
6.1.5 Patients who have a programmable shunt will not be excluded. 
6.1.6 Both pediatric and adult patients of any age are eligible. 
6.1.7 Patients or a legal guardian will sign an informed consent form approved by the IRB and 
obtained by the Principal or a Co- Investigator before patient entry. Minors will provide assent. 
 
 
 
6.2 
Patient /Subject Exclusion Criteria 
6.2.1 Patients with obstructive or symptomatic communicating hydrocephalus. 
6.2.2 Patients with an uncontrolled life-threatening infection. 
6.2.3 Patients who are pregnant: Pregnant women are excluded for fear of danger to the fetus. 
Therefore negative pregnancy test is required for all women of child-bearing age, and 
appropriate contraception is required during the study period. 
 
6.2.4 Patients who have received cranial or spinal irradiation less than 3 weeks prior to the start 
of this protocol. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 11 of 23 
 
 
 
 
6.2.5 
Patients who have received systemic chemotherapy (corticosteroids not included) less 
than 3 weeks prior to the start of this protocol. 
 
6.2.6 Severe major organ toxicity. Specifically, renal, cardiac, hepatic, pulmonary, and 
gastrointestinal system toxicity should all be less than or equal to grade 2. Patients with stable 
neurological deficits (because of their brain tumor) are not excluded. Patients with <= 3 hearing 
loss are not excluded. 
 
6.2.7 Patients must have no rapidly progressing or deteriorating neurologic examination. 
 
6.2.8 Patients who have already received >45 Gy to the craniospinal radiation or >72 Gy focal 
brain radiation. 
 
 
7.0 
Recruitment Plan 
 
Patients will be offered the opportunity to participate in this trial if they have the diagnosis of a 
CNS/leptomeningeal solid tumor (including neuroblastoma, small cell lung cancer, melanoma, 
retinoblastoma, high grade astrocytoma, medulloblastoma, central nervous system PNET, 
malignant glioma ependymoma, rhabdoid tumors, osteosarcoma, DSRCT and other tumors that 
are GD2-positive) and fulfilled the eligibility criteria.  The opportunity to participate will be 
offered to all patients, including women and minority groups. Informed consent will be obtained 
from the patients or their legal guardians by an investigator authorized to obtain consent. Patient 
will not receive any payment for their participation in this study. 
 
 
8.0 
Pretreatment Evaluation 
 
8.1 
Complete history, physical exam, and detailed neurologic exam. 
8.2 
CBC with differential and platelet count. 
 
8.3 
Serum electrolytes, creatinine, AST,  total bilirubin, TSH, HAMA, and in child-bearing 
females, beta-HCG. 
 
8.4 
CSF cytology, total protein, glucose and cell count (these are baseline routine, not for 
research purposes), HAMA. 
8.5 
Baseline MRI of the brain and spine (with and without gadolinium) within 3 weeks of the 
first injection. 
8.6 
111Indium Ommaya patency/CSF flow study prior to the first injection. 
 
9.0 Treatment/Intervention Plan 
 
9.1 General outline: Following an initial test dose of 2 mCi 131I-3F8 for dosimetry, four  weekly 
injections 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 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 12 of 23 
 
 
 
 
shunt tubing has confirmed acceptable CSF flow, the shunt may be used for the administration of 
131I-3F8. Patients can be treated in an outpatient setting or may be hospitalized overnight for 
supportive care after each injection. All patients will be monitored in accordance with Radiation 
Safety Guidelines. Patients are not anticipated to need isolation post-treatment. 
9.2 
Premedications for 131I-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 5 da ys prior to the test dose with 131I-3F8: 
SSKI: 7 drops daily (to begin 5 days pre- injection and to continue for 2 weeks after the last 
injection) 
 
Liothyronine (Liothyronine): 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 after the last 
injection) 
 
To start 1-2 da ys prior to each 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 week) 
 
To be started about 1 to 2 hours before each injection: 
 
Hydroxyzine (Vistaril): 1 mg/kg IV, then Q 4 hours x 24 hours post- injection (maximum 50 mg). 
 
Acetaminophen (Tylenol): 10 mg/kg po before injection and then Q4 hours x 24 hours post- 
injection (maximum 325 mg) 
 
Lorazepam (Ativan): 0.05 mg/kg IV x 1 (maximum 1mg) 
 
Hydromorphone (Dilaudid): 0.015 mg/kg/dose x 1, then PRN (maximum 1mg) 
 
9.2.1  Intraventricular administration of all drugs 
The antibody 3F8 is radiolabeled with iodogen method under the supervision of Dr. S Larson and 
J Lewis according to the FDA requirements specified by the IND. All patients will have an 
intraventricular reservoir (i.e. Ommaya reservoir). The Ommaya catheter site will be prepped 
and draped. A volume of CSF equal to the volume of drug to be injected will be removed, the 
drug will be injected slowly so as not to exceed a rate of 1ml/min. Sterile HSA will be flushed 
into the reservoir followed by autologous CSF flush.  After 131I-3F8 dosimetry injections, 
patients will have approximately 0.5 cc CSF and 1-2 cc blood obtained for radioactivity levels at 
approximately, 1 hr, 2 hr, 4-6 hr, 18-24 hr, 44-48 hr, 66-72 hr and ~5-7 days post injection. 
 
9.3 
Treatment and dosimetry 

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Page 13 of 23 
 
 
 
 
9.3.1 * Dose adjustments for age <3 years based on CSF volume: 
< 1year: 50% dose reduction 
1-3 years: 33% dose reduction 
>3 years: Full dose, 10 mCi 131I-3F8 per injection 
+averaging approximately 5 mCi of radioiodine/mg 3F8 
* Dose adjustments for patients with prior craniospinal radiation: 
The total maximum target CSF dose by 131I-3F8 injections will be 2400 Gy for patients with 
prior craniospinal radiation based on 131I-3F8/ scintigraphy dosimetry  estimates. This may 
require a decrease or elimination of the 3rd or 4th injection to prevent the risk of radiation toxicity 
for these patients. 
 
 
9.3.2 Dosimetry will be assessed by 
 
*CSF and blood (2 ml/sample) obtained for radioactivity levels at approximately, and 1, 2, 4, 18, 
and 44 hours after 131I-3F8 dosimetry injection. (CSF samples obtained here are for research 
purposes).  At the time of 131I-3F8 scintigraphy analysis, routine dosimetry estimations will be 
derived from the serial scintigraphy studies at approximately 4, 24, and 48 hours. 
Pharmacokinetic data obtained from scintigraphy 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, CSF space, blood and visible tumor 
nodules. 
 
9.4 
Tumor genetic studies 
 
9.4.1 Tumor DNA and matched normal DNA will be used for genomic DNA sequencing, 
copy number analysis and methylation profiling; tumor RNA will be used for 
transcriptome and microRNA profiling. The samples will not have any associated patient- 
specific identifying information, but will be linked to clinical information such as patient 
age, gender, tumor stage, tumor recurrence status, and tumor site.  The identity of 
individual patients will be kept in a secure database registered with the Office of Clinical 
Research, under the supervision of Dr. Modak according to HIPAA regulations.  This 
testing will be done in Dr. Cheung‟s Lab (Z740).  These tests will be done only on the 
tumor left over after testing for 3F8 binding. 
 
9.4.2 Immunohistochemical profile: Frozen tumors will collected to be tested for tissue 
antigens and gangliosides [including but not limited to GM2, GD2, GD3].  These tests 
will only be done on patients whose tumors are not known to bind to 3F8, and therefore 
are consented to the assessment arm of the protocol. 
 
10.0 Evaluation During Treatment/Intervention 
10.1 Evaluation during treatment 
10.1.1. Physical exam prior to each injection and after the 4th   injection 
10.1.2. Neurologic exam prior to each injection and after the 4th injection 

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10.1.3. MRI of head and spine at baseline and after 4th injection 
10.1.4. CSF Flow study prior to the first  injection 
10.1.5. CBC with differential including platelets prior to each injection and ~1-3 
months after 4th injection 
10.1.6. Comprehensive profile to each injection and ~1-3 months after 4th injection. 
*Thyroid protection such as SSKI and Cytomel will be adjusted to ensure 
adequate thyroid saturation. Serum HAMA (send to  Dr. Cheung Laboratory) 
prior to each injection . 
10.1.7. B-HCG for females of child-bearing age prior to injections 1 and 3. 
10.1.8. CSF and Blood (2 ml each sample) at ~1-4 hr, 18-24 hours, and 42-48 hours 
after the 131I-3F8 dosimetry injection 
 
Observation 
Prior to 
test dose 
with 
131I-3F8 
Post test 
dose 
with 
131I-3F8 
Prior to 
1st 
injection 
Post 1st 
131I-3F8 
Injection 
Prior to 
2nd   131I- 
3F8 
injection 
Post 2nd 
injection 
Prior to 3rd 
131I-3F8 
injection 
Post 
3rd 
inject 
ion 
Prior to 
4th   131I- 
3F8 
injection 
Follow- 
up, 1-3 
months 
after 4th 
injection 
Physical 
e xa mination 
X 
X 
X 
X 
X 
X 
Neurologic e 
xa mination 
X 
X 
X 
X 
X 
X 
MRI head 
X 
X 
MRI spine 
X 
X 
CSF flow study 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
Comprehensive 
profile 
X 
X 
X 
X 
X 
X 
CSF  cytology 
X 
X 
Serum HAMA 
X 
X 
X 
X 
X 
B-HCG (when 
applicable) 
X 
X 
Scintigraphy 
imaging 131I-3F8 
X 
CSF and Blood 
(2ml/sample)131I- 
3F8 
X 
 
10.3 Pharmacokinetic Studies 
Study of the intrathecal pharmacokinetics and blood pharmacokinetics of the 131I-3F8 dosimetry 
dose will be performed. Patients will have approximately 0.5cc of CSF obtained pre- injection, 1 
hr, 2 hr, 4-6 hr, 18-24 hr, and 42-48 hr post injection. Blood samples (2 cc of plasma) will be 
obtained at the time of CSF sampling, and may be obtained via a central venous catheter (if 
present) or an indwelling heparin lock venous catheter. Additional samples may be collected if 
needed to adequately characterize pharmacokinetics. Radioactivity will be counted in a gamma 
counter. The count information will be used for pharmacokinetic data. 
10.4 Scintigraphy 
Patients will have the CNS (head  and upper spinal cord) imaged  by 131I-3F8 scintigraphy 
approximately 4, 24, 48 hours. 

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10.5 Concomitant Therapy: 
Patients may receive systemic chemotherapy starting 3 weeks from the second injection of 131I- 
3F8. Patients must wait at least 3 weeks before they can resume injection 3 or 4. This will allow 
assessment of response while avoiding widespread progression of systemic disease. 
 
 
11.0 Toxicities/Side Effects 
 
11.1 Toxicities will be assessed via the NCI toxicity criteria (CTC 3.0). All toxicities will be 
recorded in CRDB until 30 days after the last dose of 131-I-3F8. 
11.2 Toxicities associated with 131I-3F8 include fever, headache, nausea and vomiting, pain 
allergic reaction, and/or drug extravasation. Hospitalizations for therapy administration, 
hyperglycemia or lymphopenia related to dexamethasone and self- limited fever, vomiting, or 
headache will not be considered serious adverse events (SAE) and will not be reported to the 
IRB or FDA though they will be captured in the institutional database. However, life-threatening 
infections or other life-threatening side effects will be considered SAE's and will be promptly 
reported to the Institutional Review Board of MSKCC and to the FDA. 
11.3 Neurologic changes during the study period which meet the criteria for grade  4 
neurotoxicity will be assessed by study physicians as being unrelated, possibly or probably 
caused by the injection. In the absence of clear evidence of tumor progression, it may be 
assumed that new signs and symptoms are treatment related. 
11.4 
Any deaths will be reviewed during the study by the Principal Investigators prior to 
subsequent entry of further patients. 
 
12.0 Criteria for Therapeutic Response/Outcome Assessment 
 
12.1 Adequacy of trial: All patients who fulfill the eligibility requirements, receive two treatment 
injections of 131I-3F8 and undergo extent of disease evaluation will have an adequate trial. 
12.2 The primary endpoint is overall survival at six months from the date of 1st 131I-3F8 
injection. 
12.3 Response duration is calculated from the 1st day of treatment with 131I-3F8. 
12.4 Patients developing progressive disease will be considered a treatment failure under this 
protocol. 
12.5 Response Definitions 
12.5.1 Comp lete Respo nse (CR) 
Cytologic and radiographic CR will be evaluated separately, since patients with 
cytologic clearing and clinical response may continue to have residual 
abnormalities on MRI scans. Patients with a CR must also have stable or improved 
neurologic exam. 

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o Cyto lo gic CR 
Complete clearing of all malignant cells from lumbar and ventricular CSF 
based on cytospin preparation in leukemia/lymphoma patients and 
cytology in solid tumor patients. A cytologic CR must be documented by 
two negative cytologies on two consecutive occasions at least 4 weeks 
apart (with no interval positive cytologies). 
 
 
o Rad io grap hic C R 
In patients with evidence of disease on MRI scan, complete clearing of 
MRI scan evidence of disease on 2 consecutive scans at least 4 weeks 
apart will be required. 
 
12.5.2 Stab le Disea se (S D) 
Exists when a patient fails to fulfill the criteria for either complete or partial 
response or progressive disease. 
 
12.5.3 Progressive Disease (PD) 
An increase of at least 50% in the absolute number of malignant cells in the CSF 
OR, in -solid tumor patients, an increase of greater than 25% in the size of 
measurable lesions on MR scan OR the recurrence of malignant cells in the CSF 
or new lesions on MR after a patient has attained a complete remission OR 
evidence of clinical neurologic progression. New sites of or increasing evidence of 
leptomeningeal enhancement that is not "measurable" will also be considered 
evidence of disease progression. 
 
 
 
 
13.0     Criteria For Removal From Study 
 
13.1 If at any time the patient develops grade 4 toxicity (other than controllable fever, vomiting, 
headache) attributed to the study drugs, he/she will be removed from study and receive no further 
injections. 
 
13.2 If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be 
removed from the study. 
 
13.3 If at time disease progression is observed, the patient will be removed from the study. 
 
13.4 If the patient experiences adverse events, including unacceptable toxicity or exacerbation of 
underlying disease associated with drug administration and necessitating discontinuation of 
treatment, he/she will come off the study. Patents who are removed from the study due to 
adverse events will be treated and followed according to established medical practice. All 
pertinent information concerning the outcome of such treatment will be entered in the Case 
Report Form or the Serious Event Report, as applicable. 

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Page 17 of 23 
 
 
 
 
13.5 Withdrawal of consent: The patient‟s desire to withdraw from the study may occur at any 
time. 
 
13.6 Noncompliance:  If at any time the patient is non-compliant with therapy, radiation safety 
guidelines or requests withdrawal from the study, he/she will be removed. 
 
13.7 Pregnancy: The patient will be removed from study if they are found to be pregnant. 
 
14.0 Biostatistics 
This is a phase II study to assess the clinical efficacy of weekly intrathecal 131I-3F8 for a new 
cohort of 17 patients with GD2-expressing central nervous system and leptomeningeal 
neoplasms. A “response” is defined as a patient being alive six months after their first treatment. 
We will test hypothesis that the proportion of responses is 25% or more against a null hypothesis 
that proportion of responses is 5% or less, with a power of 80% and an alpha of 5%. Using a 
Simon two-stage optimal design, nine patients will initially be accrued. If at least one responds, 
then a further 8 patients will be entered on study. If the total number of responses is three or 
more, the agent will be declared active. Under this design, the probability of declaring the agent 
inactive at the end of the first stage (0 / 9 responses) is 0.63 if the true response rate is 0.05. This 
probability decreases to 0.08 if the true response rate is 0.25, The probability of declaring the 
agent active (3 or more responses / 17) is 0.05 and 0.8 if the true response rate is 0.05 or 0.25, 
respectively. It is expected that 4-6 patients/yr will be enrolled and that this study can be 
completed within 2-3 years. 
 
Reject null hypothesis if: 
Reject alternative hypothesis if: 
First stage 
- 
0 / 9 responses 
Second stage 
≥3 / 17 responses 
≤2 / 17 responses 
 
The number of CRs, PRs, SDs and PDs will be reported. Toxicities will be reported by type and 
grade. 
 
Three additional subgroups will be added for patients with: Medulloblastoma in CR (36 
evaluable patients), Medulloblastoma with stable, but minimal disease (36 evaluable patients), 
and Retinoblastoma or Melanoma (18 evaluable patients).  For patients with neuroblastoma or 
other cancers in the CNS, 18 additional evaluable patients will be added. We have completed the 
statistics for this agent overall which have shown efficacy on this phase II study; increasing the 
number of slots will allow for in depth statistical analyses within these subgroups of patients. 
 
 
15.1 
Research Participant Registration and Randomization Procedures 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist is 
confirming whether or not the participant is eligible to enroll in the study. Study staff are 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 18 of 23 
 
 
 
 
responsible for ensuring that all institutional requirements necessary to enroll a participant to the 
study have been completed. See related Clinical Research Policy and Procedure #401 (Protocol 
Participant Registration). 
 
15.2 Potential risks are outlined above. Procedures to minimize potential risks include 
prophylactic treatment with acetaminophen, dexamethasone, SSKI drops, liothyronine.. 
Procedures to minimize radiation exposure to self and others will be in accordance to Radiation 
Safety Guidelines. 
15.3 Enrollment in this protocol is voluntary. In the event of adverse effects, standard medical 
intervention will be offered where appropriate. 
15.4 All hospital records are confidential. The patient's name or any other personal identification 
will not be used in reports or publications from this study. Laboratory tests, images and X-rays, 
if any, may be published. The Food and Drug Administration or other authorized agencies (i.e. 
the National Cancer Institute) may inspect records. Data will be collected and stored in the 
patient's hospital chart and research file, and be monitored by the principal investigators to 
ensure the safety of patients. 
 
 
15.5 There is no extra cost to the patient for being part of this study. If there is an injury as a 
result of this research study, emergency care, hospitalization and outpatient care will be made 
available by Memorial Hospital and billed to the patient as part of medical expenses. No money 
will be provided by the Hospital as compensation for a research-related injury. 
 
15. 6    Randomization 
NOT APPLICABLE 
 
16.0     Data Management Issues 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
16.1    Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extext and accuracy of evaluations and follow- up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 

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IRB Number: 05-122 A(17) 
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Page 19 of 23 
 
 
 
 
17.0 
Protection of Human Subjects 
 
The investigators agree to conduct this study in accordance with the International Conference of 
Harmonization (ICH) principles of Good Clinical Practice and with the Declaration of Helsinki 
(1989). The investigators will conduct all aspects of this study in accordance with all national, 
state, and local laws of the applicable regulatory agencies. Patients will be both children and 
adults. Patients of both sexes and all ethnic background are eligible for this study. Alternatives to 
this study include conventional chemotherapy, radiation therapy, or other phase I agents. Patients 
are responsible for the costs of physician visits and usual laboratory tests, hospitalizations a nd 
outpatient care. If there is an injury as a result of this research study, emergency care, 
hospitalization, and outpatient care will be made available by Memorial Hospital and billed to 
the patient as part of the medical expenses. No money will be provided by Memorial Hospital as 
compensation for research-related injury. Patient will not be billed for the antibody 3F8. 
As part of standard care for this medical condition, the patient will be charged for: 
*any needed hospitalization 
*doctor‟s care 
*any other drugs besides 131I-3F8 needed for treatment 
*standard laboratory tests, but not pharmacokinetic studies 
*standard radiographic studies 
*clinic visits 
17. 1 Privacy 
MSKCC‟s Privacy Office may allow the use and disclosure of protected health info rmation 
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 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 

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IRB Number: 05-122 A(17) 
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Page 20 of 23 
 
 
 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or intervention. 
Any events that occur after the 30-day period and that are at least possibly related to 
protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of 
Serious Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days 
of the event. The IRB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office as follows: 
 
 
Reports that include a Grade 5 SAE should be sent to sae grade5@ mskcc.org.  All other 
reports should be sent to sae msk ind@ mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• Subject‟s initials 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• The grade of the 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 
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 
• If an amendment will need to be made to the protocol and/or consent form 

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IRB Number: 05-122 A(17) 
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Page 21 of 23 
 
 
 
 
• If the SAE is an Unanticipated Problem 
The PI‟s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
 
17.2.1 Reporting Guidelines: 
• 
Patient Consented/registered on the assessment part only: NO SAEs will be reported 
• 
Patient Consented/registered on the treatment part: 
All SAEs will be reported to the FDA through the IND office with reference to the IND # BB- 
IND-2299 
SAEs will be defined as grade 4 and 5 toxicities excluding:  hospitalizations for therapy 
administration, hyperglycemia or lymphopenia related to dexamethasone and self-limited 
fever, vomiting, or headache will not be considered serious adverse events (SAE) and will 
not be reported to the IRB or FDA 
 
 
18.1 
Informed Consent Procedures 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 05-122 A(17) 
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Page 22 of 23 
 
 
 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0     References 
1- Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clinics 21(1): 25-66, 2003 
2. Kramer K, Kushner BH, Cheung NKV. Neuroblastoma Metastatic to  the Central Nervous 
System: the Memorial Sloan-Kettering Cancer Center Experience and A Literature Review. 
Cancer 91:1510-9, 2001 
3- Gilbert MR. Neoplastic meningitis: a unique disease process or a “test tube” for evaluating 
cancer treatments? Curr Opin Rep 5(1): 11-14, 2003 
4. Shaw PJ. Neuroblastoma With Intracranial Involvement: an ENSG Study. Med Pediatr Oncol 
20:149-55, 1992 
5. Kellie JJ, Hayes A, Bowman L, et al. Primary extracranial neuroblastoma with central nervous 
system metastases: characterization by clinicopathologic findings and neuroimaging. Cancer 
68:1999-2006, 1991 
6. Flickinger JC. Radiotherapy and radiosurgical management of brain metastases. Curr Oncol Rep 3: 
484-9, 2001 
7. Weinberg JS, Lang FF, Sawaya R. Surgical management of brain metastases. Curr Oncol Rep 3:476- 
483, 2001 
8. Kramer K, Cheung 
NKV, Humm JL, et al. Targeted Radioimmunotherapy for 
Leptomeningeal Cancer using 131-I-3F8: Patient Imaging and Dosimetry. Med Ped Oncol 
35:716-718, 2000. 
9. Bergman I, Barmada MA, Heller G, Griffin JA, Cheung NKV. Treatment of neoplastic 
meningeal xenografts by intraventricular administration of an anti-ganglioside monoclonal 
antibody 3F8. Int J Cancer 82:538-48, 1999 
10. Bigner DD, Brown MT, Friedman AH. Iodine-131-labeled antitenascin monoclonal antibody 
81C6 treatment of patients with recurrent malignant gliomas:phase I trial results. J Clin 
Oncology 16:2202-12, 1998 
11. Lundin, J.,  Osterborg, A.,  Brittinger, G., Crowther D., et al. CAMPATH-1H monoclonal 
antibody in therapy for previously treated low- grade non-Hodgkin's lymphomas: a phase II 
multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non- 
Hodgkin's Lymphoma.  J Clin Oncol.,  16:3257-3263, 1998 

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IRB Number: 05-122 A(17) 
Approval date: 20-Mar-2018 
Page 23 of 23 
 
 
 
 
12. Cheung, N-K.V., Landmeier, B., Neely, J., Nelson, A.D., Abramowsky, C., Ellery, S., 
Adams, S., Miraldi, F. Complete tumor ablation with iodine-131-I-radiolabeled 
disialoganglioside GD2 specific monoclonal antibody against human neuroblastoma xenografted 
in nude mice. J Natl Can Inst., 77: 739-745, 1986 
13. Cheung, N-K.,  Kushner, B.H.,  Cheung, I.Y.,  Kramer, K.,  et al. Anti-G(D2) antibody 
treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J 
Clin Oncol., 16: 3053-3060, 1998 
14. Yeh, S.D., Larson, S.M.,  Burch, L.,  Kushner, B.H.,  LaQuaglia, M.,  Finn, R.,  Cheung, N- 
K. Radioimmunodetection of neuroblastoma with iodine-131-3F8: correlation with biopsy, 
iodine-131-metaiodobenzylguanidine and standard diagnostic modalities. J Nuc Med., 32:769- 
776, 1991