Conditions: Neuroblastoma
Keywords: Anti-GD2 3F8 Monoclonal Antibody oral isotretinoin GM-CSF Sargramostim 13-260
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 69
Healthy volunteers: no

Brief summary:
The purpose of this study is to be able to supply an experimental combination of drugs called 3F8 and GM-CSF (also called sargramostim) to patients with high-risk neuroblastoma who may benefit from treatment.

Detailed description:
This treatment uses 3F8/GM-CSF and isotretinoin for: Group 1 patients are in 1st CR/VGPR; Group 2 patients are in a ≥2nd CR/VGPR; and Group 3 patients have primary refractory NB in BM. All patients will receive 3F8/GM-CSF through 24 months.

Road Map/Schema for Group 1 (1st CR/VGPR) and Group 2 (≥2nd CR/VGPR) patients:

Cycle 1 3F8 (iv) + GM-CSF subcutaneous (sc) (1 wk) 2-4-wk interval Cycle 2 3F8 (iv) + GM-CSF (sc) (1 wk) 2-4-wk interval\* - oral isotretinoin x14 days Cycle 3 3F8 (iv) + GM-CSF (sc) (1 wk) 2-4-wk interval - oral isotretinoin x14 days Cycle 4 3F8 (iv) + GM-CSF (sc) (1 wk) 6-8-wk interval - oral isotretinoin x14 days on, 14 days off, 14 days on Cycle 5 3F8 (iv) + GM-CSF (sc) (1 wk) 6-8-wk interval - oral isotretinoin x14 days on, 14 days off, 14 days on (6th cycle) Cycle 6 3F8 (iv) + GM-CSF (sc) (1 wk) 6-8-wk interval Cycle 7 3F8 (iv) + GM-CSF (sc) (1 wk) Continue with 6-8-wk intervals through 24 months from 1st dose of 3F8. \* assessment of BM status by standard histology

Road Map/Schema for Group 3 patients (BM positive): The break between end of a cycle of 3F8/GM-CSF and start of next cycle is approximately 2-to-4-weeks through 4 cycles after achievement of CR in BM; subsequent breaks are \~6-8 weeks. Please see roadmap below for a patient achieving CR in BM after cycle 1. Cycle 1 3F8 (iv) + GM-CSF (sc) (1 wk) 2-4-wk interval\* - BM negative Cycle 2 3F8 (iv) + GM-CSF (sc) (1 wk) 2-4-wk interval\* - oral isotretinoin x14 days Cycle 3 3F8 (iv) + GM-CSF (sc) (1 wk) 2-4-wk interval - oral isotretinoin x14 days Cycle 4 3F8 (iv) + GM-CSF (sc) (1 wk) 2-4-wk interval - oral isotretinoin x14 days Cycle 5 3F8 (iv) + GM-CSF (sc) (1 wk) 6-8-wk interval - oral isotretinoin x14 days Cycle 6 3F8 (iv) + GM-CSF (sc) (1 wk) 6-8-wk interval - oral isotretinoin x14 days on, 14 days off, 14 days on (6th cycle) Cycle 7 3F8 (iv) + GM-CSF (sc) (1 wk) 6-8-wk interval Continue with 6-8-wk intervals through 24 months from 1st dose of 3F8.

\* assessment of BM response by standard histology

Arms:
arm 1: This is a single-arm, open label, open access study to provide the anti-GD2 murine IgG3 MoAb 3F8 combined with granulocyte-macrophage colony stimulating factor (GM-CSF) to patients with high-risk neuroblastoma (NB). This immunotherapy has shown efficacy against minimal residual disease (MRD) in such patients.

Interventions: intervention 1: Anti-GD2 3F8 Monoclonal Antibody intervention 2: GM-CSF (granulocyte-macrophage colony-stimulating factor) intervention 3: oral isotretinoin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
 
 
 
 
 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Anti-GD2 3F8 Monoclonal Antibody and GM-CSF for High-Risk 
Neuroblastoma 
 
 
 
Principal Investigator/Department: 
Brian H. K ushner, MD 
Pediatrics 
Co-Principal 
Investigator(s)/Department: 
Nai-Kong V. Cheung, MD, P hD 
Pediatrics 
Investigator(s)/Department: 
Ellen M. Basu, MD, P hD 
Shakeel Modak, MD 
Stephen S. Roberts, MD 
Irina Ostrovnaya, P hD 
Pediatrics 
Pediatrics 
Pediatrics 
Epidemiology and 
Biostatistics 
Consenting Professional(s)/Department: 
Ellen M. Basu, MD, P hD 
Nai-Kong V. Cheung, MD, P hD 
Brian H. K ushner, MD 
Shakeel Modak, MD 
Stephen S. Roberts, MD 
Pediatrics 
Pediatrics 
Pediatrics 
Pediatrics 
Pediatrics 
 
 
Ple ase Note: A Consenting Profe ssional must have comple ted the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial S loan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
 
 
Page 1 of 25 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
Page 2 of 25 
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 3 
 
2.0 
OB JECTIVES AND SCIENTIFIC AIMS ................................................................................ 4 
 
3.0 
BACKGROUND AND RATIONALE ...................................................................................... 4 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................ 7 
 
4.1 
Design ................................................................................................................................... 7 
 
4.2 
Intervention ........................................................................................................................... 7 
 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS.............................................................................. 8 
 
6.0 
CRITERIA FOR SUB JECT ELIGIBILITY .......................................................................... 10 
 
6.1 
Subject Inclus ion Cr iteria ...................................................................................................... 10 
 
6.2 
Subject Exclus ion Cr iteria ..................................................................................................... 10 
 
7.0 
RECRUITMENT PLAN ........................................................................................................ 10 
 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 11 
 
9.0 
TREATMENT/INTERVENTION  PLAN............................................................................... 11 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................ 12 
 
11.0 
TOXICITIES/SIDE EFFECTS .............................................................................................. 14 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 15 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY....................................................................... 15 
 
14.0 
BIOSTATISTICS................................................................................................................... 16 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES16 
 
15.1 
Research Participant Registration .......................................................................................... 16 
 
16.0 
DATA MANAGEMENT ISSUES........................................................................................... 16 
 
16.1 
Quality Assurance ................................................................................................................ 16 
 
16.2 
Data and Safety Monitor ing .................................................................................................. 17 
 
17.0 
PROTECTION OF HUMAN SUBJECTS.............................................................................. 17 
 
17.1 
Privacy ................................................................................................................................ 17 
 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................ 18 
 
17.2.1.......................................................................................................................................... 18 
 
18.0 
INFORMED CONSENT PROCEDURES.............................................................................. 19 
 
19.0 
REFERENCES ...................................................................................................................... 19 
 
20.0 
APPENDICES........................................................................................................................ 25 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
Page 3 of 25 
 
 
 
 
 
 
ACRON YMS and ABBREVIATIONS 
 
ADCC, antibody- dependent cellular cytotoxic ity 
AE, adverse event 
ALT, alanine aminotransferase 
ANC, absolute neutrophil count 
ASCT, autologous stem-cell transplantation 
AST, aspartate aminotransferase 
BM, bone marrow 
BUN, blood urea nitrogen 
CBC, complete blood count 
CT, computed tomography 
CR, complete remission 
CRDB, Clinical Research Database 
DSM, Data and Safety Monitor ing 
DSMB, Data and Safety Monitoring Board 
DSMC, Data and Safety Monitoring Committee 
FDA, Food and Drug Administration 
GM-CSF, granulocyte-macrophage colony-stimulating factor 
HAMA, human anti-mouse antibody 
ICH, Internationa l Conference of Harmonization 
IND, investigationa l new drug 
IRB/PB, Institutiona l Review Board/Privacy Board 
iv, intravenous 
MIBG, metaiodobenzylguanidine 
MoAb, monoc lona l antibody 
MRD, minima l residua l disease 
MRI, magnetic resonance imaging 
MSKCC, Memoria l Sloan-Kettering Cancer Center 
NB, neuroblastoma 
NCI, National Cancer Institute 
NIH, National Institutes of Health 
OS, overall surviva l 
PD, progressive disease 
PET, positron emiss ion tomography 
PI, Principal Investigator 
PFS, progression-free surviva l 
PPR, Protocol Participant Registration 
q, every 
QA, quality assurance 
RA, Research Authorization 
RSA, research study assistant 
SAE, serious adverse event 
sc, subcutaneous 
VGPR, very good partia l remiss ion 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
Page 4 of 25 
 
 
 
 
 
1.0       PROTOCOL SUMMARY AND/OR SCHEMA 
 
Efficacy of anti-GD2 monoclonal antibody (MoAb) therapy is proven. This is a single-arm, open- 
label, open access study to provide the anti- GD2 murine IgG3 MoAb 3F8 combined with 
granulocyte-macrophage colony stimulating factor (GM-CSF) to patients with high-risk 
neuroblastoma (NB). This immunotherapy has shown efficacy against minimal residual disease 
(MRD) in such patients. 3F8 is not yet licensed by the Food and Drug Administration (FDA) and 
commercially available but is listed on the F DA site as orphan designated.1a 
 
2.0       OBJECTIVES AND SCIEN TIFIC AIMS 
 
The objective of this open access protocol is to provide 3F8 to patients with high-risk NB. 
The treatment IND will collect additional usage, tolerability and safety data. 
 
3.0       BACKGROUND AND RATIONALE 
 
3.1 
Dise ase backgro und: NB is the most common extracranial solid tumor of childhood; 
50-60% of patients present with an  unresectable primary tumor and  metastases in bone marrow 
(BM).1  Intensive induction chemotherapy and aggressive surgery have improved remission rates in 
young patients2-4; results  have  been  less  impressive  in  adolescents and  adults  in  whom NB  is 
especially chemoresistant.5,6 Realization of an effective strategy for eradicating MRD has remained a 
formidable challenge. Post-surgical use of local radiotherapy helps control MRD in the primary site.7 
Myeloablative therapy with autologous stem-cell transplantation (ASC T) has been the mos t common 
approach  for  eradicating  MRD  in  distant  sites.  The  vitamin  A  derivative  13 -cis-retinoic  acid 
(isotretinoin) helped to prolong relapse- free survival in a randomized study.8    Immunotherapy using 
the anti- GD2 ch14.18 MoAb plus GM-CSF and interleukin-2 in alternating cycles improved outcome 
in a randomized study.9  These results have made treatment with isotretinoin and anti-GD2 MoAb 
standard of care for high-risk NB. 
 
3.2       Rationa le fo r immunothe ra py :  Various strategies have undergone clinical testing to 
induce or augment immune- mediated attack against cancer.  However, few clinical trials have used 
monoclonal antibody-targeted immunotherapy against solid tumors in children or adults, especially 
with antibody-dependent cellular cytotoxicity (ADCC) as t he principal underlying immune cytotoxic 
mechanism. Also, an antineoplastic role for granulocytes has received scant attention. 10    A treatme nt 
program combining 3F8 and GM-CSF thus represents an attempt to help fill a gap in the emerging 
field of immunotherapy. 
 
3.3       Rationa le for 3F8 :   3F8  is a murine IgG3 MoAb that is well suited  for targeted 
immunotherapy. The reasons are several. F irst, the intensive chemotherapy required to produce the 
minimal  disease  state  optimal  for  immunotherapy  in  NB  patients  res ults  in  prolonged  severe 
lymphopenia.11 
 This setting is unfavorable for active immunotherapy but allows passive 
immunotherapy since the patient will be unable to reject allogeneic, xenogeneic, or genetically- 
engineered  antibodies.  Second,  3F8  recognizes  the  ganglioside  GD2.12    This  target  antigen  is 
expressed at high density on NB (but has restricted distribution in normal human tissues), is not 
modulated from the cell surface when bound by antibodies, and is genetically stable (unlike tumor - 
associated antigens such as immunoglobulin idiotypes on lymphoma cells).13-15  Third, scintigraphy 
using 131I-3F8 confirms that 3F8 localizes selectively to GD2(+) tumor deposits in patients. 16  The 
excellent targeting potential of 3F8 was evidenced by its high tumor to non-tumor ratio, the high 
percent  injected  dose  per  gram  uptake,  and  the  limited,  if  any,  nonspecific  liver  and  spleen 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
Page 5 of 25 
 
 
 
 
 
uptake.16,17  Fourth, 3F8 mediates destruction in vitro of GD2(+) human solid tumor cells by human 
complement18 and by human lymphocytes, cultured monocytes, and neutrophils.19-21 Finally, the 
capacity of 3F8 to activate complement on NB cells (which lack decay accelerating factor 22) raises 
the  possibility,  not  only of complement- mediated  lysis  in  patients,  but  also  of the  release  of 
complement fragments that may elicit an inflammatory influx of granulocytes capable of lysing 3F8 - 
labeled tumor cells. F urthermore, the deposition of complement fragments C3b and iC3b on NB cells 
may enhance ADCC because the receptor for iC3b – variously called Mac-1, CR3, CD11b/CD18, or 
άMβ2-integrin –  is a key element in anti- GD2 MoAb- mediated tumor cell kill by neutrophils,23,24 
which are the most abundant circulating class of leukocyte. 
 
3.4       Rationa le fo r GM -CSF:   GM-CSF has the potential for amplifying 3F8 antit umor 
activity in patients via effects on granulocytes and tissue-based macrophages.  Reasons for combining 
GM-CSF with 3F8 include the following. F irst, granulocyte production is only transiently suppressed 
with chemotherapy and GM-CSF increases numbers of circulating neutrophils and eosinophils, does 
not affect complement levels, and is well tolerated compared to other cytokines such as interleukin- 
2.25 Second, granulocytes from patients receiving chemotherapy and from normal volunteers are 
effective in mo unting ADCC against NB cells via non-oxidative mechanisms, and GM-CSF enhances 
this cytotoxicity.24,26-30  Third, eosinophilic infiltration of some cancers has favorable prognostic 
significance, and eosinophils exhibit potent antitumor activity in animal models.31,32 Fourth, activated 
monocytes- macrophages efficiently phagocytose N B cells, and exposure in vitro or in vivo to GM - 
CSF  primes  monocytes- macrophages  for  greater  antineoplastic  cytotoxicity.33-38   Fifth,  GM-CSF 
enhances the proliferation,  maturation, and  function of antigen-presenting cells,  including antigen 
processing and presentation by macrophages and dendritic cells25,39,40  - effects that might promote 
induction, or antitumor activity, of an idiotypic network.41-44  Finally, GM-CSF is not a growth factor 
for NB cells in vitro.45 
 
3.5       GM -CSF-me dia te d activatio n of ne utro phils : Neutrophils are the predominant c lass 
of circulating leukocytes; chemotherapy only transiently decreases their numbers and largely spares 
their  cytotoxic  capabilities.  These  features  are  advantageous  for  immune-based  attack  aga inst 
cancer.10  We and others have shown that Mac-1 (CD11b/CD18), FcRII, and FcRIII are required for 
optimal ADCC in a system using human neutrophils as effectors,  human N B cells as targets, and 
clinically active anti- GD2 MoAbs as mediators.23,24  Efficient tumor-cell kill occurs despite the large 
size of the targets (which precludes a role for phagocytosis) and their relative resistance to reac tive 
oxygen species.29  GM-CSF enhancement of ADCC in this system correlates with upregulation of 
Mac-1 and with increased exocytosis of azurophil (primary) granules which contain cathepsin G and 
defensins capable of lysing N B cells.30  To elucidate the cytotoxic mechanisms of anti-GD2 MoAb- 
mediated  ADCC,  we  used  blocking  MoAbs,  neutrophils  devoid  of Mac-1  (from  donors  with 
leukocyte adhesion deficiency), and neutrophils that do not generate reactive oxygen species (from 
donors with chronic granulomatous disease),23  while others used blocking MoAbs, electron 
microscopy, a nd neutrophils from healthy donors as well as from patients.24 Activation of neutrophils 
by GM-CSF is correlated with improved anti-NB effects of treatment with anti-GD2 MoAb.46 
 
 
 
3.6       Clinical e xpe rie nce with 3F8 plus GM -CSF:  The optimal method of using GM-CSF 
with the aim of enhancing ADCC in patients with solid tumors has only recently been elucidated. In 
the past, we chose to administer GM-CSF by a 2- hr iv infusion (followed by a 1-hr interval before 
starting 3F8 infusion) because GM-CSF disappears rapidly (<2-3 hr) from the blood with that 
schedule.47,48 We wished to avoid the prolonged (>12 hr) bioactive levels in blood associated with the 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
Page 6 of 25 
 
 
 
 
 
subcutaneous (sc) route; our concern was that high serum levels of GM-CSF might impede 
granulocyte trafficking into tissues.49 However, for circulating tumor cells in BM or blood, this 
concern is dwarfed by the more potent antitumor effects from prolonged cytokine exposure following 
subcutaneous injection.25 
 
The 03-077 study of 3F8+scGM-CSF immunotherapy plus isotretinoin enrolled patients in 1st 
complete/very good partial remission (CR/VGP R) (n=85), patients with primary refractory NB in 
BM (n=79), and patients in >2 CR/VGP R (n=101). Salient findings included: 
 
1)        Acute toxicities were manageable which allowed outpa tient treatment.  This finding stands in 
stark contrast with studies using other anti-GD2 MoAbs either alone or in combination with 
interleukin-2, where treatment is inpatient, often in an intensive care unit, with complications such as 
capillary leak syndrome.9 
 
2)        For patients in 1st  CR/VGPR, prior myeloablative therapy + ASCT had no impact on 5- year 
progression-free survival (PFS) 62% or overall survival (OS) 81%.50 This supports the welcome 
possibility of avoiding the risk of significant acute and long-term toxicities of myeloablative therapy. 
 
3)        For patients with primary refractory NB, C R rate in BM by histology was 87% and C R rate of 
metaiodobenzylguanidine  (MIBG)  scans  was 38%.  These  results  vividly document  the  anti-NB 
activity of anti- GD2 MoAb immunotherapy, i.e., the possibility of overcoming histologically- and/or 
radiologically- visible  chemoresistant  NB  in  BM  using  an  anti- GD2  MoAb  regimen  that  has 
manageable toxicity and is administered outpatient. 
 
4)        Patients treated in >2 CR/VGPR achieved 48- mo nth PFS 33% and OS 53%, with no adverse 
impact  if patients  had  received  anti-GD2  MoAb  and  isotretinoin  as part of initial (pre-relapse) 
therapy  and with only 2/35 very long-term relapse- free survivors having received ASC T as part of 
salvage. These results are noteworthy, given that studies show <5% long-term OS after relapse51-55 
and anti- GD2 MoAb, isotretinoin, and ASCT are standard treatments for newly-diagnosed patients.56 
Indeed,  the results support a change  in  mind-set: no  longer should  relapse of high-risk  NB be 
considered “invariably lethal”,57 but rather a curative strategy should be applied. 
 
5)        Positive MRD after 2 cycles of 3F8+scGM-CSF was a significantly adverse independent 
prognostic factor for all groups of patients.50,58,59  This finding should be taken into account when 
determining subsequent therapy in a given patient. 
 
6)        Correlative  studies  highlight  the  anti- neoplastic  potency  of  myeloid  effectors  whereas 
lymphocytes are the effectors usually heralded in cancer immunotherapy. 
 
7)        GM-CSF by sc route is associated with better PFS and OS than by iv route,60  as used in the 
predecessor study of 3F8+ivGM-CSF.61 
 
3.7       Isotre tinoin (13 -cis-re tinoic ac id)  was shown  in  a randomized  national study to 
decrease the risk of relapse in patients treated in complete remission.8  This agent has subsequently 
become standard of care for N B patients in complete remission. It will be used in this protocol after 
patients are evaluated for response (and for toxicity) to 3F8/GM-CSF. 
 
3.8       Inte rpre tatio ns and implicat io ns   The ease of administration of the treatments (a 
subcutaneous  injection,  which  is  given  at  home,  and  a  30- minute  intravenous  infusion  in  the 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
Page 7 of 25 
 
 
 
 
 
outpatient clinic), plus their transient acute side-effects, are compatible with widespread usage of this 
regimen beyond our hospital – a strong positive factor in furthering product development. 
 
In addition to the outpatient treatment with anti- GD2 MoAb, the Memorial S loan-Kettering 
Cancer Center (MSKCC) neuroblastoma treatment program remains unique  in that ASC T is  not 
included and  the immunotherapy is available for patients  in >2nd  C R/VGP R.  Results to date, as 
summarized in section 3.6, are highly encouraging and may have implications world-wide. 
 
 
 
 
4.0 
OVERVIEW OF S TUD Y DES IGN/IN TERVENTION 
 
4.1       Design 
 
This treatment uses 3F8/GM-CSF and isotretinoin for: Group 1 patients are in 1st  CR/VGP R; 
Group 2 patients are in a ≥2nd CR/VGP R; and Group 3 patients have primary refractory NB 
in BM. All patients will receive 3F8/GM-CSF through 24 months. 
 
 
 
4.2       Inte rve ntion 
Road Map /Sc he ma for Gro up 1 (1st  CR/VGP R) a nd Gro up 2 (≥ 2 nd CR/VGPR) patie 
nts: Cycle 1 
3F8 (iv) + GM-CSF subcutaneous (sc) (1 wk) 
2-4-wk interval 
Cycle 2            3F8 (iv) + GM-CSF (sc) (1 wk) 
2-4-wk interval*  –  oral isotretinoin x14 days 
Cycle 3            3F8 (iv) + GM-CSF (sc) (1 wk) 
2-4-wk interval –  oral isotretinoin x14 days 
Cycle 4            3F8 (iv) + GM-CSF (sc) (1 wk) 
6-8-wk interval –  oral isotretinoin x14 days on, 14 days off, 14 days on 
Cycle 5            3F8 (iv) + GM-CSF (sc) (1 wk) 
6-8-wk interval –  oral isotretinoin x14 days on, 14 days off, 14 days on (6th cycle) 
Cycle 6 
3F8 (iv) + GM-CSF (sc) (1 wk) 
6-8-wk interval 
Cycle 7            3F8 (iv) + GM-CSF (sc) (1 wk) 
 
Continue with 6-8-wk intervals through 24 months from 1st dose of 3F8. 
* assessment of BM status by standard histology 
 
Road Map/Sc he ma for Gro up 3 patie nts (BM positive):  The break between end of a cycle of 
3F8/GM-CSF and start of next cycle is approximately 2-to-4-weeks through 4 cycles after 
achievement of CR in BM; subsequent breaks are ~6-8 weeks.  P lease see roadmap below for 
a patient achieving CR in BM after cycle 1. 
 
Cycle 1            3F8 (iv) + GM-CSF (sc) (1 wk) 
2-4-wk interval*  –  BM negative 
Cycle 2            3F8 (iv) + GM-CSF (sc) (1 wk) 
2-4-wk interval*  –  oral isotretinoin x14 days 


Memorial Sloan Kettering Cancer Center
IRB Number: 13-260 A(4) 
Approval date: 30-Mar-2018 
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Cycle 3 
3F8 (iv) + GM-CSF (sc) (1 wk) 
2-4-wk interval –  oral isotretinoin x14 days 
Cycle 4 
3F8 (iv) + GM-CSF (sc) (1 wk) 
2-4-wk interval –  oral isotretinoin x14 days 
Cycle 5 
3F8 (iv) + GM-CSF (sc) (1 wk) 
6-8-wk interval –  oral isotretinoin x14 days 
Cycle 6 
3F8 (iv) + GM-CSF (sc) (1 wk) 
6-8-wk interval –  oral isotretinoin x14 days on, 14 days off, 14 days on (6th cycle) 
Cycle 7 
3F8 (iv) + GM-CSF (sc) (1 wk) 
6-8-wk interval 
 
Continue with 6-8-wk intervals through 24 months from 1st dose of 3F8. 
* assessment of BM response by standard histology 
 
The treatment schedule may require minor adjustment as clinically indicated or due to 
circumstance (e.g., due to Pediatric Day Hospital closure for holidays or due to inclement weather). 
Patients can complete the missed day of 3F8 the following week, so they receive a full 5-day cycle. 
GM-CSF will be continued through the 3F8 make-up day at the 500 mcg/m2 dose. 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
3F8 monoclonal antibody (IND number of BB-IND-8449) 
 
m3F8  is an investigational new drug developed at MSKCC and manufactured by a 
qualified CMO in compliance with GMP guidance appropriate for phase I clinical trials.  The 
final product specifications, analytical test methods and storage conditions/stability are 
described   in  the  CMC   section  of  this  IND.      Briefly,   m3F8 is  purified   by  column 
chromatography followed by viral filtration and finale sterile filtration. The final product is 
tested to assure that it is free of aggregates, nucleic acid, murine viruses, bacteria, fungi, 
mycoplasma  and   pyrogens.   m3F8   is  also   tested   for   antibody  specificity.      For   iv 
administration, 3F8 should be diluted into 10 ml 5% human serum albumin and millipore (0.2 
µm) filtered before use.  Route of Administration: iv infusion. 
  
 
5.2 
Sargramostim (YEAS T-DERIVED HUMAN RECOMBINANT GRANULOCYTE- 
MACROPHAGE COLONY STIMULATING F ACTOR; GM-CSF) 
 
5.2.1 Source and Pharmacology: Yeast derived recombinant human GM-CSF. 
 
5.2.2    Supplier: LEUKINE (sargramostim) is distributed by Genzyme Corporation, 
Cambridge, MA and manufactured by Bayer HealthCare P harmaceuticals, Seattle, WA. 
 
5.2.3    Formulation and Stability: Sargramostim is available as a sterile, white, 
preservative- free,  250  mcg  single  use  vial  of  lyophilized  powder  or  a  500  mcg/1  mL 
injectable solution. 
 
The 250 mcg vials require aseptic reconstitution with 0.5 mL Sterile Water for 
Injection, USP (without preservative). During reconstitution, the Sterile Water for Injection, 
USP should be directed at the side of the vial and the contents gently swirled to avoid foaming 


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during dissolution. Avoid excessive or vigorous agitation; do not shake. The reconstituted 
sargramostim solutions are clear, colorless, isotonic with a pH of 7.4 ± 0.3, and contain 500 
mcg/mL of sargramostim.  The single-use 250 mcg vials contain no antibacterial preservative, 
and therefore should be administered as soon as possible, and within 6 hours following 
reconstitution. They are intended for single use only and should not be re-entered or reused. 
Do not save any unused portion for later administration.  Do not use beyond the expiration 
date printed on the vial. 
 
Vials containing 500 mcg/1 mL of sargramostim are already in solution and are 
multiple dose vials. For subcutaneous administration, further dilution is not required . Liquid 
sargramostim may be stored  for up  to 20  days at 2-8°C once the vial has been entered. 
Discard any remaining solution after 20 days. 
 
Store sargramostim powder, or reconstituted solutions,  under refrigeration at 2 -8°C 
(36-46°F); do not freeze or shake. 
 
Aseptic  technique  should  he  employed  in  the  preparation  of  all  sargramostim 
solutions. To assure correct concentration following reconstitution, care should be exercised 
to eliminate any air bubbles from the needle hub of the syringe used to prepare t he diluent. 
Parenteral products should be inspected visually for particulate matter and discoloration prior 
to administration whenever solution and container permit. 
 
5.2.4 
Route of Administration: Subcutaneous 
 
 
 
5.3 
 13-cis-Retinoic  
Acid  
(NDC  
#0004-0155-01,0004-0169,  
0004-0156-01- 
ISOTRETINOIN, ACCUTANE) 
 
5.3.1    Source and Pharmacology:    The exact  mechanism of retinoic acid- induced 
maturation of tumor cells is not known. In neuroblastoma cell lines it has been shown to down 
regulate MYCN RNA and protein expression, and such down regulation correlates with the 
ability  of  isotretinoin  to  induce  tumor  cell  growth  arrest.  Recent  studies  using  gene 
transfection directly implicate down regulation of MYCN expression by isotretinoin as a key 
event in achieving susta ined arrest of neuroblastoma cell proliferation.  Retinoic acid also 
appears to enhance normal hematopoietic differentiation by increasing the responsiveness of 
myeloid and erythroid progenitor cells to the action of myeloid colony stimulating activity 
and erythropoietin, respectively. Me tabo lism: Retinoic acid is 99.9% bound in plasma (almost 
entirely  to  albumin)  and  has  a  half- life  of  10-20  hours.  The  major  metabolite  is  4- 
oxoisotretinoin, and  excretion is in  the urine and  feces.  A single oral dose of 100mg/m2 
isotretinoin will produce peak plasma levels of 1-2mM. The mean peak time as 3.2 hours after 
80mg orally, with a terminal t½ of 10 to 20 hours. Administering 160 mg/m2/day to children 
after ASCT has been shown to achieve 13-cis-retinoic acid levels of 5 to 7 micromular. 
 
5.3.2    Formulation and Stability: Isotretinoin, which is the 13-cis isomer of retinoic 
acid, will be used. This is a yellow--orange crystalline powder with a molecular weight of 
300.44.  Isotretinoin is sensitive to light and oxygen, and so it should not be removed from the 
capsule for longer than one hour prior to administration to the patient and it should be kept in 
subdued light as much as possible. 


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5.3.3    Guidelines for Administration: Take orally with fat-containing food or milk to 
enhance  absorption.  Administration of the entire capsule  is to  be encouraged  and  small 
children can be trained to swallow them using similar sized candy. 
 
5.3.4  Supplier: Isotretinoin is available commercially under the trade name 
ACCUTANE (Roche Laborato ries)  in 10mg,  20mg,  and  40mg soft  gelatin capsules.  See 
package insert for further information. 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1       Subje ct Inclusion Crite ria 
 
• Diagnosis of NB as defined by international criteria,62  i.e., histopathology (confirmed 
by the MSKCC Department of Pathology) or BM metastases plus high urine 
catecholamine levels. 
• High-risk NB, as defined by risk-related treatment guidelines and the International NB 
Staging  S ystem,  i.e.,  stage  4  with  (any  age)  or  without  (>18  months)  MYCN- 
amplification,63 or MYCN-amplified NB other than stage 1.64,65 
• Patients are in CR/VGP R or have primary refractory NB in BM – i.e., NB resistant to 
standard therapy, as evidenced by persistence of NB in BM by histology or MIBG 
scan, but all other findings in scans show VGP R. 
• Children and adults are eligible. 
• Signed informed consent indicating awareness of the scheduling and side effects, as 
well as testing requirements, of this program. 
  
 
6.2       Subje ct Exclusion Crite ria 
 
• Existing  severe  major  organ  dysfunction,  i.e.,  renal,  cardiac,  hepatic,  neurologic, 
pulmonary,  or  gastrointestinal toxicity >  grade 3,  except  for  grade 3  hemato logic 
toxicity. 
• Progressive disease (P D) (section 12). 
• History of allergy to mouse proteins. 
• Active life-threatening infection. 
• Human anti- mouse antibody (HAMA) titer >1000 Elisa units/ml. 
• Pregnant women 
• Inability to comply with protocol requirements. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be offered participation in this open access study by their attending physician in 
the Department of Ped iatrics, MSKCC. No patient will be identified by chart review or direct 
advertising. The attending physician will be responsible for explaining the study, obtaining 
written  informed  consent,  and  registering  the  patient  on  study.  Patients  will  mainly  be 


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Page 11 of 25 
 
 
 
 
 
children and adolescents because of the nature of N B (90% of patients are <6 years old at 
diagnosis). Patients of both sexes and all ethnic backgrounds are eligible for this study. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Pre-treatment evaluations should be completed within 30 days of start of treatment. 
 
8.1       Complete history and physical examination. 
 
8.2 
Complete blood count (C BC), serum creatinine, blood urea nitrogen, serum aspartate 
aminotransferase, serum alanine aminotransferase, and serum total bilirubin 
 
8.3       BM aspirates from bilateral anterior and bilateral posterior iliac crests, and biopsies 
from any two  separate sites.  The specimens are studied by standard  histoche mica l 
methods for the presence of tumor cells. 
 
8.4       Computed tomography (C T) or magnetic resonance imaging (MRI) of primary tumor 
site, plus other specific or suspected sites of tumor. 
 
8.5       Scintigraphic  studies  (MIBG  scan66   and/or  positron  emission  tomography  [P ET] 
scan.67). 
 
8.6       Serum for analysis of HAMA, if applicable (i.e., for patients previously treated with 
murine or chimeric antibody). If the patient was previously treated with an antibody, 
HAMA results since last antibody treatment can be used. 
 
8.7       Pregnancy test, if applicable 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1       Schedule:  The  total dosage  o f 3F8  per  cycle  is  100  mg/m2,  administered  at  20 
mg/m2/day and infused iv over ~1.5 hr or less (0.5 hr is customary), with analgesics and 
antihistamines  used  as  needed  for  expected  side-effects.  3F8  is  started  after  GM-CSF 
administration. GM-CSF is dosed at 250 mcg/m2/day from day –5 to day +1 (Wed nesday to 
Tuesday is customary), and is 500 mcg/m2/day thereafter (i.e., on days +2 to +4; Wednesday 
to  Friday),  as  in  the  predecessor  protocol.61   Patients  come  off study  for  PD  or  a  life- 
threatening grade 4 toxic ity from 3F8; otherwise, patients will continue treatment through 24 
months. It is expected that patients will receive ~4-to-10 cycles.  Patients may receive local 
radiation therapy. 
 
For Group 1 and 2 patients (enrolled respectively on study in 1 st  or >2nd CR/VGP R, 
i.e., with no evidence of disease), the break between end of a cycle and start of next cycle is 
approximately 2-to-4 weeks through 4 cycles; subsequent breaks are ~ 6-8 weeks. Isotretinoin 
is started after cycle 2 of 3F8/GM-CSF.   It is only to be started  after cycle 1  if HAMA 
develops and precludes timely administration of cycle 2. Road map/schema is in section 4.2. 
For Group 3 patients (enrolled on study for treatment of primary refractory disease), 
the break between end of a cycle of 3F8/GM-CSF and start of next cycle is approximately 2- 


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to-4-weeks through 4 cycles after achievement of CR in BM; subsequent breaks are ~ 6-8 
weeks.  Isotretinoin is started after cycle 2 of 3F8/GM-CSF.  It is only to be started after cycle 
1 if HAMA develops and precludes timely administration of cycle 2.  Road map/schema is in 
section 4.2. 
Patients who develop early HAMA, which precludes timely treatments with 3F8/GM- 
CSF, are eligible to receive low-dose maintenance regimens such as irinotecan alone,68 
temozolomide alone,69 irinotecan-temozolomide,70 or cyclophosphamide-topotecan.71 These 
patients can also receive anti- HAMA agents such as rituximab and cyclophosphamide. They 
resume treatment with 3F8/GM-CSF if HAMA becomes negative. 
 
9.2       3F8/GM-CSF treatment schedule (one cycle). 
 
Days -5 to -1: 
GM-CSF 250 mcg/m2/day, subcutaneously. 
Days 0 and +1:  GM-CSF 250 mcg/m2/day, subcutaneously. 
3F8 20 mg/m2/day by iv infusion over ~1.5 hr or less (usually 0.5 hr). 
 
Days +2 to +4:  GM-CSF 500 mcg/m2/day, subcutaneously. 
3F8 20 mg/m2/day by iv infusion over ~1.5 hr or less (usually 0.5 hr). 
 
Note:  The daily GM-CSF is not administered if the absolute neutrophil count (ANC) 
is >20,000/ µl. The last documented ANC count will be used to determine whether GM-CSF 
will be administered or not. If HAMA develops, cycles are deferred until HAMA titer 
decreases to <1000 Elisa units/ml. Emla cream (lidocaine 2.5% and prilocaine 2.5%) can be 
used to prevent pain from GM-CSF shots. 
 
9.3       Isotretinoin is administered at 160 mg/m2/d, divided into two doses, x14 days. This 
treatment can be repeated after a minimum rest period of 14 days, for a total of 6 cycles. It is 
not taken on the same days as 3F8. All patients receive a minimum of 2 cycles of 3F8/GM - 
CSF before starting isotretinoin (only to be started after cycle 1 if HAMA develops and 
precludes timely administration of cycle 2). All patients take a total of 6 cycles of isotretinoin, 
but those patients who have persistence of disease (but no progressive disease) can take th is 
agent  until  BM and  MIBG show C R.  Dose  reductions  due  to  expected  side  effects  of 
isotretinoin (e.g., headaches, dry skin, etc.) are allowed. 
 
10.0 
EVALUATION DURING TREATMENT/IN TERVENTION 
 
Note : If for any re ason te sts cannot be comple ted on day 0, the y will be comple ted on day 1. 
 
10.1 
CBC on days 0 and +3 (Mondays and Thursdays).   If ANC is >10,000/ µl, CBC is 
repeated the next day. 
 
10.2     C3 and CH50 on day 0 before and approximately 3 hours after 3F8 in cycle 1 
 
10.3     HAMA is checked before each cycle of 3F8 (Dr. C heung, Research Lab). 
 
10.4 
Serum  creatinine,  blood  urea  nitrogen,  serum  aspartate  aminotransferase,  serum 
alanine aminotransferase, and serum total bilirubin on days 0 and +4 of each cycle. 


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10.5 
BM studies (section 8.4) at end of cycle 2 and subsequently, BM studies are repeated 
in conjunction with MIBG or PET scan (section 10.7) through 2 years while on study 
in patients with history of BM or cortical bone involvement, but are repeated ~every 6 
months in other patients (i.e., patients who are stage 2 or 3, or were stage 4 by virtue 
of metastases in distant lymph nodes). 
 
10.6 
CT and/or MRI of primary site approximately every 3 months through 2 years while 
on study. 
 
10.7 
MIBG and/or PET scan approximately every 3 months through 2 years while on study. 
 
10.8 
Pregnancy screen (females of child-bearing age) before starting isotretinoin. 
 
 
Table 4: Evaluations on Protocol 
Te sts 
Pre -tre atme nt 
During Tre atme nt 
During Followup 
Complete history and 
physical 
✓
- 
- 
Complete blood count 
✓
On Day 0 (Monday) and 
3 (Thursday) of each 
cycle. 
If ANC >10,000/µl, 
CBC is repeated the 
next day.  CBC is not 
repeated after Day 4. 
- 
C3 & CH50 
- 
Before and 
approximately 3 hours 
after 3F8 on Day 0 
(Monday) of cycle 1. 
- 
Liver and Renal function 
tests (ALT, AS T, BUN and 
creatinine) 
✓
On Day 0 (Monday) and 
4 (Friday) of each cycle. 
- 
Pregnancy test, if applicable 
✓
Prior to starting cycle 1 
of isotretinoin 
- 
Blood for HAMA 
✓, if applicable 
Before each cycle 
- 
Bone marrow studies 
✓
After cycle 2, and 
subsequently with 
MIBG or P ET through 2 
years for patients with 
history of BM or cortical 
bone involvement. 
For patients who are 
stage 2 or 3, or stage 4 
Approximately q 3 
months for 2 years from 
first treatment or until 
patient is off study, 
whichever is earlier and 
thereafter as clinically 
indicated 


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by virtue of metastases 
in distant lymph nodes: 
approximately every 6 
months while on study 
CT and/or MRI 
✓, of primary tumor 
site, plus other specific 
or suspected sites of 
tumor 
~Q3 months of primary 
site 
Approximately q 3 
months for 2 years from 
first treatment or until 
patient is off study, 
whichever is earlier and 
thereafter as clinically 
indicated 
MIBG and/or PET scan 
✓
~Q3 months 
Approximately q 3 
months for 2 years from 
first treatment or until 
patient is off study, 
whichever is earlier and 
thereafter as clinically 
indicated 
 
 
11.0 
TOXICITIES /SIDE EFFECTS 
 
11.1 
Toxicities are graded by the Common Toxicity Criteria (Version4.0) developed by the 
National Cancer Institute (NCI) of the USA. 
 
 
11.2 
3F8:  Reversible  side-effects  include  pain,  paresthesia,  hypertension,  hypotension, 
tachycardia,  urticaria,  fever,  nausea,  emesis,  and  rarely,  diarrhea,  serum sickne ss, 
hyponatremia, somnolence and posterior reversible encephalopathy syndrome. Other 
potential side-effects that may occur are bronchospasm, anaphylaxis, peripheral 
neuropathy, impaired accommodation of the eye, and poor reactivity of pupils to light. 
 
 
11.3 
GM-CSF: Common side-effects include bone pain, flushing, local reaction at site 
of injection,  leukopenia shortly after injection, and decrease in platelet count.  Rare 
side-effects (predominantly in adults) include allergic reactions, weight gain, pleural 
or pericardial effusion,  pericardial embolism,  thrombosis,  and  difficulty  breathing 
after first injection. 
 
11.4 
Isotretinoin:  Dry  skin,  cheilitis,  dry  eyes,  hypercalcemia,  pseudotumor  cerebri, 
headaches, hepatotoxicity, teratogenic effect on fetus, depressio n, suicidal ideation. 


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12.0 
CRITERIA FOR THERAPEUTIC RES PONSE/OUTCOME ASS ESSMENT 
 
12.1 
Response duration is calculated from first day of treatment with 3F8. 
 
12.2 
All patients are considered a treatment failure under this protocol if P D develops. 
 
12.3 
Disease status  is defined  by the International Neuroblastoma  Response  Criteria, 62 
supplemented by results of MIBG scans. 
 
▪ Complete response/remission (C R): no evidence of disease. 
▪ Very good partial response/remission (VGPR): >90% decrease in all disease 
parameters,   including   primary  tumor,   except  bone   scan   unchanged   or 
improved; bone marrow must be free of disease; MIBG scan negative in 
osteomedullary sites. 
▪ Partial response/remission: >50% decrease in all disease parameters, except 
bone scan unchanged or improved; no more than 1 positive bone marrow site; 
MIBG scan improved in all lesions. 
▪ Mixed response: >50% decrease in >1 but not all disease markers, MIBG scan 
improved in some but not all sites. 
▪ Stable disease: <50% decrease in all tumor markers. 
▪ Progressive disease (P D): new lesion, or >25 % increase in any disease marker. 
 
12.4 
Adequacy of trial: All patients who fulfill the eligibility requirements and receive  a 
first dose of 3F8 will have an adequate trial. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUD Y 
 
13.1 
All patients come off study if PD develops at any time after cycle 1 (see section 12.3). 
 
13.2 
All patients come off study if there is a life-threatening grade 4 toxicity clearly 
attributable to 3F8. 
 
13.3     The investigators will make every reasonable effort to keep each patient in the study 
until all planned treatments and assessments have been performed.  The investigators 
may discontinue study drug treatment for the following reasons: 
 
• Adve rse  e ve nts ,  including  unacceptable  toxicity  or  exacerbation  o f  underlying 
disease, associated with study drug administration and necessitating discontinuation of 
treatment.   Patients who are removed from the study due to adverse events will be 
treated and followed according to established, acceptable medical practice.   All 
pertinent information concerning the outcome of such treatment will be entered in the 
Case Report Form or on the Serious Event Report, as applicable. 
• Withdrawal of conse nt.  The patient's desire to withdraw from the study may occur at 
any time.  The investigator should carefully consider whether the patient’s withdrawal 
of consent is due to an adverse event, and if so, record the adverse event as the reason 
for withdrawal. 


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Page 16 of 25 
 
 
 
 
 
• Withdrawal by the physician for clinical reasons not related to study drug tr eatment, 
for example, clinical need to administer a concomitant medication that is excluded by 
the protocol, in the absence of an adverse event. 
• Violation of the study protocol, including failure to return for required treatments or 
assessments. 
 
14.0 
BIOSTATIS TICS 
 
This trial concerns the anti-NB activity of 3F8/GM-CSF. The response endpoints are relapse- free 
survival for patients treated in C R/VGP R (Groups 1 and 2) and CR of BM disease for patients with 
primary refractory NB (Group 3). Response will be as sessed and compared to historical data, in the 
context of the large experience with the 03-077 predecessor study (section 3.7). 
 
We will treat NB patients with 3F8/GM-CSF provided they meet eligibility criteria of this protocol. 
This protocol will remain open until such a time that 3F8 is licensed for broader use (i.e., as an FDA- 
approved drug). All enrolled patients who receive any 3F8 will be considered in the evaluation of 
safety/toxicity. 
 
15.0 
RESEAR CH PAR TICIPANT REGIS TRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1     Research Participant Re gistration 
 
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 C hecklist. The individua l signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related C linical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research S tudy 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 
 
Registration  reports  will  be  generated  by  the  RSA  to   monitor  patient  accruals  and 
completeness of regsitration data.   Routine data quailty reports will be generated to assess 
missing data and incons istencies.   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. 


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Random-sample data quality and protocol compliance audits will be conducted by the study 
team on an ongoing basis. 
 
16.2     Data and Safe ty Monitoring 
 
The Data and Safety Monitoring (DSM) P lans at Memorial S loan-Kettering Cancer Center 
were approved by the National Cancer Inst itute in September 2001.   The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of C linical Trials” which can be found at: 
http ://ca ncertria ls. nc i. nih. go v/resea rc hers/dsm/inde x. html. The DS M Plans at MSKCC were 
established and are monitored by the O ffice of C linical Research.   The MSKCC Data and 
Safety     Monitoring     P lans     can     be     found     on     the     MSKCC     Intranet     a t: 
http ://inside2 /c linre searc h/Doc ume nts/MSKCC%20Da ta%20a nd%20Sa fety%20Mo nitoring% 
20Pla ns.pd f 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.   There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for P hase I a nd 
II clinical trials, and the Data and Safety Monitoring Board (DSMB) for P hase III clinic a l 
trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol w ill be assessed for its 
level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, 
in- house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
The investigator agrees to conduct this study in accordance with the International Conference 
on Harmonization (ICH) principles of Good C linical P ractice and with the Declaration of 
Helsinki (1989).  The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws of the applicable regulatory agencies. 
 
Most patients will be children, adolescents, and young adults because of the nature of t hese 
tumors.   Patients of both sexes and all ethnic backgrounds are eligible for this study. 
Alternative treatments are available and will be discussed with patient or legal guardian. 
Patients are responsible for the costs of physician visits and usual laboratory tests, 
hospitalizations, and outpatient care.  They are not responsible for the cost of 3F8.  If there is 
an injury as a result of this research study, emergency care, hospitalization, and outpatient 
care will be made available by Memorial Hospit al 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. 
 
17.1     Privacy 


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MSKCC’s Privacy O ffice 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 (IRB/P B). 
 
17.2     Se rious Adve rse Eve nt (S AE) Re porting 
 
Any SAE must be reported to the IRB/P B as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research D atabase (CRDB) SAE report be submitted 
electronically to the SAE O ffice at  sae@ mskcc.org.  The report should contain the following 
information: 
 
Fields populated from C RDB: 
 
• 
Subject’s name (generate the report with only  initials if it will be sent outside of 
MSKCC) 
• 
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 
• 
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 
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 C RDB AE report should be completed as above and the FDA assigned IN D/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
 
 
 
17.2.1 
 
SAEs are defined as grade 4  toxicities other than fatigue,  weight  loss or gain, anorex ia, 
nausea, anxiety, constipation, urinary retention from opioid analgesics, somnolence, 
hallucinations,  disorientation,  confusion,  agitation, anxiety  from antihistamine and  opioid 


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Page 19 of 25 
 
 
 
 
 
premedications, hypomagnesemia, fever, rash, dry skin from isotretinoin, urticaria from 3F8 
or GM-CSF, myelosuppression from the combination of 3F8 and GM-CSF, pain and transient 
hypoxia from opioids, and breath-holding with or without transient oxygen requirement.  P re- 
existing conditions,  e.g.,  hearing  loss,  abnormal liver  func tion tests  from total parenteral 
nutrition,   and   alopecia,   are   not   counted   as  S AEs.   Hospitalizations  that  arise   from 
complications of chemotherapy are considered part of standard care and therefore will not be 
reported. 
 
18.0     INFORMED CONSENT PROCEDUR ES 
 
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/P B-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/P rivacy 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 r esearch specific information.   In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
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 
 
1a. 
Search Orphan Drug Designations and Approvals. US Department of Health and Human 
Services, US Food and Drug Administration. 


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Page 20 of 25 
 
 
 
 
 
http ://www.acce ssdata. fda. go v/scrip ts/opd listing/oopd /OOPD_Results_2.c fm? Inde x_Number=26880 
8. Accessed November 19, 2013. 
 
1.         Maris JM: Recent advances in neuroblastoma.  N Engl J Med; 362:2202-11, 2010 
 
2.         Pearson  A,  P inkerton  CR,   Lewis  IJ,  et  al:  High-dose  rapid  and  standard   induction 
chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: A randomised trial. Lancet 
Oncol 9:247-256, 2008 
 
3.         Kushner BH, Kramer K, LaQ uaglia MP, Modak S, Yataghene K, Cheung N-KV:  Reduction 
from seven to five cycles of intensive induction chemotherapy in children with high-risk 
neuroblastoma.  J C lin O ncol 22:4888-4892, 2004 
 
4.         Park    JR,    Scott   JR,    Stewart   CF,    et   al:   P ilot    induction   regimen    incorporating 
pharmacokinetically guided topotecan for treatment of newly diagnosed high risk neuroblastoma: A 
Children’s Oncology Group study. J C lin O ncol 29:4351-4357, 2011 
 
5.         Franks LM,  Bollen A, Seeger RC, et al:   Neuroblastoma in adults and adolescents.   An 
indolent course with poor survival.  Cancer 79:2028-35, 1997 
 
6.         Kushner  BH,  Kramer  K,  LaQ uaglia  MP,  Modak  S,  Cheung  N -KV:    Neuroblastoma  in 
adolescents and adults: The Memorial S loan-Kettering experience. Med Pediatr Oncol 41:508-515, 
2003 
 
7.         Kushner BH, Wolden S, LaQuaglia MP, Kramer K, Verbel D, Heller G, Cheung N -KV: 
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20.0 
APPENDICES 
 
Appendix A: Research Patient Diaries