Clinical trial NCT03332667
Conditions: Neuroblastoma
Sponsor: New Approaches to Neuroblastoma Therapy Consortium
Start date: 2018-09-12; Completion date: 2024-02-23
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
131I-Metaiodobenzylguanidine (131I-MIBG) is one of the most effective therapies utilized for neuroblastoma patients with refractory or relapsed disease. In this pediatric phase 1 trial, 131I-MIBG will be given in combination with dinutuximab, a chimeric 14.18 monoclonal antibody. This study will utilize a traditional Phase I rolling 6 dose escalation design to determine a recommended phase 2 pediatric dose. An expansion cohort of an additional 6 patients will then be enrolled. If tolerable, vorinostat will then be added to the third dose level. A 6 patient expansion cohort may then be enrolled.

Detailed description:
131I-Metaiodobenzylguanidine (131I-MIBG) is one of the most effective therapies utilized for neuroblastoma patients with refractory or relapsed disease. Data from pre-clinical and adult studies suggest that radiation can enhance the efficacy of immunotherapy and targeted therapies such as dinutuximab. This first pediatric phase 1 trial of 131I-MIBG in combination with dinutuximab and vorinostat aims to determine the recommended phase 2 pediatric dose of these three therapies in combination.

Arms: arm 1: Patients will receive 131I-MIBG on day 1 at 12 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. Patient will receive GM-CSF on days 8-17 and 29-38 at 250 mcg/m2. All patients will receive autologous hematopoietic stem cell infusion on day 15 (+/- 2) of therapy arm 2: Patients will receive 131I-MIBG on day 1 at 15 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. Patient will receive GM-CSF on days 8-17 and 29-38 at 250 mcg/m2. All patients will receive autologous hematopoietic stem cell infusion on day 15 (+/- 2) of therapy arm 3: Patients will receive 131I-MIBG on day 1 at 18 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. Patient will receive GM-CSF on days 8-17 and 29-38 at 250 mcg/m2. All patients will receive autologous hematopoietic stem cell infusion on day 15 (+/- 2) of therapy arm 4: Vorinostat will be given on days 0-13 at 180 mg/m2/dose. Patients will receive 131I-MIBG on day 1 at 18 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. Patient will receive GM-CSF on days 8-17 and 29-38 at 250 mcg/m2. All patients will receive autologous hematopoietic stem cell infusion on day 15 (+/- 2) of therapy
Interventions: intervention 1: 131I-MIBG intervention 2: Dinutuximab intervention 3: Vorinostat intervention 4: Sargramostim intervention 5: Potassium Iodide
Intervention descriptions: intervention 1: Patients will receive 131I-MIBG on day 1. 131I-MIBG dose will be based on the dose level assigned at the time of patient registration intervention 2: Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy. Dinutuximab dose will be based on the dose level assigned at the time of patient registration. intervention 3: Vorinostat will be given on day 0-13. Vorinostat dose will be based on the dose level assigned at the time of patient registration. intervention 4: Sargramostim (GM-CSF) will be given on day 8-17 at 250 mcg/m\^2 intervention 5: Potassium iodide will be given by mouth at a dose of 6mg/kg 8-12 hours prior to infusion of 131I-MIBG on Day 1 and then 1mg/kg/dose by mouth starting 4-6 hours after completion of MIBG infusion and continuing every 4 hours on protocol days 1-7 and then 1mg/kg/dose by mouth once daily on protocol days 8-45

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
NANT 2017-01: A PHASE I STUDY OF 131I-MIBG WITH DINUTUXIMAB +/- VORINOSTAT FOR 
RELAPSED/REFRACTORY NEUROBLASTOMA 
 
NCT03332667 
 
Protocol Version 02/21/2022 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
1 
 
   
 
NEW APPROACHES TO NEUROBLASTOMA THERAPY (NANT) CONSORTIUM 
 
NANT 2017-01:  A PHASE I STUDY OF 131I-MIBG WITH DINUTUXIMAB +/- VORINOSTAT FOR 
RELAPSED/REFRACTORY NEUROBLASTOMA 
IND# 137554 
 
COORDINATING CENTER 
Children’s Hospital Los Angeles / NANT Operations Center 
 
PARTICIPATING INSTITUTIONS AND CONTACT PHYSICIANS 
 
UCSF School of Medicine, 550 16th Street, 4th Floor San Francisco, CA 94158 
Kieuhoa Vo, MD, Phone: 415-476-3831; Email: kieuhoa.vo@ucsf.edu  
 
Children’s Hospital Los Angeles, 4650 Sunset Boulevard, MS 54 Los Angeles, CA 90027 
Araz Marachelian, MD, Phone: 323-361-8573; Email: amarachelian@chla.usc.edu 
 
Cincinnati Children’s Hospital, 3333 Burnett Avenue MLC 7015 Cincinnati, OH 45229 
Brian Weiss, MD, Phone: 513-636-9863; Email: brian.weiss@cchmc.org 
 
Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 3056 Philadelphia, PA 19104 
Yael P. Mosse, MD, Phone: 215-590-0965; Email: mosse@chop.edu 
 
C.S. Mott Children’s Hospital, 1500 East Medical Center Drive, D4202 MPB Ann Arbor, MI 48109 
Rajen Mody, MD, Phone: 734-232-9335; Email: rmody@med.umich.edu 
 
Seattle Children’s Hospital, 4800 Sand Point Way Northeast, MS-6D1 Seattle, WA 98105 
Navin Pinto, MD, Phone: 206-987-5783; Email: navin.pinto@seattlechildrens.org 
 
Children’s Hospital Boston, Dana-Farber Cancer Institute, 450 Brookline Ave, Suite 350 Boston MA 02115 
Suzanne Shusterman, MD, Phone: 617-632-4901; Email: suzanne_shusterman@dfci.harvard.edu 
 
Children’s Healthcare of Atlanta, 1760 Haygood Dr., HSRB E372, GA 30322 
Kelly Goldsmith, MD, Phone: 404- 727-2655; Email: kgoldsm@emory.org  
 
University of Chicago, Comer Children’s Hospital, 900 East 57th Street KCBD RM 5100 Chicago, IL 60637 
Ami Desai, MD, Phone: 773-843-3943; Email: adesai12@peds.bsd.uchicago.edu 
 
Cook Children’s Healthcare System, 901 Seventh Avenue, Suite 220 Fort Worth, TX 76104 
Meaghan Granger, MD, Phone: 682-885-4007; Email: mgranger@cookchildrens.org 
 
Children’s Hospital Colorado, 13123 East 16thAve. B-115, Aurora, CO 80045 
Margaret Macy, MD, Phone: 720-777-8856; Email: Margaret.macy@childrenscolorado.org 
 
 
 
 
Protocol Chair 
Thomas Cash, MD, MSc 
Children’s Healthcare of Atlanta 
Phone:  404-785-0910 
Email: thomas.cash@choa.org  
 
 
Protocol Vice-Chair 
Kelly Goldsmith, MD 
Children’s Healthcare of Atlanta 
Phone: 404-727-2655 
Email: kgoldsm@emory.edu 
 
Protocol Vice-Chair 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles 
Phone:323-361-8573 
Email: amarachelian@chla.usc.edu 
 
 
 
 
Activated: 01/05/2018 
  Version Date:  02/21/2022 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
2 
 
TABLE OF CONTENTS 
 
IND SPONSOR 7 
ABSTRACT 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
13 
2.0 
BACKGROUND 
14 
2.1  
NEUROBLASTOMA 
14 
2.2 
Clinical Experience with 131I-MIBG for Neuroblastoma 
14 
2.3 
Clinical Experience with 131I-MIBG in Combination with Other Agents for Neuroblastoma 
14 
2.4 
Clinical Experience with Dinutuximab for Neuroblastoma 
14 
2.5 
Pre-clinical and Clinical Experience with Dinutuximab in Combination with Chemotherapy for 
Neuroblastoma 
15 
2.6 
Rationale for Combining Dinutuximab with Radiation Therapy 
15 
2.7 
Summary and Rationale for Clinical Use of 131I-MIBG with Dinutuximab 
16 
2.8 
Correlative and Biology Studies 
16 
2.9  
Preclinical Experience with Vorinostat in Neuroblastoma 
18 
2.10  
Rationale for Testing Vorinostat in Combination with 131I-MIBG and Dinutuximab 18 
2.11  
Rationale for Protocol Amendments 
19 
3.0 
 PATIENT ELIGIBILITY CRITERIA AND REGISTRATION 
21 
3.1 
 Patient Preparation for Study Entry and Registration 
21 
3.2 
Inclusion Criteria 
22 
3.3 
Exclusion Criteria 
27 
3.4 
Regulatory 
27 
4.0 
TREATMENT PROGRAM 
28 
4.1 
Treatment Overview 
28 
4.2      Drug Administration 
30 
4.3 
Dose Escalation Schedule 
37 
4.4 
Definition of Dose-Limiting Toxicity (DLT) 
37 
4.5 
Dose Modification and Recommendations for Management of Dinutuximab/GM-CSF  Toxicity
 
40 
5.0 
SUPPORTIVE CARE 
47 
5.1   
Prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) 
47 
5.2 
Use of Myeloid Growth Factors 
47 
5.3 
Antiemetics 
47 
5.4 
Fever During MIBG 
47 
5.5  
Supportive Care During Dinutuximab Therapy 
47 
5.6 
Other 47 
6.0  
 DRUG INFORMATION 
48 
6.1 
131I-Meta-Iodo-Benzyl-Guanidine (DraxImage® Therapeutic 131I-MIBG) 
48 
6.2 
Dinutuximab (Chimeric Monoclonal Antibody 14.18; Chimeric MOAB 14.18; human/murine  anti-GD2 
monoclonal  antibody; chimeric anti-GD2; chimeric mAb 14.18; ch14.18;  Unituxin®) NSC# 764038
 
50 
6.3 
SARGRAMOSTIM (Granulocyte Macrophage Colony Stimulating Factor, rhu GM-CSF, rGM- CSF, 
GM-CSF, Leukine®) NSC #613795 
53 
6.4 
POTASSIUM IODIDE (KI, SSKI) 
55 
6.5 
VORINOSTAT (ZOLINZA™) 
55 
7.0    
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
58 
7.1 
Clinical and Laboratory Assessments 
58 
7.2 
Recommended Follow-Up Observations 
60 
7.3  
Documentation of Tumor Response 
60 
8.0 
CORRELATIVE BIOLOGY STUDIES (SEE APPENDIX II) 
61 
8.1 
Characterization of Immune and Cytokine Profile Following 131I-MIBG Therapy (Required) 
61 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
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8.2 
Human anti-Chimeric Antibody (HACA) and Neutralizing Anti-Drug Antibody (ADA) Levels  
(Required) 
63 
8.3 
Shipping Instructions 
64 
8.4 
Minimal Residual Disease by TaqMan low density array (NB5/TLDA) (Required) 
65 
8.5 
RNA Gene Expression Studies (Optional) 
65 
8.6 
Isolation of DNA for Future Gene Expression Studies (Optional) 
67 
8.7 
Storage of Remaining Biologic Samples for Future Analysis (Optional) 
67 
8.8 
Evaluation of the Tumor Microenvironment (Optional) 
67 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
69 
9.1 
Criteria for Removal from Protocol Therapy 
69 
9.2 
Off Study Criteria 
69 
10.0 
STATISTICAL CONSIDERATIONS 
70 
10.1 
Sample Size and Study Duration 
70 
10.2  
Definitions 
71 
10.3 
Dose Escalation 
72 
10.4 
Analysis of Results 
76 
10.5 
Monitoring Plan for Specific Toxicities 
77 
10.6  
Analysis of Correlative Studies 
77 
10.7     Inclusion of Women and Minorities 
77 
11.0 
NANT RESPONSE CRITERIA V2.0 
78 
11.1 
Soft Tissue Response Criteria 
78 
11.2 
Bone Marrow Response Criteria 
80 
11.3. 
Bone Response Criteria Using MIBG Scans (for MIBG avid tumors) 
82 
11.4 
Bone Response Criteria Using FDG-PET Scans (only for MIBG non-avid tumors) 83 
11.5 
Urine Catecholamines 
84 
11.6 
Definition of Overall Response 
84 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
88 
12.1 
Purpose 
88 
12.2 
Definitions 
88 
12.3 
Expedited Serious Adverse Event Reporting to NANT Operations 
89 
12.4 
Expedited Adverse Event Reporting to the FDA 
89 
12.5 
NANT Operations Center Role in Expedited Adverse Event Reporting to the FDA and  Participating 
Sites 
90 
12.6  
Adverse Event Reporting Requirements for United Therapeutics Corporation 
91 
12.7  
Adverse Event Reporting Requirements for Jubilant DraxImage 
91 
12.8 
Reporting Secondary AML/MDS 
91 
12.9   
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
91 
13.0 
RECORDS AND REPORTING 
92 
14.0 
REFERENCES 
93 
15.0 
SAMPLE INFORMED CONSENT 
98 
16.0 
SAMPLE INFORMED ASSENT 
136 
APPENDIX I: 
PERFORMANCE STATUS SCALES/SCORES 
146 
APPENDIX II: SUMMARY FOR CORRELATIVE STUDIES 
147 
APPENDIX III: ADJUSTED BODY WEIGHT CALCULATION FOR STEM CELL DOSING 
150 
APPENDIX IV: COMPOUNDS THAT INTERFERE WITH MIBG METABOLISM AND UPTAKE 
151 
APPENDIX V: QUALITY CONTROL FOR FREE IODINE IN 131I-MIBG (DETECTION OF RADIOLYTIC152 
DECOMPOSITION) 
152 
APPENDIX VI: ISOLATION AND STORAGE OF PLASMA AND PERIPHERAL BLOOD MONONUCLEAR CELLS 
(PBMCS) 
153 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
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INFORMATION REGARDING CERTIFICATE OF CONFIDENTIALITY 
 
The New Approaches to Neuroblastoma Therapy (NANT) consortium has received a Certificate of Confidentiality from 
the federal government, which will help us protect the privacy of our research subjects.  The Certificate protects against 
the involuntary release of information about subjects collected during the course of our covered studies.  The researchers 
involved in the studies cannot be forced to disclose the identity or any information collected in the study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative 
proceedings.  However, the subject or family member, or the researcher may choose to voluntarily disclose the protected 
information under certain circumstances.  For example, if the subject or his/her guardian requests the release of 
information in writing, the Certificate does not protect against that voluntary disclosure.  Furthermore, federal agencies 
may review our records under limited circumstances, such as a DHHS request for information for an audit or program 
evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect 
against the required reporting by hospital staff of information on suspected child abuse, reportable communicable 
diseases, and/or possible threat of harm to self or others. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
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STUDY COMMITTEE 
 
STUDY CHAIR 
Thomas Cash, MD, MSc 
Children's Healthcare of Atlanta 
1760 Haygood Drive, HSRB W350 
Atlanta, GA 30322 
Phone: 404-785-0910  
Fax: 404-727-4455 
Email: thomas.cash@choa.org 
STUDY VICE CHAIR 
Kelly Goldsmith, MD                       
Children’s Healthcare of Atlanta    
1760 Haygood Drive, HSRB E372  
Atlanta, GA 30322                           
Phone: 404-727-2655                     
Fax: 404-727-4455                          
Email: kgoldsm@emory.edu           
                                                      
 
STUDY VICE CHAIR 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles 
Division of Hematology/Oncology  
4650 Sunset Boulevard, MS 54 
Los Angeles, CA 90027 
Office:323-361-8573 
Fax: 323-361-1803 
Email: amarachelian@chla.usc.edu 
STUDY STATISTICIAN 
Yueh-Yun Chi, PhD 
Children’s Hospital Los Angeles 
Division of Hematology/Oncology  
4650 Sunset Boulevard, MS 57 
Los Angeles, CA 90027 
Phone: 323-261-8582 
Fax: 323-865-0133 
Email: ychi@chla.usc.edu 
 
COMMITTEE MEMBER 
Shahab Asgharzadeh, MD 
Children’s Hospital Los Angeles 
4650 Sunset Boulevard, MS-57 
Los Angeles, CA 90027 
Phone: 323-361-8643 
Fax: 323-361-4902 
Email: sasgharzadeh@chla.usc.edu 
 
COMMITTEE MEMBER 
Steve DuBois, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue, Dana 3 
Boston, MA  02215 
Phone : 617-632-5460 
Fax: 617-632-4811 
Email: steven_dubois@dfci.harvard.edu 
 
COMMITTEE MEMBER 
W. Clay Gustafson MD/PhD 
UCSF Pediatric Hematology/Oncology 
1550 4th St, Rock Hall Rm 382 
San Francisco, CA 94158 
Phone: 415-502-3602 
Fax: 415-502-4372 
Email: Clay.Gustafson@ucsf.edu 
 
 
COMMITTEE MEMBER 
Gregory Yanik, MD 
C.S. Mott Children’s Hospital 
1500 E. Medical Center Drive B1-208 
Ann Arbor, MI 48109 
Office: 734-936-8785 
Fax: 734-936-8788 
Email: 
rmody@med.umich.edugyanik@umich.edu 
 
COMMITTEE MEMBER 
Katherine Matthay, MD 
UCSF School of Medicine, Mailstop 0434 
550 16th Street, 4th Floor 
San Francisco, CA 94158-2549 
Phone: 415-476-0603 
Fax: 415-476-5356 
Email: kate.matthay@ucsf.edu 
 
 
 
PROTOCOL NURSE 
Beth Hasenauer, RN 
Children’s Hospital Los Angeles 
NANT Operations 
4650 Sunset Blvd, MS-54 
Los Angeles, CA  90027 
Phone: 323-361-5631 
Fax: 323-361-1803 
Email: chasenauer@chla.usc.edu  
PROTOCOL COORDINATOR 
Alina Stout, MPH 
Children’s Hospital Los Angeles 
NANT Operations 
4650 Sunset Blvd, MS-54 
Los Angeles, CA  90027 
Phone: 323-361-8392 
Fax: 323-361-1803 
Email: astout@chla.usc.edu 
 
 
 
RESEARCH COORDINATOR 
NANT Operations Center 
Children’s Hospital Los Angeles 
4650 Sunset Blvd., MS-54 
Los Angeles, CA 90027 
Phone:323-361-5687 
Fax:323-361-1803 
Email: nantcrf@chla.usc.edu 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
6 
 
NANT CONSORTIUM INSTITUTIONS 
 
Kieuhoa Vo, MD 
UCSF School of Medicine 
550 16th Street, 4th Floor 
San Francisco, CA 94158-2549 
Office:415-476-3831;  
Fax: 415-476-5356 
Email: kieuhoa.vo@ucsf.edu 
 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles 
Division of Hematology/Oncology 
4650 Sunset Boulevard, MS 54 
Los Angeles, CA 90027 
Office:323-361-8573 
Fax: 323-361-1803 
Email: amarachelian@chla.usc.edu 
 
Rajen Mody, MD 
C.S. Mott Children’s Hospital 
1500 E. Medical Center Drive D4202 
MPB 
Ann Arbor, MI 48109-5718 
Office: 734-232-9335 
Fax: 734-615-0464 
Email: rmody@med.umich.edu 
 
Brian Weiss, MD 
Cincinnati Children’s Hospital 
Department of Pediatric Oncology 
3333 Burnett Avenue, MLC 7015 
Cincinnati, OH 45229 
Office:513-636-9863 
Fax: 513-636-3549 
Email: brian.weiss@cchmc.org 
Yael P. Mosse, MD 
Children's Hospital of Philadelphia 
Division of Oncology 
3501 Civic Center Boulevard, 
CTRB 3056 
Philadelphia, PA 19104 
Office: 215-590-0965  
Fax: 267-426-0685 
Email: mosse@chop.edu 
Suzanne Shusterman, MD 
Children’s Hospital Boston 
Dana-Farber Cancer Institute 
450 Brookline Avenue, Suite 350 
Boston, MA 02115 
Office: 617-632-4901 
Fax: 617-632-3270 
Email:suzanne_shusterman@dfci.harva
rd.edu 
Margaret Macy, MD 
Children’s Hospital Colorado 
13123 East 16thAve. B-115 
Aurora, CO 80045 
Office: 720-777-8856 
Fax: 720-777-7289 
Email: 
Margaret.macy@childrenscolorado.
org 
Navin Pinto, MD 
Seattle Children’s Hospital 
Division Hematology/Oncology 
4800 Sand Point Way NE MS6D1 
Seattle, WA  98105 
Office: 206-987-5783 
Fax: 206-987-3946 
Email: navin.pinto@seattlechildrens.org 
Ami Desai, MD 
University of Chicago 
Comer Children’s Hospital 
900 East 57th Street KCBD, RM5100 
Chicago, IL 60637 
Office: 773-843-3943 
Fax:773-702-9881 
Email: :adesai12@peds.bsd.uchicago.edu 
 
Meaghan Granger, MD 
Cook Children’s Healthcare System 
901 Seventh Avenue, Suite 220 
Fort Worth, TX 76104 
Office: 682-885-4007 
Fax: 682-885-1713 
Email: mgranger@cookchildrens.org 
Kelly Goldsmith, MD 
Children’s Healthcare of Atlanta. 
1760 Haygood Dr., HSRB E372 
Atlanta, GA 30322 
Office: 404-727-2655 
Fax: 404-727-4455 
Email: kgoldsm@emory.edu 
 
 
 
 
 
 
 
 
 
 
 


 
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IND SPONSOR 
 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles 
Division of Hematology/Oncology  
4650 Sunset Boulevard, MS 54 
Los Angeles, CA 90027 
Office:323-361-8573 
Fax: 323-361-1803 
Email: amarachelian@chla.usc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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ABSTRACT 
 
Relapsed neuroblastoma is incurable in the majority of cases. One of the most effective therapies utilized 
when patients have refractory or relapsed disease is 131I-Metaiodobenzylguanidine (131I-MIBG). Previous 
studies have proven that it is safe to combine 131I-MIBG with putative radiation sensitizers, and an ongoing 
clinical trial seeks to determine if MIBG in combination with these agents is more efficacious than giving 
MIBG alone. Dinutuximab, a chimeric 14.18 monoclonal antibody that targets the tumor cell surface marker 
glycosphingolipid GD2 ganglioside (GD2), has significantly improved the event-free survival for patients 
with high-risk neuroblastoma when given as part of upfront therapy. A recent study performed by the 
Children’s Oncology Group (COG) has demonstrated that dinutuximab can be safely given with cytotoxic 
chemotherapy, and unlike previous studies with dinutuximab as a single agent, can produce responses 
even in patients with bulky disease. Data from pre-clinical and adult studies suggest that radiation can 
enhance the efficacy of immunotherapy and targeted therapies such as dinutuximab. We propose a phase 
I, dose-escalation study of 131I-MIBG given in combination with dinutuximab (Part A). The primary objective 
of this part of the study is to define the recommended phase 2 dose (RP2D) of 131I-MIBG and dinutuximab 
when given in combination, and to define and describe the toxicities. In Part B, we will add vorinostat to the 
131I-MIBG and dinutuximab combination, at the RP2D determined in Part A. The rationale for this is based 
on pre-clinical data demonstrating that vorinostat increases GD2 cell surface expression in neuroblastoma 
cells, leading to increased anti-tumor activity when combined with anti-GD2 antibody in murine models of 
neuroblastoma, and clinical data from NANT 11-01 demonstrating that the addition of vorinostat to 
therapeutic 131I-MIBG produces a higher objective response rate compared to 131I-MIBG alone. The primary 
objective of Part B is to define the RP2D of vorinostat in combination with 131I-MIBG and dinutuximab, and 
to define and describe the toxicities of this combination. 
 
 


NANT 2017-01 Amendment 5 v02.21.2022 
9 
SIGNATURE PAGE 
NANT 2017-01: A Phase I Study of 131I-MIBG with Dinutuximab +/- Vorinostat for Relapsed/Refractory 
Neuroblastoma 
Amendment #5 Protocol Version: 02/21/2022 
This protocol has been approved by: 
Name: Araz Marachelian, M.D., M.S. 
Study Role: NANT Medical Director 
Signature: ________________________ 
Date: ________________________ 
Name: Thomas Cash, M.D., M.Sc. 
Study Role: Study Chairperson 
Signature: ________________________ 
Date: ________________________ 
This protocol describes the NANT 2017-01 131I-MIBG with Dinutuximab +/- Vorinostat study and provides 
information about procedures for patients taking part in this study. 
This protocol has been reviewed and acknowledged by: 
Name:   __________________________ 
Study Role: Site Principal Investigator 
Signature: ________________________ 
Date:  ________________________ 
02/21/2022
02/21/2022


 
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TABLE 1: EXPERIMENTAL DESIGN SCHEMA FOR PART A 
 
DAY 
1 
2-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18-28 
131I-MIBG (M) 
dose level 
assignment 
M 
GM-CSF (G) 
250 mcg/m
2 
 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
DINUTUXIMAB (D) 
dose level 
assignment 
 
D 
D 
D 
D 
Stem Cell Infusion 
(HSC) 
 
 
 
HSC 
+/- 
2d 
 
DAY 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
43-57 
GM-CSF (G) 
250 mcg/m
2 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
DINUTUXIMAB (D) 
dose level assignment  
D 
D 
D 
D 
 
 
 
 
 
 
  
Disease Evaluation 
(Eval) 
 
 
 
Eval 
 
Patients receive 131I-MIBG on Day 1. The dose of 131I-MIBG and dinutuximab will be based on the dose 
level assigned at the time of patient registration.  Dinutuximab is given intravenously on Days 8-11 and 29-
32 of therapy, with GM-CSF 250mcg/m2 given on Days 8-17 and 29-38. All patients receive autologous 
hematopoietic stem cell infusion on Day 15 (+/- 2) of therapy. This must occur at a NANT site.  
 
Course duration is defined as 57 days.  All patients will undergo disease restaging between Days 43 – 57.  
Patients may receive up to two courses of therapy as long as all protocol-defined criteria are met prior to 
the start of the second course.  
  
TABLE 2: Dose Escalation Schema for Part A 
 
Dose Level 
131I-MIBG (mCi/kg/dose) 
Dinutuximab 
(mg/m2/dose) 
0 
12 
14 
Starting Dose Level: 
1 
12 
17.5 
 
2 
15 
17.5 
3 
18 
17.5 
Dose escalation will begin at Dose Level 1, with escalation up to Dose Level 3 following the Rolling 6 dose 
escalation design.  If Dose Level 1 is deemed intolerable per the dose escalation rules, then Dose Level 0 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
11 
 
will be evaluated.  Patients will be treated at the assigned dose of 131I-MIBG and dinutuximab.  There will 
be no intrapatient dose escalation. 
 
 
TABLE 3: EXPERIMENTAL DESIGN SCHEMA FOR PART B 
 
DAY 
0 
1 
2-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18-28 
Vorinostat (V) 
dose level 
assignment 
V 
V 
V 
V 
V 
V 
V 
V 
V 
 
 
 
 
 
131I-MIBG (M) 
dose level 
assignment 
 
M 
GM-CSF (G) 
250 mcg/m
2 
 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
DINUTUXIMAB (D) 
17.5 mg/m2 
 
D 
D 
D 
D 
Stem Cell Infusion 
(HSC) 
 
 
 
HSC 
+2d / 
-1d 
 
DAY 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
43-57 
GM-CSF (G) 
250 mcg/m
2 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
DINUTUXIMAB (D) 
dose level assignment  
D 
D 
D 
D 
 
 
 
  
Disease Evaluation 
(Eval) 
 
 
 
Eval 
 
Patients receive vorinostat on Days 0 to +13 (14 days) followed by 131I-MIBG on Day 1. The dose of 
vorinostat and 131I-MIBG will be based on the dose level assigned at the time of patient registration.  
Dinutuximab 17.5 mg/m2 will be given intravenously on Days 8-11 and 29-32 of therapy, with GM-CSF 250 
mcg/m2 given on Days 8-17 and 29-38. All patients will receive autologous hematopoietic stem cell infusion 
on Day 15 (+ 2d/-1d) of therapy. There must be at least 24 hours between the last dose of vorinostat and 
stem cell infusion. Stem cell infusion must occur at a NANT site.  
 
Course duration is defined as 57 days.  All patients will undergo disease restaging between Days 43 – 57.  
Patients may receive up to two courses of therapy as long as all protocol-defined criteria are met prior to 
the start of the second course.  
 
 
 
 
 


 
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TABLE 4: Dose Escalation Schema for Part B 
 
Dose Level 
Vorinostat 
(mg/m2/dose)# 
131I-MIBG 
(mCi/kg/dose) 
Dinutuximab 
(mg/m2/dose) 
Starting Dose Level 
4 
180 
18 
17.5 
 
4a* 
150 
18 
17.5 
#Maximum vorinostat dose: 400 mg 
*De-escalation Dose Level 4a to enroll only if Dose Level 4 is not tolerated 
 
The starting dose level for Part B will be Dose Level 4. Patients on this dose level will receive vorinostat at 
180 mg/m2/dose,131I-MIBG at 18 mCi/kg/dose, and dinutuximab at 17.5 mg/m2/dose. Enrollment will follow 
the Rolling 6 dose escalation design. If Dose Level 4 is deemed intolerable per the dose escalation rules, 
then Dose Level 4a will be evaluated. There will be no intrapatient dose escalation. Once the RP2D is 
established in Part B, we will enroll a 6-patient expansion cohort to obtain additional toxicity and biologic 
correlate data with the MIBG, dinutuximab, and vorinostat combination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
a. To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) 
of 131I-MIBG administered with fixed doses of dinutuximab in children with relapsed or refractory 
neuroblastoma. 
 
b. To define and describe the toxicities of 131I-MIBG in combination with dinutuximab administered 
on this schedule to this population. 
 
c. To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) 
of vorinostat in combination with 131I-MIBG and dinutuximab in children with relapsed or 
refractory neuroblastoma. 
 
d. To define and describe the toxicities of vorinostat in combination with 131I-MIBG and  
dinutuximab administered on this schedule to this population. 
 
1.2 
Secondary Aim 
 
a. To preliminarily define the response rate of 131I-MIBG in combination with dinutuximab in 
patients with relapsed or refractory neuroblastoma within the confines of a Phase I study. 
 
b. To preliminarily define the response rate of vorinostat in combination with 131I-MIBG and  
dinutuximab in patients with relapsed or refractory neuroblastoma within the confines of a 
Phase I study. 
 
1.3 
Exploratory Aims 
 
a. To assess the immune and cytokine profile of patients on this regimen and describe the 
relationship between immune and cytokine profile and response to treatment.  
 
b. To describe the production of human anti-chimeric antibodies (HACA) and neutralizing anti-
drug antibodies (ADA) when 131I-MIBG is given in conjunction with dinutuximab +/- vorinostat. 
 
c. To assess peripheral blood and bone marrow minimal residual disease at study entry and 
following treatment with 131I-MIBG and dinutuximab +/- vorinostat, quantified using a 
neuroblastoma-specific NB-5 assay by TaqMan low density array (TLDA). 
 
d. To assess the tumor immune-microenvironment (gene expression; immune effector cells, 
activities and signaling molecules; immune target expression) following treatment with 131I-
MIBG and dinutuximab +/- vorinostat.  
 
e. To study the association between changes in the tumor immune-microenvironment (gene 
expression; immune effector cells, activities and signaling molecules; immune target 
expression) with response following treatment with 131I-MIBG and dinutuximab +/- vorinostat. 
 
 
 
 
 
 


 
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2.0 
BACKGROUND 
 
2.1  
Neuroblastoma  
Neuroblastoma is the most common extracranial solid tumor of childhood. While it comprises only 8% of all 
childhood cancer cases, neuroblastoma is responsible for 12% of cancer deaths in children under 15 years 
of age (1,2). Approximately 50% of neuroblastoma patients are classified as high-risk, and over half of 
these children will die from their disease despite intensive multi-modal therapy (3,4). The prognosis is even 
more grim for patients whose disease is refractory to initial therapy or who experience a recurrence of their 
tumor during or after completion of therapy, as the vast majority of these patients cannot be cured (5,6).  
 
2.2 
Clinical Experience with 131I-MIBG for Neuroblastoma 
Metaiodobenzylguanidine (MIBG) is a norepinephrine analog that is selectively taken up by sympathetic 
nervous system tissue through the cell surface norepinephrine transporter (7). Approximately 90% of 
neuroblastoma tumors accumulate MIBG, making this a potential therapeutic target (8,9). MIBG labeled 
with iodine-123 (123I-MIBG) has become a key component of the diagnostic, staging, and response 
evaluation in neuroblastoma. MIBG labeled with iodine-131 (131I-MIBG) can be used as a systemic, targeted 
radiotherapy and has demonstrated activity in both relapsed/refractory and newly diagnosed patients (10-
15). In a single-agent phase I dose-escalation study, 131I-MIBG showed a response rate of 37% in children 
with relapsed disease, with 10 mCi/kg being the minimum dose at which responses were seen (16). A 
phase II study at the recommended phase II dose of 18 mCi/kg, showed a 36% response rate with another 
34% of patients with stable disease (17). The primary toxicity of 131I-MIBG is myelosuppression, particularly 
thrombocytopenia, and about one-third to one-half of patients will require autologous hematopoietic stem-
cell transplantation (AHSCT) (16-18). Because of this, it is now standard practice to prophylactically perform 
an AHSCT in the majority of patients approximately 2 weeks after MIBG infusion. Non-hematologic toxicity 
is rare, with grade 3 or 4 hepatic toxicity in 5%, pulmonary toxicity in 3.6%, infectious toxicity in 10.9%, and 
febrile neutropenia in 9.7% (17). 
 
2.3 
Clinical Experience with 131I-MIBG in Combination with Other Agents for Neuroblastoma 
Several clinical trials have sought to improve upon the success of single agent 131I-MIBG by combining it 
with other chemotherapeutic agents. The New Approaches to Neuroblastoma Therapy (NANT) consortium 
conducted a phase I study of 131I-MIBG in combination with vincristine and irinotecan. This combination 
was well-tolerated at a maximum 131I-MIBG dose of 18 mCi/kg. Dose-limiting toxicities (DLTs) included 
grade 3 diarrhea (dose level 15 mCi/kg), grade 3 ALT elevation (dose level 18 mCi/kg), and grade 3 
hallucination (dose level 18 mCi/kg). There were no unexpected hematologic toxicities and the objective 
response rate was 25% (19). A subsequent pilot study showed that by giving the irinotecan over one week 
instead of two that you could reduce the amount of grade 3 or 4 diarrhea without compromising the efficacy 
(20). A second phase I study conducted by NANT tested 131I-MIBG in combination with vorinostat. The 
recommended phase II doses were 131I-MIBG 18 mCi/kg and vorinostat 180 mg/m2/day. At this dose level, 
0 of 5 patients had a DLT and the objective response rate was 17% (21). These two trials have proven that 
131I-MIBG can be safely given with other systemic anti-cancer agents, with toxicities limited to those specific 
to the known side effects of the concomitant chemotherapy. A phase II trial comparing these two regimens 
to single-agent 131I-MIBG is ongoing. 
 
2.4 
Clinical Experience with Dinutuximab for Neuroblastoma 
Dinutuximab is a chimeric (ch) 14.18 monoclonal antibody that targets the disialoganglioside GD2. While 
GD2 is nearly ubiquitously expressed on neuroblastoma cells, its expression on human tissues is limited to 
peripheral neurons, melanocytes, and peripheral pain fibers, making it an ideal therapeutic target (22-24). 
Phase I and II clinical trials of ch 14.18 both alone and in combination with cytokines such as GM-CSF 
and/or interleukin-2 (IL2) have demonstrated signals of efficacy against neuroblastoma (25-28). This led to 
a randomized phase III trial performed by the Children’s Oncology Group (COG) comparing dinutuximab 
combined with GM-CSF, IL2, and isotretinoin to isotretinoin alone as post-consolidation therapy. This trial 
was stopped early because the event-free survival (EFS) for patients treated with dinutuximab was 
significantly better than for patients treated with isotretinoin alone (66% vs. 46%; P = 0.01) (29). Very few 
patients with bulk disease achieved an objective response, a finding that has been supported by other 
studies (29,30). Despite this, dinutuximab is now considered part of the standard upfront therapy for patients 


 
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with high-risk neuroblastoma. While this immunotherapy has proven to be effective, it has a significant side 
effect profile, especially when given with IL2; however, these toxicities are typically manageable. Common 
grade 3 or 4 toxicities include neuropathic pain (52%), hypotension (18%), fever (39%), acute capillary leak 
(23%), hypersensitivity reactions (25%), infection (39%), hyponatremia (23%), hypokalemia (35%), and 
ALT elevation (23%) (29). 
 
2.5 
Pre-clinical and Clinical Experience with Dinutuximab in Combination with Chemotherapy 
for Neuroblastoma 
Preclinical studies suggest that anti-GD2 monoclonal antibodies (mAb) can augment the effects of cytotoxic 
chemotherapy. In a small cell lung cancer (SCLC) cell line, the combination of cisplatin and anti-GD2 mAb 
resulted in enhanced cytotoxicity, at least in part due to the anti-GD2 mAb inducing direct apoptosis of the 
SCLC cells (31). In a second study with a neuroblastoma cell line (IMR-32), the addition of the anti-GD2 
14G2a antibody resulted in additive effects on cell killing when combined with carboplatin and synergistic 
effects when combined with doxorubicin and topotecan (32). 
 
A recent phase II trial conducted by the Children’s Oncology Group (COG) randomized patients to receive 
either dinutuximab or temsirolimus with chemotherapy (irinotecan and temozolomide) for the treatment of 
high-risk neuroblastoma patients with primary refractory disease and those in first relapse. Among the 17 
patients randomized to the dinutuximab arm, 9 (53%) had an objective response (partial response = 4, 
complete response = 5), which included 3 patients with bulky disease and 3 patients with prior anti-GD2 
exposure (33). This 53% objective response rate (ORR) was remarkably better than the 15% ORR seen 
with irinotecan/temodar alone (34). No unanticipated toxicity was experienced in patients treated on the 
dinutuximab arm, and this stratum was determined to be the optimal combination for further study (33). 
 
A study being conducted by St. Jude Children’s Research Hospital is testing the safety and efficacy of 
giving their anti-GD2 antibody, hu14.18K332A, to all newly diagnosed high-risk neuroblastoma patients 
(NCT01576692). Preliminary data from an interim analysis show that the response rate on this study after 
two cycles of anti-GD2 antibody plus topotecan/cyclophosphamide is 80%, and that the regimen-related 
toxicity was tolerable (35). This response rate is notably better than the 40% response rate seen in a 
previous study that gave topotecan/cyclophosphamide alone (36).  
 
These two studies combining an anti-GD2 antibody with cytotoxic therapy suggests that this approach is 
safe and may produce better response rates than either of the agents given alone. 
 
2.6 
Rationale for Combining Dinutuximab with Radiation Therapy 
Additional data combining dinutuximab with other therapies are limited, however preclinical and clinical 
studies in adult malignancies have shown that the effects of immunotherapy can be augmented if patients 
are first exposed to radiation (37-41). This is supported by the clinical phenomenon known as the abscopal 
effect where tumor regression occurs at sites distant to the irradiated field through radiation-induced, 
immune-mediated anti-tumor mechanisms. Data have shown that this occurs through the release of pro-
inflammatory cytokines and enhanced expression of tumor-associated antigens, death receptors, and co-
stimulatory molecules on tumors cells exposed to radiation which increases their recognition and killing by 
T cells (42-47). Given antibody-based therapies rely on antibody-dependent cellular cytotoxicity (ADCC), 
radiation, by promoting systemic activation of the immune system, creates the optimal environment to 
augment immunotherapy anti-tumor response.  
 
In adult clinical trials across a variety of malignancies, clinical responses have been seen when radiation 
therapy has been combined with several different types of immunotherapy including dendritic cell (DC) 
vaccines, immune checkpoint blockade, cytokines and other immunoadjuvants (48-55). In a case reported 
by Hiniker et al., a patient with metastatic melanoma had complete regression of all metastatic lesions when 
treated with ipilimumab and concurrent radiation (54 Gy in three fractions)(56). Grimaldi et al. reported 21 
patients with melanoma who had progressed on immune checkpoint blockade, and 11 (52%) of these 
subsequently demonstrated an abscopal response when treated with radiation (51). In a phase I trial, 
intratumoral injections of autologous DCs were given to patients with advanced hepatocellular carcinoma 
2 days after a single fraction of radiotherapy (52). A partial response was reported in 2/14 patients. In a 


 
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different study where DCs were injected into sarcomas during fractionated radiotherapy given as 
neoadjuvant treatment, 12 of 17 patients were free from progression of their cancer at 1 year (57). This 
preliminary data and data from multiple other studies have served as the background for scores of ongoing 
clinical trials testing the radiation plus immunotherapy approach (58). 
 
These pre-clinical and clinical data provide rationale for combining a systemic radiation therapy such as 
131I-MIBG with the immunotherapy dinutuximab. In an effort to take advantage of the systemic, radiation-
induced, inflammatory-mediated, anti-tumor effect (abscopal effect) potentially produced by the 131I-MIBG, 
we will administer the 131I-MIBG prior to the dinutuximab. This sequence will allow us to administer the 
dinutuximab at a time when the immune system is already activated and primed to augment the anti-tumor 
effects produced by the immunotherapy dinutuximab.  
 
2.7 
Summary and Rationale for Clinical Use of 131I-MIBG with Dinutuximab 
Relapsed/refractory neuroblastoma is incurable in the majority of cases, underscoring the critical need for 
novel therapeutic approaches. 131I-MIBG, a targeted, systemic radiotherapy, is the most effective salvage 
therapy available for this population of patients, and recent data suggests it can be safely combined with 
chemotherapy. Dinutuximab, an anti-GD2 monoclonal antibody, has significantly improved the outcomes 
for patients with newly diagnosed neuroblastoma. Dinutuximab, when given in combination with 
chemotherapy, can be administered safely and produces promising response rates against even bulky 
relapsed/refractory neuroblastoma. Lastly, radiation therapy induces systemic, anti-tumor immune 
responses to augment the effects of immunotherapy. We therefore propose a phase I trial testing 131I-MIBG 
with dinutuximab for patients with relapsed/refractory neuroblastoma. In order to maximize the systemic, 
immune-mediated, anti-tumor effects of this combination and determine the optimal dosing to produce this 
synergy, we will administer the standard dose of dinutuximab (17.5 mg/m2/dose) to all patients while 
escalating the 131I-MIBG. 
 
2.8 
Correlative and Biology Studies 
 
2.8.1  
Characterization of Immune and Cytokine Profile Following 131I-MIBG Therapy 
Dinutuximab works by binding to cell surface GD2 and inducing cell lysis. This occurs via antibody-
dependent cell-mediated cytotoxicity (ADCC) mediated mainly by natural killer (NK) cells, neutrophils, and 
monocytes, and to a lesser degree by complement-dependent cytotoxicity (CDC) (29,59-62). Immune-
activating cytokines augment the ADCC by increasing the number of granulocytes and macrophages (GM-
CSF), as well as NK cells and antigen-specific T cells (IL-2) (59,61).  
 
131I-MIBG is a myelosuppressive therapy that requires autologous stem cell rescue in up to 50% of patients 
(16-18). The median time to platelet nadir post 131I-MIBG is 24 days (range: 8-47) and median time to 
absolute neutrophil count (ANC) nadir is 42 days (range: 10-68) (63). While 131I-MIBG causes neutropenia 
in the majority of cases, it is unclear what impact 131I-MIBG has on the other effector cells of the immune 
system and the cytokines they produce, or what impact this has on the patient’s ability to activate ADCC. 
We will collect blood at baseline and at serial time points to evaluate the number and function of the effector 
cells involved with ADCC, as well as the pro-inflammatory cytokines that may augment the effects of 
immunotherapy and stimulate an immune-mediated anti-tumor response. 
 
 
2.8.2 
Descriptive Profile of Human Anti-Chimeric Antibody (HACA) and Neutralizing Anti-Drug Antibody 
(ADA) 
Due to the chimeric nature of dinutuximab, some patients will develop HACA as part of their immune 
response. Studies performed in neuroblastoma patients have shown that the development of HACA does 
not occur in a significant number of patients, and the development of neutralizing ADA occurs rarely. 
However, a recent pharmacokinetic study of ch14.18 antibody suggested that while non-neutralizing 
antibodies may not have a biologic effect, they can still form immune complexes that are removed by the 
reticuloendothelial system leading to increased clearance of the drug (64). Also, the clinical impact of ADA 
may be dependent on the titer of the antibody (64). There are no data describing the effect of 131I-MIBG on 
the development of HACA or neutralizing ADA. We will describe the HACA and ADA profile in patients post-
131I-MIBG therapy and during treatment with dinutuximab, and correlate this with anti-tumor response. 
 


 
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2.8.3 
Five Gene NB-5 Assay by TLDA for Neuroblastoma Tumor Cell Detection 
Dr. Robert Seeger’s laboratory developed the NB-5 assay, a five gene TLDA array for sensitive detection 
of neuroblastoma tumor cells in peripheral blood and bone marrow. Five genes [chromogranin A (CHGA), 
doublecortin (DCX), dopadecarboxylase (DDC), paired-like homeobox 2B (PHOX2B), and tyrosine 
hydroxylase (TH)] are highly expressed by neuroblastoma cell lines and tumors. These same genes are 
rarely expressed by normal blood cells, peripheral blood stem cells (PBSC), and bone marrow. Four 
housekeeping genes are used for quality control and data analysis. Heterogeneity in expression of the 
detection genes among neuroblastoma cell lines (n=22) and primary untreated stage 4 neuroblastoma 
tumors (n=23) is minimal. However, the use of five genes assures that heterogeneity will not impact tumor 
cell detection.  
 
Spiking experiments demonstrate the sensitivity of neuroblastoma cell detection using this 5-gene 
signature. Detection sensitivity with five genes (including TH) is superior to that of a single gene (TH). The 
five-gene detector has nearly 100% sensitivity to detect neuroblastoma RNA at a dose of 10-5, whereas 
the TH-only detector has sensitivity of <60%. In terms of neuroblastoma cell detection, the 5-gene signature 
can detect a 10-6 neuroblastoma cell frequency in PBMC with 81% probability compared to <30% for a TH-
alone detector.  
 
NB-5 Detection Gene Score (DG score) is highly correlated with Immunocytology Score (number of tumor 
cells/106 total cells) when Immunocytology is positive in bone marrow. Forty-four unselected fresh bone 
marrow specimens were tested by both assays. The rank correlation between the TLDA DG Score and 
Immunocytology Score was r = -.93 (p < 0.001), which demonstrates a clear relationship between the two 
assays. The NB-5 assay also can detect tumor cells in bone marrow that are not detected by 
Immunocytology. Thirty-six of the 44 bone marrows were negative by Immunocytology, but 20 of these 
were positive by NB-5. These data further confirm that the NB-5 assay is more sensitive than 
Immunocytology for detecting tumor cells. Moreover, detection of occult bone marrow tumor cells by NB-5 
appears to have clinical relevance. In patients with newly diagnosed high-risk neuroblastoma, detection of 
tumor cells by TLDA in a bone marrow sample negative by Immunocytology at the end of therapy was 
associated with significantly worse event-free survival than bone marrow samples negative for tumor cells 
by TLDA assay.  
In the NANT biology study, mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in BM and blood 
from 101 patients concurrently with clinical disease evaluations (65). Correlation between NB-mRNA (delta 
cycle threshold [ΔCt] for the geometric mean of genes from the TaqMan® Low Density Array NB5 assay) 
and morphologically-defined tumor cell percentage in BM, 123I-meta-iodobenzylguanidine (MIBG) Curie 
score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox 
regression was used to analyze the relationship between Ct and progression-free survival (PFS). NB-
mRNA was detectable in 83% of BM (185/223) and 63% (89/142) of blood specimens, and their Cts were 
correlated (Spearman r=0.67, p<0.0001) although BM Ct was 7.9±0.5 Ct stronger than blood Ct. When BM 
morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), 
and 81% (82/101) of BMs. When all three were negative, NB-mRNA was detected in 55% (11/20) of BMs. 
BM NB-mRNA correlated with BM morphology or MIBG positivity (p<0.0001 and p=0.007). BM and blood 
ΔCts correlated with PFS (p<0.001; p=0.001) even when BM was morphologically negative (p=0.001; 
p=0.014). Multivariate analysis showed that BM and blood ΔCts were associated with PFS independently 
of clinical disease and MYCN gene status (p<0.001; p=0.055). This five-gene NB5 assay for NB-mRNA 
improves definition of disease status and correlates independently with PFS in relapsed/refractory NB.   
 
The current study includes an exploratory aim to evaluate neuroblastoma cell detection in blood and bone 
marrow by NB5 assay within the context of this study. These samples will be obtained as part of the 
companion NANT biology study (N04-05). 
 
2.8.4 
Evaluation of the Tumor Microenvironment (TME) and Immune Response Genetic Signatures 
Recent studies in neuroblastoma have demonstrated an increasingly important role of the TME in 
contributing to neuroblastoma cell growth, metastasis, drug resistance, and evasion from immune-mediated 
destruction (66,67). An analysis of tumor tissue from patients with high-risk neuroblastoma demonstrated 
higher infiltration of tumor-associated macrophages (TAMs) in metastatic compared to locoregional tumors, 


 
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and patients with metastatic tumors at age ≥ 18 months had higher expression of inflammation-related 
genes than those with metastatic tumors at age < 18 months (66). This so-called inflammatory subtype of 
neuroblastoma is thought to have a high risk of recurrence and a poor prognosis. In this study we will 
evaluate the most recently obtained soft tissue tumor samples when present for the presence of TAMs, as 
well as tumor infiltrating lymphocytes (TILs), and correlate this with response to therapy. We will also 
evaluate for the presence of the immune checkpoint proteins CD274 (PDL1) and CD276 (B7H3) as these 
may affect the activity of the effector T and NK cells and impact immune activation and potentially ADCC. 
Furthermore, expression of immune response related genes may be predictive of anti-tumor effect and 
ADCC in patients treated with dinutuximab and 131I-MIBG. RNA samples obtained from the blood prior to 
and following therapy, and samples collected after administration of 131I-MIBG and dinutuximab will be used 
for analysis of expression of a panel of genes related to immune function (including cell surface receptors, 
proteases, cytokines and cytokine receptors, cell cycle and protein kinases, etc.) and for more global 
analysis via RNASeq (68). We will also perform these analyses on tumor tissue when available. 
 
2.9  
Preclinical Experience with Vorinostat in Neuroblastoma 
Vorinostat, known as a pan-histone deacetylase (HDAC) inhibitor due to its ability to inhibit both class-I and 
class-II HDACs, is a potent inhibitor of HDAC activity at low nanomolar concentrations (69). A variety of 
HDAC inhibitors have demonstrated the ability to promote apoptosis and differentiation across multiple 
neuroblatoma cell lines (70-74). Preclinical testing of vorinostat in xenograft mouse models derived from 
neuroblastoma cell lines demonstrated statistically significant prolongation of event-free survival in 4/6 cell 
lines tested (75). Preclinical studies have demonstrated additional potential benefits of vorinostat in 
neuroblastoma, such as the ability to increase expression of the norepinephrine transporter and increase 
MIBG uptake in vitro and in vivo within 24 hours of vorinostat exposure (76). Vorinostat has also been 
shown to sensitize neuroblastoma cells to the effects of ionizing radiation, and enhance the efficacy of 
radiation when given in combination (77). These data provided rationale for the NANT 07-03 phase 1 study 
testing 131I-MIBG plus vorinostat in patients with relapsed/refractory neuroblastoma (21). 
 
 
2.10  
Rationale for Testing Vorinostat in Combination with 131I-MIBG and Dinutuximab 
Preclinical data demonstrate that vorinostat upregulates GD2 cell surface expression in vitro (murine 
9464D, human IMR-32 and SKNAS cell lines) and in vivo (C57Bl/6 mice bearing 9464D tumors) 
neuroblastoma models (69,78). While the exact mechanism of how vorinostat increases GD2 expression 
remains unclear, preliminary investigations suggest that it either works directly by affecting the acetylation 
of GD2 synthase or indirectly through transcriptional regulation of the GD2 synthase stabilizing gene (69). 
By increasing the number of macrophages with activating Fc receptors and decreasing the number of 
myeloid-derived suppressor cells, vorinostat creates a permissive tumor microenvironment for anti-GD2 
immunotherapy (69). Most importantly, Kroesen et al., using their TH-MYCN transgenic mouse model, 
demonstrated that the anti-GD2 antibody plus vorinostat combination was synergistic, and led to both 
significantly superior inhibition of neuroblastoma tumor growth and survival compared to vorinostat alone 
(9/9 mice alive at day 45 in combination compared to 4/9 mice in single agent). This provides rationale for 
clinically testing vorinostat in combination with anti-GD2 antibody therapy in patients with 
relapsed/refractory neuroblastoma. 
 
The NANT 2011-01 study was a randomized, pick-the-winner, phase 2 trial that sought to determine 
whether the addition of one of two different putative radiation sensitizers, vincristine/irinotecan (Arm B) or 
vorinostat (Arm C), given in combination with 131I-MIBG (18 mCi/kg), produced superior response rates 
compared to 131I-MIBG monotherapy (Arm A) in patients with relapsed/refractory neuroblastoma. Patients 
treated on Arm C of N11-01 received vorinostat at 180 mg/m2/day on days -1 to +12 (14 days) with 131I-
MIBG on day 1 (18 mCi/kg) based on the preceeding phase 1 trial (NANT 07-03) that established this as 
the RP2D and demonstrated that this combination was safe and well-tolerated (21). On NANT 11-01, after 
one course of therapy in 105 response-evaluable patients, the objective response rate (ORR) on Arms A 
(N=36), B (N=35), and C (N=34) were 17% (95% CI: 7-33%), 14% (95% CI: 5-31%), and 32% (95% CI: 18-
51%), respectively (79). An additional 7 patients on Arm C met criteria for a minor response per NANT 
criteria. Rates of ≥ grade 3 non-hematologic toxicity were comparable between the 131I-MIBG monotherapy 
and 131I-MIBG + vorinostat arm, accounting for the known vorinostat toxicities. These data demonstrate that 
the addition of vorinostat to 131I-MIBG produces almost twice the ORR compared to 131I-MIBG monotherapy. 


 
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We will administer vorinostat on the same dose and schedule, unless intolerable, as was utilized in the 
N11-01 study. 
 
Potential overlapping toxicities between vorinostat and dinutuximab may include GI toxicities such as loss 
of appetite, abdominal pain, nausea/vomiting, diarrhea, and elevated liver function tests, and 
nephrotoxicities such as elevated creatinine and electrolyte wasting. We do not expect increased 
hematologic toxicity from the vorinostat + dinutuximab combination. The NANT phase 1 trial (NANT 08-02) 
that combined vorinostat with cis-retinoic acid showed that ≥ grade 3 non-hematologic toxicity from 
vorinostat is infrequent (80). In 28 DLT-evaluable patients, there were no grade 4, cycle 1 treatment-related, 
non-hematologic events, and grade 3 events were limited to pain (N=3 events), cheilitis (N=1), nausea 
(N=1), vomiting (N=1), AST/ALT elevation (N=3), and rash (N=1). NANT 11-01 demonstrated that only one-
third of the patients treated on Arm C (131I-MIBG + vorinostat) experienced a > grade 3 non-hematologic 
toxicity, and no patients experienced ≥ grade 3 diarrhea (74). The first 2 dose levels (N=11) of NANT 17-
01 have shown low rates of treatment related non-hematologic toxicity, with no episodes of grade 4 non-
hematologic toxicity, and grade 3 events limited to abdominal pain (N=2), GGT increased (N=1), and 
hypokalemia (N=1). Based on these data, we anticipate that any overlapping toxicities between vorinostat, 
131I-MIBG, and dinutuximab will be low grade and easily managed. 
 
2.11  
Rationale for Protocol Amendments  
 
Amendment #1  
 
Pre-activation amendment dealt with updates and clarifications in required observations, drug information, 
and statistical design, in addition to administrative changes. 
 
Amendment #2 
 
The 3+3 design was replaced by Rolling 6 design. Due to the long duration of each course the study 
committee deemed the Rolling 6 design to be more efficient; especially in the light of recent approval from 
the FDA to charge patients for the investigational use of 131I-MIBG. In addition, language was updated 
regarding plasma and PBMC separation and storage (Appendix VI). This new language simplifies the 
process through using CPT tubes, removes the need for sites to make the freeze media as this will be 
provided by Emory. As a result, Appendix VII is no longer needed and specific instructions were provided 
for the volume of freeze media to add. Language was also added to allow sites to use local procedures for 
plasma and PBMC isolation if approved by study committee. After discussion with FDA, NDP was removed 
supplier for 131I-MIBG. At this time Jubilant Radiopharma will be the only supplier for 131I-MIBG. The GM-
CSF toxicity table in the consent was revised to better reflect the package insert and protocol. A new 
subsection was added to outline general instructions for ordering dinutuximab. After discussion with study 
committee, HACA and ADA collection time points were revised to be consistent with HACA and ADA 
collection time points in current NANT studies.  Two additional sampling times were added to complete 
HACA/ADA levels analysis. 
 
Amendment #3 
 
Based on review of hepatic toxicity in patients treated on this protocol, DLT language was revised to exclude 
Grade 3 GGT (attributable to protocol therapy) as a DLT since ALT, AST and bilirubin are the main 
parameters used for eligibility and required observations, and are the parameters that are most clinically 
meaningful. Statistical language was updated to reflect Rolling 6 design. Additional administrative edits 
were implemented throughout the protocol.  
 
 
Amendment #3A 
 
Language was revised in sample consent regarding risk and results of germline genetic testing. Language 
was added in section 6.0 (Drug Information) regarding unit dose vials and radiochemical purity testing. 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
20 
 
Amendment #4A 
 
Based on results of the NANT 2011-01 study and preclinical data suggesting HDAC inhibitors can synergize 
with anti-GD2 antibody, this amendment added Part B which will test vorinostat in combination with 131I-
MIBG and dinutuximab/GM-CSF. We will test one dose level of vorinostat in combination with the 
MTD/RP2D of 131I-MIBG /Dinutuximab/GM-CSF from Part A of this study (18 mCi/kg/dose), with 1 dose de-
escalation level if needed, and then enroll to an expansion cohort testing the vorinostat, 131I-MIBG, and 
dinutuximab/GM-CSF combination. Eligibility changes to reflect part B requirements were made.  Changes 
related to GM-CSF were made to exclude patients who previously had to permanently discontinue GM-
CSF due to toxicity, clarify GM-CSF administration, and remove any minimum requirement of GM-CSF 
received to be evaluable for dose-escalation purposes. To align with other NANT trials, the definition of 
evaluable for response was modified to state that any patient on Part A who receives 131I-MIBG or any 
patient that receives a dose of vorinostat on Part B will be evaluable for response. Patients previously 
treated on study prior to amendment #4A will have their response re-classified using this updated definition, 
and all patients enrolled on study after amendment #4A will have to meet this updated definition to be 
considered evaluable for response. Additionally, the definition of evaluable for dose escalation 
consideration (DLT-evaluable) was modified with this amendment. The new definition of evaluability applies 
only for patients treated on the Part A dose expansion cohort and patients on Part B. Patients treated on 
the Part A dose escalation cohort both before and after amendment #4A will continue to use the previous 
definition of DLT-evaluable (i.e., patients treated on study prior to amendment #4A will not be re-classified 
using the amendment #4A definition of DLT-evaluable). A new Informed consent for Part B was added.  In 
addition, changes to response to clarify version 2.0 for bone marrow response were included.  Other 
administrative changes were made to the protocol. 
 
 
Amendment #5 
 
The protocol was amended to remove the 131I-MIBG radiochemical purity testing requirement prior to 131I-
MIBG infusion that was previously mandated on this protocol. This change was made for consistency with 
the most up-to-date Jubilant Radiopharma Nuclear Medicine Manual (Version 8). Prior references to 
“Jubilant Draximage” were updated to “Jubilant Radiopharma” to correspond with the company’s name 
change. Additionally, editorial changes have been made throughout the protocol document.  
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
21 
 
3.0 
 PATIENT ELIGIBILITY CRITERIA AND REGISTRATION 
 
3.1 
 Patient Preparation for Study Entry and Registration 
The NANT Operations Center will accept treatment reservations for this study once the patient has been 
reviewed at an 131I-MIBG treatment center as a possible candidate for this study.   
  
3.1.1 
 Patient Registration on Study 
NANT trials have two components for data entry workflow: 1. Data collection on paper CRF and data entry 
at the NANT Operations Center through the CAFÉ database and 2. Remote data entry via Medidata Rave 
clinical data management system. 
 
This is a dose escalation study and treatment slots are obtained through the standard NANT reservation 
process by sending an email to NANTrsvp@chla.usc.edu 
 
Sites begin the reservation process by completing a subject screen form in Medidata.  This generates a 
unique subject screen number (S-xxx).  The site uses this number to reserve a treatment slot for the patient 
with the NANT Operations Center (NANTrsvp@chla.usc.edu) .  Once assigned a treatment slot by the 
NANT Operations Center, sites should send signed informed consent/assent and all source documentation 
confirming eligibility to the NANT Operations Center at Children’s Hospital Los Angeles by email to 
nantcrf@chla.usc.edu or if unable to email by FAX at 323-361-1803, Monday through Friday, 8:30am – 
5:00pm Pacific Time except holidays. 
 
Once all necessary source documentation is received in the NANT Operations Center, sites can complete 
the enrollment process by submitting the eligibility form in Medidata Rave.  The NANT Operations Center 
will verify eligibility and assign a unique NANT registration and study subject number in Medidata Rave.  
The dose level for treatment will be assigned by the NANT Operations Center at the time of study 
registration.  Once study registration is completed, the NANT Operations Center will send an email to the 
site confirming registration and dose level for treatment.  This registration email must be received prior to 
starting any protocol therapy or the patient will be declared ineligible.  The registration email will be sent to 
the treating facilities, Study Chair, Study Vice-Chair, and relevant committee members.  The registration 
steps are summarized in Table 3 below. 
  
Table 5:  Summary of Registration Steps 
Step 
Process  
Comment 
1 
Site completes a subject screen form in Medidata-Rave 
and communicates the assigned unique patient 
screening number to NANT Operations Center.  NANT 
Operations Center assigns a treatment slot for the 
patient and notifies the site. 
 
Treatment slots are assigned based on reservation 
requests processed through the NANT Operations 
Center. 
Use email address: 
NANTRSVP@chla.usc.edu for 
treatment slot reservations. 
2 
Site completes demographics and eligibility form in 
Medidata Rave in addition to required paper CRFs. 
 
3 
NANT Operations Center verifies eligibility and assigns 
unique NANT registration and study subject number in 
Medidata Rave. NANT Operations Center assigns the 
dose level for treatment. 
 
4 
NANT Operations Center sends an email confirming 
registration. 
Confirmation sent to the treating 
facilities, Study Chair, Study Vice-
Chair, 
and 
relevant 
committee 
members. 
5 
Patient can begin treatment as specified in the protocol 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
22 
 
 
A registration worksheet is available on the web site (www.NANT.org) in the data forms packet to assist 
institutions with registration requirements for this protocol. Please contact NANT Operations Center at the 
contact information below for questions on registration.  
 
 
 Contact Person: 
 
Research Coordinator  
 
 
 
 
NANT Operations Center 
 
 
 
 
Children’s Hospital Los Angeles 
 
 
 
 
4650 Sunset Blvd, MS #54 
 
 
 
 
Los Angeles, CA 90027 
 
 
 
 
Phone:  (323) 361-5687 
 
 
 
 
FAX:  (323) 361-1803 
 
 
 
 
nantcrf@chla.usc.edu 
 
 
 
 
 
To allow non-English speaking patients to participate in this study, bilingual health services will be provided 
in the appropriate language when feasible. 
 
Timing of Registration and Treatment Initiation: 
Patients must be enrolled before treatment begins.  The date protocol therapy is projected to start must be 
no later than seven (7) days after the date of study registration.  Contact NANT Operations Center for any 
situations which may delay the start of protocol therapy beyond 7 days after study registration. 
 
3.1.2  
Co-Enrollment on NANT 2004-05 
Co-enrollment on NANT 2004-05 (NANT Neuroblastoma Biology Study) is required for all patients enrolling 
on this trial.  Patients are strongly encouraged to submit bone marrow as well as blood prior to starting 
therapy on NANT 2017-01 and continue to submit with each disease evaluation. 
 
IMPORTANT NOTE:  
The eligibility criteria listed below are interpreted literally and cannot be waived. These criteria apply 
to Part A and B of the study unless otherwise specified.  
 
3.2 
Inclusion Criteria 
 
 
3.2.1 
Age 
Patients must be ≥ 1 year and < 30 years of age at the time of study registration.  
 
3.2.2 
Diagnosis 
Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma and/or 
demonstration of tumor cells in the bone marrow with increased urinary catecholamines. 
 
3.2.3  
Disease Risk Group 
Patients must have high risk neuroblastoma according to COG risk classification at the time of study 
registration.  Patients who were initially considered low or intermediate risk, but then reclassified as high risk 
are also eligible. 
 
3.2.4   Response to Prior Therapy (using INRC definitions)  
Patients must have at least ONE of the following: 
 
3.2.4.1  Recurrent/progressive disease after the diagnosis of high risk neuroblastoma at any time prior 
to study registration – regardless of response to frontline therapy. Note that this excludes patients initially 
considered low or intermediate risk that progressed to high risk disease but have not progressed after the 
diagnosis of high risk neuroblastoma.  
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
23 
 
3.2.4.2 If no prior history of recurrent/progressive disease since the diagnosis of high risk 
neuroblastoma 
3.2.4.2.1 Refractory disease: A best overall response of no response/stable disease since 
diagnosis of high risk neuroblastoma AND after at least 4 cycles of induction therapy.  
 
3.2.4.2.2  Persistent disease: A best overall response of partial response since diagnosis of high 
risk neuroblastoma AND after at least 4 cycles of induction therapy:  
 
i. 
If a patient with persistent disease has 3 or more MIBG avid sites (including all soft 
tissue and/or bone lesions) OR a Curie Score of ≥ 3, then no biopsy is required for 
eligibility.  
 
ii. 
If a patient with persistent disease has only 1 or 2 MIBG avid sites (including all soft 
tissue and/or bone lesions)  then biopsy confirmation of neuroblastoma and/or 
ganglioneuroblastoma in at least one site (bone marrow, bone, or soft tissue) is 
required.  Bone and/or soft tissue lesions may be biopsied at any time point prior to 
study registration, bone marrow must be done at the time of study registration.  
 
3.2.5 
Sites of Disease: MIBG Uptake  
Patients must have evidence of MIBG uptake into tumor at ≥ 1 site (bone or soft tissue) within 28 days prior 
to study entry and subsequent to any intervening therapy.  
 
3.2.6  
Autologous peripheral blood stem cells (PBSC) 
• 
The minimum dose for peripheral blood stem cells is 2.0 x 106 viable CD34+ cells/kg. Patients 
who do not meet this minimum requirement for available PBSCs are not eligible. 
• 
Only un-purged stem cells are allowed unless a center has separate FDA approval for infusion 
of purged stem cells.  
• 
For patients whose body weight exceeds ideal body weight (IBW) by more than 20%, adjusted 
body weight may be used for the calculation of PBSC dose (Reference: Bone Marrow 
Transplant. 40(7):665-9; Appendix III).  
 
3.2.7 
Performance Status  
Patients must have must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 50 (Appendix I). 
 
Note: Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be 
considered ambulatory for the purpose of assessing the performance score. 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
24 
 
3.2.8 
Prior Therapy 
  
3.2.8.1 Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to study registration.  Patients must not have received the therapies 
indicated below within the specified time period prior to study registration on this study as follows: 
 
 
 
Therapy Type 
Administration 
Restriction WITHIN 
the Specified Time 
Period Prior to 
Study Registration 
Comments 
1 
Myelosuppressive chemotherapy 
Biologic antineoplastics 
14 days 
Includes cytotoxic agents given 
on a low dose metronomic 
schedule as well as retinoids 
2 
Investigational medications 
• 
Covered under another IND 
 14 days 
 
3 
Monoclonal antibodies (MoAb) 
• Includes dinutuximab 
 7 days or  
3 half-lives  
but not longer than 
30 days 
With recovery of any associated 
toxicities. 
MoAb half-life table at 
www.nant.org for MoAb specific 
half lives 
4 
Cellular Therapy 
• Modified T-cells, NK cells, dendritic cells etc. 
 21 days 
With recovery of any associated 
toxicities. 
5 
External Beam Radiation 
5a 
• 
Small port radiation 
 14 days 
 
5b 
• 
Large field radiation 
12 weeks 
Craniospinal, whole abdominal, 
total lung, >50% marrow space 
5c 
• 
Other substantial  bone marrow 
radiation 
6 weeks 
 
6 
131I-MIBG Treatment (therapeutic dosing) 
6a 
• 
Last 131I-MIBG infusion 
12 weeks 
 
6b 
• 
No disease progression on first restaging after any previous 131I-MIBG therapy 
6c 
• 
Cumulative lifetime dose of 131I-MIBG  not to exceed 20 mCi/kg 
7 
Hematopoietic Stem Cell Transplant (autologous infusion only) 
7a 
• 
Following myeloablative therapy 
12 weeks 
 
7b 
• 
Following non-myeloablative therapy 
Eligible at any time as long as other eligibility criteria are 
met. 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
25 
 
3.2.9 
 Concomitant Medications 
3.2.9.1 Patients must not have received the concomitant medications indicated below within the specified 
time period prior to study registration or planned treatment start date on this study as follows: 
 
 
Therapy Type 
Administration Restriction 
WITHIN the Specified Time 
Period Prior to Study 
Registration 
Comments 
1 
Other anti-cancer agents  
or radiotherapy 
At time of study registration or 
while on study  
 
2 
Systemic corticosteroids at 
pharmacologic doses 
7 days 
• Inhaled steroids are permitted 
to treat asthma  
• ≤ 2mg/kg of hydrocortisone or 
equivalent is permitted as blood 
product premedication to avoid 
allergic reactions 
• Physiologic dosing is permitted 
for patients with known adrenal 
insufficiency  
3 
Medications that prolong QTc 
(Part B only) 
7 days 
• Patients must not be receiving 
medications known to prolong 
the QT interval (see first column 
of table in Appendix VII) 
• Note this includes pentamidine, 
azithromycin and methadone 
among other medications 
 
4 
Valproic acid (Part B only) 
30 days 
 
5 
Medications interfering with 
131I-MIBG uptake 
7 days before  
 planned 131I-MIBG treatment 
start date  
AND  
 7 days after 131I-MIBG 
infusion 
Refer to Appendix IV 
6 
IVIG 
 
 14 days before 
planned treatment start date 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
26 
 
3.2.10 Organ Function Requirements 
 
3.2.10.1 Hematologic Function:  
Patients must meet the following hematologic criteria for enrollment regardless of bone marrow disease 
involvement: 
a. ANC ≥ 750/uL (no short-acting hematopoietic growth factors within 7 days of blood draw 
documenting eligibility and no long-acting hematopoietic growth factors within 14 days of 
blood draw documenting eligibility); and 
b. Platelet count ≥ 50,000/µl, transfusion independent (no platelet transfusions or platelet growth 
factors within 7 days of blood draw documenting eligibility). 
c. There is not an eligibility criterion for hemoglobin; however, patients must have hemoglobin ≥ 
10 g/dL on the day of or prior to each 131I-MIBG infusion (PRBC transfusions permitted). 
 
3.2.10.2 Renal Function:  
Patients must have adequate renal function defined as age-adjusted serum creatinine ≤ 1.5 x normal for 
age (see below): 
 
Age 
Maximum Allowable 
Serum Creatinine 
< 5 years 
0.8 mg/dL 
>5 and < 10 years 
1.0 mg/dL 
>10 and < 15 years 
1.2 mg/dL 
>15 years 
1.5 mg/dL 
 
3.2.10.3 Liver Function: 
a. Total bilirubin ≤ 1.5 x ULN for age; and, 
b. SGPT (ALT) < 3 x ULN for age (Note that for ALT, the upper limit of normal (ULN) for all 
NANT sites is defined as 45 U/L.). 
 
3.2.10.4 Lung Function: 
Normal lung function with no dyspnea at rest, exercise intolerance, or oxygen requirement. 
 
3.2.10.5 Central Nervous System (CNS) Function:  
a.  Patients with a history of intraparenchymal or leptomeningeal based CNS disease must have 
no clinical or radiological evidence of active CNS disease at the time of study enrollment.  
b. Patients with skull based tumors with direct intracranial extension are eligible as long as there 
are no neurologic signs or symptoms related to the lesion. 
 
3.2.10.6 Cardiac Function: 
a.  Normal ejection fraction (≥ 55%) documented by either echocardiogram or radionuclide MUGA 
evaluation OR normal fractional shortening (≥ 27%) documented by echocardiogram  
b. Corrected QT (QTc) interval ≤ 480 msec (Part B only) 
 
3.2.10.7 Reproductive Function 
a. All post-menarchal females must have a negative serum or urine beta-HCG within 7 days prior 
to study registration.  
b. Male and female subjects of reproductive age and childbearing potential must agree to use two 
acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, 
diaphragm with spermicide, condom with spermicide, or abstinence) or to abstain from 
heterosexual intercourse for the duration of their participation in the study, or for 3 months after 
last dose of protocol therapy, whichever is longer. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
27 
 
3.2.10.8  Physician deems that there is reasonable ability to obtain vorinostat via commercial supply      
(Part B only). 
 
3.3 
Exclusion Criteria 
3.3.1 
Pregnancy, breast feeding, or unwillingness to use effective contraception during the study 
participation 
3.3.2 
Patients and/or families who, in the opinion of the investigator, may not be able to comply with the 
safety monitoring/radiation isolation requirements of the study. 
3.3.3 
Patients with disease of any major organ system that would compromise their ability to withstand 
therapy. 
3.3.4 
Patients must not have received prior allogeneic stem cell transplant. 
3.3.5 
Subjects who have received prior solid organ transplantation. 
3.3.6 
Patients must not have received prior total body irradiation. 
3.3.7 
Patients who are on hemodialysis. 
3.3.8 
Patients with an active or uncontrolled infection.  
3.3.9 
Known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. 
(testing of patients not known to be infected with these viruses is not required prior to study 
registration). 
3.3.11 Patients with a history of having to permanently discontinue anti-GD2 antibody therapy, GM-CSF, 
or vorinostat (Part B only) due to toxicity are not eligible.  
3.3.12 Prior anti-GD2 therapy given in combination with therapeutic 131I-MIBG, including those treated on 
Part A of NANT 2017-01.  
3.3.13 Prior HDAC inhibitor given in combination with therapeutic 131I-MIBG (Part B only). 
3.3.14 The maximum total allowable dose of 131I-MIBG that can be given per institutional guidelines must 
be at least 90% of the calculated 131I-MIBG dose or the patient is not eligible.  
3.3.15 Patient declines participation in NANT 2004-05, the NANT Biology Study. 
3.3.16 Patients with a history of deep venous thrombosis that was not associated with the presence of a 
central venous catheter (Part B only). 
 
3.4 
Regulatory 
 
3.4.1 
Informed Consent 
The patient and/or the patient’s legally authorized guardian must acknowledge in writing that consent 
to become a study subject has been obtained, in accordance with institutional policies approved by 
the US Department of Health and Human Services. 
 
3.4.2 
Protocol Approval 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
28 
 
4.0 
TREATMENT PROGRAM 
 
4.1 
Treatment Overview 
 
4.1.1 
Part A 
 
Patients receive 131I-MIBG on Day 1. The dose of 131I-MIBG and dinutuximab will be based on the dose 
level assigned at the time of patient registration.  Dinutuximab is given intravenously on Days 8-11 and 29-
32 of therapy, along with GM-CSF 250 mcg/m2 on Days 8-17 and 29-38. All patients receive autologous 
hematopoietic stem cell infusion on Day 15 (+/- 2) of therapy. This must occur at a NANT site.  
 
Course duration is defined as 57 days or longer if hematopoietic recovery to eligibility criteria occurs after 
Day 57. All patients will undergo disease restaging between Days 43 – 57 or later if recovery to start ourse 
2 is delayed.  Patients may receive up to two courses of therapy as long as all protocol-defined criteria are 
met prior to the start of the second course.  
 
 
DAY 
1 
2-7 
8 
9 
10 
11 12 
13 
14 
15 
16 
17 
18-28 
131I-MIBG (M) 
dose level assignment 
M1 
GM-CSF (G) 
250 mcg/m
2 
 
G2 
G 
G 
G 
G 
G 
G 
G 
G 
G2 
DINUTUXIMAB (D) 
dose level assignment 
 
D3 
D 
D 
D 
Stem Cell Infusion 
(HSC) 
 
 
 
 
 
 
 
 
HSC 
+/- 
2d 
 
 
DAY 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
43-57 
GM-CSF (G) 
250 mcg/m
2 
G2 
G 
G 
G 
G 
G 
G 
G 
G 
G2 
DINUTUXIMAB (D) 
dose level assignment 
D3 
D 
D 
D 
 
 
 
  
Disease Evaluation 
(Eval) 
 
 
 
Eval4 
1It is strongly encouraged to begin 131I-MIBG on Tuesday – Thursday to allow biologic correlates to be received on 
Wednesday – Friday.  Contact NANT Operations Center/Study Chair if treatment is delayed and will not start on a 
Tuesday-Thursday schedule. 
 
2GM-CSF is administered for 10 doses starting on the same day as the Day 8 and Day 29 dinutuximab dose 
respectively.  If the start of dinutuximab is delayed, the GM-CSF dose should be held and started on the first day of the 
dinutuximab infusion.  If the Day 8 or Day 29 GM-CSF dose is given but then the respective dinutuximab dose is not 
started the same day, additional doses of GM-CSF should not be given beyond the planned 10 doses with each cycle 
of dinutuximab unless required for Grade 4 neutropenia (ANC < 500/μL). Refer to Section 4.2.4.2 for extending GM-
CSF administration beyond Day 17 and 38. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
29 
 
3Refer to protocol Section 4.2.3.3 for criteria to receive dinutuximab on Day 8 and Day 29.  
 
4Disease evaluation is to occur between Days 43-57.  In case of treatment delays with dinutuximab during Course 1, 
the time interval between performing end of Course 1 disease evaluation and administration of Course 2 131I-MIBG is 
not to exceed 4 weeks. 
 
4.1.2 
Part B 
 
Patients receive vorinostat on Days 0 to +13 (14 days) and 131I-MIBG on Day 1. The dose of vorinostat and 
131I-MIBG will be based on the dose level assigned at the time of patient registration. Patients will receive 
a total of 14 doses of vorinostat. Missed doses may be made up provided there is at least 24 hours between 
vorinostat and infusion of stem cells, and stem cell infusion is not delayed beyond Day 17; vorinostat should 
not be administered after stem cell infusion regardless of the number of doses received. Patients should 
not exceed 14 total doses of vorinostat for any reason. If a patient vomits within 15 minutes of vorinostat 
dose administration, the patient should be re-dosed. If the patient vomits after the second dose, the patient 
should not be re-dosed again. If a patient vomits more than 15 minutes from dose administration, the patient 
should not be re-dosed. Refer to Section 4.2.5.1 and 6.5.4 for vorinostat drug administration guidelines. 
 
Dinutuximab 17.5 mg/m2 is given intravenously on Days 8-11 and 29-32 of therapy, along with GM-CSF 
250 mcg/m2 on Days 8-17 and 29-38. All patients receive autologous hematopoietic stem cell infusion on 
Day 15 (+2/-1) of therapy. This must occur at a NANT site.  
 
Course duration is defined as 57 days or longer if hematopoietic recovery to eligibility criteria occurs after 
Day 57.  All patients will undergo disease restaging between Days 43 – 57 or later if recovery to start Course 
2 is delayed.  Patients may receive up to two courses of therapy as long as all protocol-defined criteria are 
met prior to the start of the second course.  
 
 
DAY 
0 
1 
2-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18-28 
Vorinostat (V) 
dose level 
assignment 
V 
V 
V 
V 
V 
V 
V 
V 
V5 
 
 
 
 
 
131I-MIBG (M) 
dose level 
assignment 
 
M1 
GM-CSF (G) 
250 mcg/m
2 
 
G2 
G 
G 
G 
G 
G 
G 
G 
G 
G2 
DINUTUXIMAB (D) 
17.5 mg/m2 
 
D3 
D 
D 
D 
Stem Cell Infusion 
(HSC) 
 
 
 
HSC5 
+2d/-
1d 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
30 
 
 
DAY 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
43-57 
GM-CSF (G) 
250 mcg/m
2 
G2 
G 
G 
G 
G 
G 
G 
G 
G 
G2 
DINUTUXIMAB (D) 
dose level assignment 
D3 
D 
D 
D 
 
 
 
  
Disease Evaluation 
(Eval) 
 
 
 
Eval4 
1It is strongly encouraged to begin 131I-MIBG on Tuesday – Thursday to allow biologic correlates to be received on 
Wednesday – Friday.  Contact NANT Operations Center/Study Chair if treatment is delayed and will not start on a 
Tuesday-Thursday schedule. 
 
2GM-CSF is administered for 10 doses starting on the same day as the Day 8 and Day 29 dinutuximab dose, 
respectively.  If the start of dinutuximab is delayed, the GM-CSF dose should be held and started on the first day of the 
dinutuximab infusion.  If the Day 8 or Day 29 GM-CSF dose is given but then the respective dinutuximab dose is not 
started the same day, additional doses of GM-CSF should not be given beyond the planned 10 doses with each cycle 
of dinutuximab unless required for Grade 4 neutropenia (ANC < 500/μL). Refer to Section 4.2.4.2 for extending GM-
CSF administration beyond Day 17 and 38. 
 
3Refer to protocol Section 4.2.3.3 for criteria to receive dinutuximab on Day 8 and Day 29.  
 
4Disease evaluation is to occur between Days 43-57.  In case of treatment delays with dinutuximab during Course 1, 
the time interval between performing end of Course 1 disease evaluation and administration of course 2 131I-MIBG is 
not to exceed 4 weeks. 
 
5There must be at least 24 hours between the last dose of vorinostat and stem cell infusion. Infusion of stem cells 
should not be delayed beyond Day 17. 
 
 
4.2      Drug Administration 
 
4.2.1 
131I-MIBG Therapy 
 
DOSE: Based on dose level assignment at study registration. Refer to Section 4.3 dose escalation. 
 
DAY: 
Day 1 of therapy intravenously via either a central or a peripheral IV catheter over 1.5 to  2 
 
hours.    
 
 
Starting therapy on Tuesday – Thursday is strongly encouraged. Notify NANT Operations 
Center/Study Chairperson if treatment is delayed for any reason and will not start on a Tuesday – 
Thursday. 
 
The primary 131I-MIBG supplier for this study is Jubilant Radiopharma, Canada. 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
31 
 
 
4.2.1.1. General Instructions for Drug Ordering and Administration 
• 
To allow time for appropriate planning, the weight that is used to order the 131I-MIBG dose can 
be obtained at the time of initial consult or consent. However, due to the potential for significant 
weight changes while waiting to initiate therapy, the 131I-MIBG dose that is administered MUST 
be calculated based on a weight obtained within 7 days before the date of 131I-MIBG 
administration.   
 
Sites will use the “131I-MIBG Order Notification Form for NANT 2017-01”, available on the NANT 
website, and the site specific 131I-MIBG Order form provided by Jubilant Radiopharma to order 
a 131I-MIBG dose from supplier. NANTCRF@chla.usc.edu is to be copied on all drug orders 
and correspondence regarding 131I-MIBG dose planning between site and supplier.   
 
• 
The therapeutic dose of 131I-MIBG will be infused intravenously over 1.5-2 hours on Day 1 of 
therapy with appropriate hydration, radiation isolation, thyroid blocking with potassium iodide 
(SSKI), and bladder protection with a Foley catheter.  
 
• 
The maximum absolute dose of 131I-MIBG that may be infused on this protocol is 1200 mCi. 
The dose administered should be within 10% of the prescribed dose. There will be no 
adjustment for obesity except to cap the absolute dose at 1200 mCi. 
 
• 
Radiopurity is checked by the supplier prior to shipment. As of 10/20/21, radiochemical 
purity testing at clinical sites following receipt of 131I-MIBG is no longer required. Should 
clinical sites still wish to perform radiochemical purity testing, a suggested technique can 
be found in Appendix V. 
 
• 
The patient will remain in a radiation protected isolation room until radiation emissions meet 
institutional/state guidelines. Radiation levels will be measured at least once daily by Radiation 
Safety using a handheld monitor standing at a distance of one meter from the patient. It usually 
takes 3-5 days for the patient to be cleared and then they can be discharged.  
 
• 
Patients should be transfused as needed to achieve a documented hemoglobin of ≥ 10 
g/dL on the day of or one day prior to 131I-MIBG administration. 
 
4.2.1.2 Hydration 
In order to ensure adequate hydration, patients will receive a minimum of 1.5-times maintenance 
rate IV fluids starting the night prior to 131I-MIBG infusion and continuing until the radiation dose 
rate is < 7 mRem/hr at 1 meter. Once < 7 mRem/hr, IV hydration is at the discretion of the treating 
institution. 
 
4.2.1.3 Bladder Protection 
A Foley catheter is strongly recommended for all patients prior to 131I-MIBG infusion and required 
of all patients < 12 years of age. Patients ≥ 12 years of age may decline Foley catheter placement 
at investigator discretion if they agree to void every 2 hours throughout the first 48 hours after 131I-
MIBG infusion. If for physical/anatomic reasons it is not possible to successfully place or retain a 
catheter, then the treatment may proceed for continent patients who are able to comply with voiding 
every 2 hours throughout the first 48 hours following the infusion. For continent patients, the 
catheter may be removed after 72 hours or after the patient’s dose rate at 1 meter is < 7 mRem/hr, 
whichever occurs earlier. For incontinent (diapered) patients, the catheter is recommended to 
remain in place until the patient is released from radiation isolation.  
 
 


 
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4.2.1.4 Thyroid Protection 
Potassium iodide solution (SSKI) will be given in a loading dose of 6 mg/kg by mouth 8-12 hours 
prior to the infusion of 131I-MIBG on Day 1, and then 1 mg/kg/dose by mouth starting 4-6 hours after 
completion of the 131I-MIBG infusion, and continuing every 4 hours on protocol Days 1 to 7, and 
then 1 mg/kg/dose by mouth once daily on protocol Days 8 to 45.  
  
If 131I-MIBG infusion is delayed due to shipment or other issues and the patient has already received 
their loading dose, a suggested practice is to hold any further SSKI and to repeat the loading dose 
as above; this is to spare the patient and family an additional day of q4h SSKI dosing. An acceptable 
alternative approach is to just start the subsequent SSKI doses on schedule as though the 131I-
MIBG infusion had been completed on schedule. 
 
 
4.2.1.5 Radiation Isolation 
Following the 131I-MIBG infusion, patients must remain in radiation isolation until the patient’s 
radiation emissions meet state/institutional guidelines for release. 
 
4.2.1.6 Imaging 
An MIBG imaging study similar to the diagnostic scan will be done at the time of release from 
radiation isolation and will not require an additional injection. This is to confirm tumor MIBG uptake 
and to survey for occult sites of disease. SPECT is not required for this MIBG scan. Sedation is 
generally not necessary for this scan. 
 
4.2.1.7 Whole Body Dosimetry 
Whole body dosimetry will not be calculated in real time.  However, serial measurements of 
radiation levels will be obtained. While in radiation isolation, whole-body monitoring will be 
performed using a ceiling-mounted meter at consistent patient geometry. The person obtaining the 
measurement should be certain the patient is centered under the monitor and that the height of the 
bed has not been changed.  
 
All times are noted from the beginning of the 131I-MIBG infusion and assume a 2-hour infusion.  
The minimum whole body measurements will be taken as follows, and saved in the computer log. 
All times are measured from the beginning of the MIBG infusion.  
 
 
TIME 
SCHEDULE 
Infusion  
0, 1, 2 (including end infusion, with 
time marked) 
Post-Infusion Hours 2-8 
Every 30 minutes hours 2-8 
Post-Infusion Hours 8-24 
Hours 8, 12, 16, 20, 24 
Subsequent Days 
Every 8 hours until hospital 
discharge or hour 120, whichever 
occurs first 
 
If the ceiling mounted monitor is not functional for any reason, then measurements will be 
taken with a handheld ion chamber at 1 meter from the umbilicus with consistent geometry and 
distance beginning at the completion of the infusion (hour 2) and at hours 3, 4, 5, 6, 7, 8, then every 
8 hours thereafter. 
 
 


 
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4.2.2 
Autologous Peripheral Stem Cell Infusion  
 
DOSE: Minimum dose 2.0 x 106 viable CD34+ cells/kg. 
 
DAY: 
Day 15 +/- 2 days (Part A) or +2/-1 day (Part B) to avoid weekend or holiday infusion, to 
accommodate logistical/scheduling issues, or to avoid occurring within 24 hours of last dose of 
vorinostat.   
 
 
 
Stem cell infusion is planned for 14 days after 131I-MIBG infusion. If the 131I-MIBG infusion is 
 
delayed, the date of stem cell infusion should be re-dated for 14 days after 131I-MIBG infusion. 
 
Stem cells must be infused at the treating NANT institution.  
 
 
4.2.2.1 General Instructions for Peripheral Stem Cell Administration  
• 
In situations in which the DMSO concentration in the stem cell product would exceed an 
accepted level for infusion within a 24-hour period, stem cell products may be infused over two 
days to meet this standard.  
 
• 
Stem cell infusion may occur sooner than Day 15 if indicated (i.e. due to an infectious or 
bleeding complication) after consultation with the Study Chairperson or designee. 
 
• 
For patients whose body weight exceeds ideal body weight (IBW) by more than 20%, adjusted 
body weight may be used for calculation of PBSC dose (Reference: Bone Marrow Transplant. 
40(7):665-9; Appendix III).  
 
4.2.2.2 Pre-medications for Stem Cell infusion  
Stem cells will be infused following institutional guidelines for prophylaxis of hypersensitivity 
reactions and monitoring.  
 
4.2.2.3 Location of Stem Cell Infusion  
Stem cell infusion is considered a supportive care measure on this protocol.  Stem cells must be 
infused at the treating NANT institution.  
 
4.2.3 
Dinutuximab 
 
DOSE: Based on dose level assignment at study registration for Part A. Refer to Section 4.3 dose 
 
escalation. All patients on Part B will receive 17.5 mg/m2/dose. 
 
 
DAY: 
Days 8-11 and Days 29-32 intravenously over approximately 10 hours if tolerated.  
 
 
Refer to Section 4.2.3.1 Instructions for Dinutuximab Administration, Section 4.2.3.2 Criteria to 
 
Receive Dinutuximab and Sections 4.2.3.3 – 4.2.3.5 for recommendations on pre-medication, 
 
pain management and monitoring during infusion.   
 
4.2.3.1 General Instructions for Drug Ordering 
 
• 
Sites will use the “Dinutuximab Order Form for NANT 2017-01”, available on the NANT website, to 
place an order for dinutuximab. A copy of the drug order form is to be sent to NANTCRF@chla.usc.edu 
 
• 
To conserve dinutuximab vials, recommendation has been made to not use 2 vials per day until 
patient’s BSA exceeds 1.1 m2. For patients between BSA 1.0-1.1 m2, this is less than a 10% 
deviation; which is allowed. 
 
 


 
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4.2.3.2 Instructions for Dinutuximab Administration 
• 
Each daily dose of dinutuximab should be infused IV over approximately 10 hours, starting at 
0.88 mg/m2/hr x 0.5 hr, then increasing to 1.75 mg/m2/hr for the remainder of the dose, if 
tolerated. The infusion duration may be extended up to 20 hours for anticipated toxicities (pain, 
fever, tachycardia, tachypnea, hypotension), not responding to other supportive measures, and 
the duration should be recorded.   
 
• 
The maximum infusion time is 20 hours; dinutuximab administration must be stopped after 20 
hours even if the total dose has not been administered. The total dose given in 20 hours should 
be recorded.   
 
4.2.3.3 Criteria to Receive Dinutuximab 
• 
Day 8 Dose  
The day 8 dinutuximab dose can be given anytime from Day 6 until Day 11 as long as ALL of the 
following criteria are met: 
o 
Cleared the 131I-MIBG (radiation level < 7 mRem/hr at 1 meter) 
o 
No evidence of infection, or if present, infection under control with negative blood culture  
o 
ALT ≤ 450 U/L (10 x ULN where ULN = 45 U/L).  
o 
Total bilirubin ≤ 5 x ULN (Grade 2) 
o 
Creatinine ≤ 3 x ULN (Grade 2) 
o 
If the Day 8 dose is delayed beyond Day 11 then patient is off protocol therapy.  If the delay 
is the result of toxicity, this event would be considered a DLT 
o 
QTc ≤ 480 msec (Part B only) 
 
• 
Day 29 Dose 
The start of the Day 29 dinutuximab infusion may be delayed up to 2 weeks if needed to meet the 
following criteria: 
o 
At least 3 weeks have passed since the start of the Day 8 dinutuximab infusion 
o 
Meet the renal function requirements as outlined in Section 3.2.9.2   
o 
ALT ≤ 225 U/L (5 x ULN (grade 2) where ULN = 45 U/L). 
o 
Absolute phagocyte count (APC) ≥ 750/μL 
o 
No evidence of infection, or if present, infection under control with negative blood culture  
o 
No DLT prior to start of the Day 29 infusion 
o 
If the Day 29 dose is delayed beyond 2 weeks then patient is off protocol therapy.  If the 
delay is the result of toxicity, this event would be considered a DLT 
 
4.2.3.4 Recommended Premedications:  
• 
Hydroxyzine (0.5-1 mg/kg; max dose 50 mg) PO or diphenhydramine (0.5-1 mg/kg; max dose 
50 mg) IV over 10 minutes to start approximately 20 minutes prior to dinutuximab infusion; may 
be repeated every 6 hours as needed during dinutuximab infusion. Note: intravenous 
hydroxyzine is NOT recommended.  
 
• 
Acetaminophen (10-15 mg/kg; max dose 650 mg) PO given approximately 20 minutes prior to 
dinutuximab infusion; may be repeated every 4-6 hours either scheduled or as needed for fever.  
 
4.2.3.5 Recommended Pain Management:  
• 
Morphine sulfate loading dose immediately prior to dinutuximab administration. A dose of 50 
mcg/kg is recommended, though this may be adjusted based on a given patient’s pain history 
or institutional guidelines. Other narcotics such as hydromorphone or fentanyl can be used 
instead of morphine. 
• 
Continue with morphine sulfate drip titrated to effect. The recommended dose range for the 
continuous infusion is 20-50 mcg/kg/hr to continue for 2 hours after completion of the 
dinutuximab infusion, although institutional standards may be utilized. Other narcotics such as 
hydromorphone or fentanyl can be used instead of morphine.  


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
35 
 
 
• 
Gabapentin may be used in conjunction with other pain medications per institutional practice.  
 
• 
If additional or alternative pain medications (lidocaine, ketamine, etc.) are needed, it is strongly 
recommended that this be done in consultation with pediatric pain management specialists.  
 
4.2.3.6 Monitoring during Dinutuximab Infusion:  
• 
Vital signs should be assessed every 15 minutes for the first hour of the infusion, then hourly 
during the remainder of the infusion if stable after the first hour. More frequent assessment may 
be required based on the patient’s clinical condition. Between antibody doses, vitals should be 
assessed every 4 hours.  
 
• 
Strict observation of intake and output is required on the days of dinutuximab administration.  
 
• 
Patients should be weighed daily on the days of dinutuximab administration. 
 
 
 


 
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36 
 
4.2.4 
Sargramostim (GM-CSF) 
DOSE: 250 mcg/m2/dose. 
 
DAY: 
Once daily on Days 8-17 and Days 29-38. 
 
4.2.4.1 Instructions for GM-CSF Administration 
• 
The standard route of administration is subcutaneous (SQ); use of an insuflon catheter is 
permitted.  
 
• 
In extenuating circumstances, IV administration over 2 hours is permitted. The reason for IV 
administration of this agent must be documented. 
 
• 
See Section 4.2.4.2 for criteria to extend GM-CSF administration.   
 
• 
If the Day 8 or Day 29 GM-CSF dose is given but then the respective dinutuximab dose is not 
started the same day, additional doses of GM-CSF should not be given beyond the planned 10 
doses with each cycle of dinutuximab. 
 
4.2.4.2 Growth Factor Support Outside Planned GM-CSF Doses on Days 8-17 and Days 29-38  
• 
It is strongly recommended that GM-CSF be the only growth factor used on this study. The use 
of filgrastim (G-CSF) or pegfilgrastim, even if the patient experiences febrile neutropenia, is 
strongly discouraged.  
 
• 
GM-CSF is strongly recommended for any patient who develops Grade 4 neutropenia [absolute 
neutrophil count (ANC) < 500/μL]. If GM-CSF is started or continued during this time, it is 
recommended that it be continued until the ANC is > 2000/μL. 
 
• 
If a patient experiences Grade 4 neutropenia while receiving vorinostat prior to the Day 8 
dinutuximab/GM-CSF dose, GM-CSF can be initiated early once they clear radiation isolation. 
If GM-CSF is started prior to the Day 8 dinutuximab dose, the GM-CSF should still be continued 
at least until the Day 17 GM-CSF dose, i.e. the patient should still receive the full 10 doses of 
GM-CSF associated with the Day 8 dinutuximab dose. 
 
4.2.5 
Vorinostat 
DOSE: Based on dose level assignment at study registration. Refer to Section 4.3.2 dose escalation. The 
maximum vorinostat dose is 400 mg. 
 
DAY: Days 0 to +13 (14 total doses) of therapy once daily by mouth, NG, or G-tube 
 
4.2.5.1 Instructions for Vorinostat Administration 
• 
Vorinostat will be given for 14 days continuously, even if the 131I-MIBG portion of therapy is delayed 
due to production or other logistical reasons or if dinutuximab start date is delayed.  
• 
Missed doses may be made up provided there is at least 24 hours between vorinostat and infusion 
of stem cells, and stem cell infusion is not delayed beyond Day 17; vorinostat should not be 
administered after stem cell infusion regardless of the number of doses received. Patients should 
not exceed 14 total doses of vorinostat for any reason. 
• 
If a patient vomits within 15 minutes of vorinostat dose administration, the patient should be re-
dosed. If the patient vomits after the second dose, the patient should not be re-dosed again. If a 
patient vomits more than 15 minutes from dose administration, the patient should not be re-dosed. 
• 
For patients unable to swallow capsules, vorinostat will be given as a 50 mg/mL extemporaneous 
liquid suspension (see Section 6.6.4 for preparation instructions) with dosing according to the 
nomogram in Appendix VIII. The maximum vorinostat dose is 400 mg. (Please contact NANT 
Operations if extemporaneous liquid suspension is not available) 
• 
Patients who are able to swallow capsules may receive vorinostat capsules instead of suspension 
if their calculated vorinostat dose is within +/- 10% of a 100 mg increment (e.g. 100 mg, 200 mg, 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
37 
 
300 mg, or 400 mg). Otherwise, they will need to receive vorinostat as suspension and dosed 
according to the nomogram in Appendix VIII. The maximum vorinostat dose is 400 mg. 
• 
Vorinostat should be taken with food or within 30 minutes after a meal. The dose should be taken 
in the morning whenever possible. 
 
4.2.5.2 Instructions for Ordering Vorinostat 
• 
Vorinostat will be obtained via commercial supply. 
 
4.3 
Dose Escalation Schedule 
 
4.3.1 
Part A 
 
 
Dose Level 
131I-MIBG (mCi/kg/dose) 
Dinutuximab (mg/m2/dose) 
0 
12 
14 
Starting Dose Level: 
1 
12 
17.5 
 
2 
15 
17.5 
3 
18 
17.5 
 
Dose escalation will begin at Dose Level 1, with escalation up to Dose Level 3 following the Rolling 6 dose 
escalation design. If Dose Level 1 is deemed intolerable per the dose escalation rules, then Dose Level 0 
will be evaluated. Patients will be treated at the dose of 131I-MIBG and dinutuximab assigned at study 
registration.  There will be no intrapatient dose escalation. 
 
The starting dose of 131I-MIBG is 12 mCi/kg at Dose Level 1.  The dinutuximab dose is 17.5 mg/m2/dose. If 
the starting dose level (Dose Level 1) is not tolerated, patients will be enrolled to Dose Level 0, which keeps 
the 131I-MIBG dose at 12 mCi/kg, but reduces the dinutuximab dose to 14 mg/m2/dose.  
 
4.3.2 
Part B 
 
 
Dose Level 
Vorinostat 
(mg/m2/dose)# 
131I-MIBG 
(mCi/kg/dose) 
Dinutuximab 
(mg/m2/dose) 
Starting Dose Level 
4 
180 
18 
17.5 
 
4a* 
150 
18 
17.5 
#Maximum vorinostat dose: 400 mg 
*De-escalation dose level 4a to enroll only if dose level 4 is not tolerated 
 
The starting dose level for Part B will be Dose Level 4. Patients on this dose level will receive vorinostat at 
180 mg/m2/dose and 131I-MIBG at 18 mCi/kg/dose (the MTD/RP2D determined in Part A). Dinutuximab will 
be given at 17.5 mg/m2/dose. Enrollment will follow the Rolling 6 dose escalation design. If Dose Level 4 is 
deemed intolerable per the dose escalation rules, then Dose Level 4a will be evaluated.  Patients will be 
treated at the assigned dose of vorinostat and 131I-MIBG.  There will be no intrapatient dose escalation. 
Once the MTD/RP2D is established in Part B, we will enroll 6 evaluable patients in an expansion cohort to 
further test the MIBG, vorinostat, and dinutuximab/GM-CSF combination. 
 
 
4.4 
Definition of Dose-Limiting Toxicity (DLT)  
Toxicity will be graded using the CTCAE criteria, version 5. The CTCAE provides descriptive 
terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be 
downloaded from the CTEP home page (http://ctep.cancer.gov).  Any dose-limiting toxicity should 
be reported immediately through the NANT Operations Center to the Study Chairperson.  
 
 


 
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38 
 
4.4.1 
Definition of Evaluable for Dose Escalation 
A patient will be considered evaluable for dose escalation purposes if they receive ≥ 90% of the 
assigned dose of 131I-MIBG, ≥ 80% of the assigned doses of dinutuximab and GM-CSF (GM-CSF 
criterion only applicable to Part A dose-escalation), and > 78% of the assigned doses of vorinostat 
(at least 11 days; Part B only) during Course 1. Patients who receive less than 90% of the assigned 
131I-MIBG dose, less than 80% of the assigned dinutuximab or GM-CSF doses (Part A dose-
escalation only), or less than 78% of the assigned vorinostat doses (less than 11 days; Part B only) 
for reasons other than toxicity will be replaced for the purposes of evaluating the dose level for 
dose escalation/de-escalation purposes, unless they experience a DLT in first course. All patients 
who receive 131I-MIBG in Part A or vorinostat in Part B are evaluable for toxicity reporting.  
 
4.4.2 
Definition of Dose-Limiting Toxicity 
DLT will be defined as any of the following events that are possibly, probably, or definitely 
attributable to study regimen. Only dose limiting toxicities as described below that occur during 
Course 1 that are possibly, probably or definitely related to the regimen (and not excluded in Section 
4.4.3 below) will be used for determination of the MTD/RP2D of 131I-MIBG (Part A) or vorinostat 
(Part B) although all DLTs during any course will be reported. Patients who experience a DLT 
during the first course of therapy will not be offered further treatment on study. 
 
Certain frequently observed side effects known to be related to dinutuximab are transient, and can 
be well-controlled clinically. These transient side effects, if well-controlled clinically, will not be 
used in this study to determine dose limiting toxicity. The list of toxicities that will NOT be 
considered DLT are outlined in Section 4.4.3. 
 
4.4.3 
Non-Hematologic Dose Limiting Toxicity 
Non-hematologic dose-limiting toxicity is defined as any Grade 3 or Grade 4 non-hematologic 
toxicity that is possibly, probably, or definitely attributable to the combination of therapy with the 
specific exclusion of the following:  
 
1 
Grade 3 nausea or vomiting 
2 
Grade 3 or 4 serum amylase elevation that resolves to grade 2 within 14 days and is not 
accompanied by grade 2 lipase elevation or grade ≥ 3 salivary gland toxicity (dry mouth; 
parotid pain). 
3 
Grade 3 infection 
4 
Grade 3 fever 
5 
Grade 3 febrile neutropenia 
6 
Grade 3 fatigue lasting ≤ 72 hours 
7 
Pupillary dilation and/or accommodation defects not accompanied by vision loss 
8 
Grade 3 pain that resolves to ≤ grade 2 within 72 hours 
9 
Grade 3 diarrhea that resolves to ≤ grade 1 with supportive care within 5 days 
10 
Grade 4 fever (ie. Temp > 40○ C) during dinutuximab administration that resolves within 48 
hours of dinutuximab completion 
11 
Grade 3 skin toxicity that improves to ≤ grade 2 with treatment (e.g. IV Benadryl)  within 48 
hours 
12 
Grade 3 urine output decreased that resolves within 24 hours of completion of dinutuximab 
13 
Grade 3 proteinuria that returns to ≤ grade 1 within 5 days of completion of dinutuximab 
14 
Grade 3 weight gain that resolves to ≤ grade 2 within 3 days of completion of dinutuximab 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
39 
 
15 
Grade 3 weight loss or anorexia that resolves to ≤ Grade 2 within 3 days 
16 
Grade 3 dehydration that resolves to ≤ Grade 2 within 3 days 
17 
Grade 3 electrolyte abnormality (Na, K, Cl, CO2, Ca, Mg, PO4) that returns to ≤ Grade 2 
within 3 days with or without treatment 
18 
Grade 3 hypoalbuminemia 
19 
Grade 3 hypotension and grade 3 hypertension that resolves to < Grade 1 within 48 hours 
20 
Grade 4 hypotension associated with dinutuximab that resolves to ≤ Grade 2 with supportive 
care not including pressors 
21 
Grade 3 or Grade 4 AST that returns to ≤ Grade 2 within 7 days 
22 
Grade 3 or Grade 4 ALT that returns to ≤ Grade 2 within 7 days.  Note:  The ALT ULN = 45 
U/L on this study. 
23 
Grade 3 GGT; Grade 4 GGT that returns to ≤ grade 2 within 7 days 
24 
Grade 3 bilirubin elevation that returns to ≤ Grade 2 within 7 days 
25 
Grade 3 or Grade 4 alkaline phosphatase elevation that returns to ≤ Grade 2 within 7 days 
26 
Grade 3 neurotoxicity (i.e. interference with function plus objective weakness) will not be a 
DLT if transient and reversing within 3 days of completion of dinutuximab for any course, or 
within 2 weeks of completion for grade 3 sensory changes interfering with daily activities.  
Subjective findings (e.g. tingling, hot or cold hands, taste change, etc.) are expected and will 
not be a DLT. 
27 
Grade 3 allergic reactions or anaphylaxis that is readily controlled with supportive anti-
allergic (non-steroidal) treatments (ie: Benadryl, epinephrine) 
28 
Grade 3 capillary leak syndrome 
29 
Grade 3 cough, dyspnea, hypoxia and bronchospasm that decrease to ≤ Grade 2 within 72 
hours 
30 
Grade 3 or Grade 4 somnolence that resolves to < Grade 2 on stopping supportive care 
medications (ie; narcotics, diphenhydramine, meperidine, etc.) during dinutuximab 
 
Note: Any non-hematologic toxicity that leads to a patient receiving < 78% of assigned vorinostat doses 
will also be classified as a DLT in Part B. 
 
4.4.4 
Definition of Engraftment and Hematologic Dose Limiting Toxicity 
 
 
4.4.4.1  Definition of Engraftment 
• 
Neutrophil engraftment will be defined as an ANC ≥ 500/μL for a minimum of 3 days following 
neutrophil nadir, with or without growth factor support. Date of neutrophil engraftment will be 
the first day of 3 days with ANC ≥ 500/μL. 
 
• 
Platelet engraftment will be defined as platelets ≥ 20,000/μL for a minimum of 3 days following 
platelet nadir without platelet transfusion for one week. Date of platelet engraftment will be the 
first day of 3 days with platelets ≥ 20,000/μL. If a patient has a platelet transfusion and then 
does not have another platelet count < 20,000/μL, the date of platelet engraftment will be the 
first date with platelet count ≥ 20,000 following platelet transfusion. 
 
 


 
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4.4.4.2 Definition of Hematologic Dose Limiting Toxicity 
• 
Once stem cell infusion is given, hematologic dose limiting toxicity will be defined as any of the 
following in the absence of progressive bone marrow disease: 
o 
Neutrophils (ANC) < 500/µL at 28 days after stem cell infusion 
o 
Platelets < 20,000/μL at 56 days after stem cell infusion 
o 
Infusion of additional stem cells for any medical reason after the initial stem cell infusion 
has been given AND prior to engraftment of neutrophils or platelets after that initial stem 
cell infusion.  
 
4.5 
Dose Modification and Recommendations for Management of Dinutuximab/GM-CSF 
 
Toxicity  
 
4.5.1 
There will be no dose reductions of either 131I-MIBG or dinutuximab on this study. The infusion rate 
of dinutuximab may be decreased due to toxicity as outlined below. Patients who experience a DLT 
will come off protocol therapy at that point in time. 
 
4.5.2 
Treatment of dinutuximab-induced hypotension (without evidence of allergic reaction) 
 
If hypotension is severe and accompanied by poor perfusion, end organ dysfunction, or acidemia,  
Pediatric Advanced Life Support (PALS) guidelines should be followed and dinutuximab infusion 
should be discontinued. 
 
A. If moderate hypotension is observed (without poor perfusion, end organ dysfunction, or 
academia): 
o 
Immediately hold dinutuximab 
o 
Give normal saline bolus (20 mL/kg as rapidly as possible) 
o 
Stop or adjust doses of narcotics and sedating H1 blockers 
o 
Consider use of Trendelenberg position 
 
B.  If hypotension persists after the above measures have been taken: 
o 
Reassess perfusion and end organ function; follow PALS algorithm if needed 
o 
Repeat NS bolus 
o 
Consider use of albumin if albumin < 3 gm/dL 
o 
Consider use of PRBCs if Hb < 10 gm/dL 
o 
Consider transfer to intensive care setting 
  
C. If hypotension persists following 2 volume boluses, give an additional bolus and prepare to 
administer pressors 
o 
Epinephrine is preferred over dopamine if possible 
 
D. Resumption of dinutuximab 
For patients whose hypotension resolves promptly and completely with limited volume 
resuscitation and without requirement for pressor support, dinutuximab may be restarted at 
50% of the previous infusion rate. The dinutuximab may be restarted on the same day if it is 
possible to do so within 20 hours of the start of the day’s infusion. If blood pressures are stable 
for 2 hours, the infusion may be given at full rate for that day and subsequent days. If the patient 
again experiences hypotension requiring multiple volume boluses (e.g., > 60 mL/kg) when 
dinutuximab is given at full rate but tolerates the 50% infusion rate, the remaining days’ doses 
of dinutuximab should be given at the 50% rate of infusion. If > 20 hours have elapsed since 
the start of the infusion, restart dinutuximab the following day. 
 
o 
If blood pressures are stable for 2 hours after resumption of dinutuximab at the reduced 
rate, the remainder of the antibody infusion may be given at the full rate. 
 
o 
If hypotension recurs at the reduced rate, the measures above should again be taken and 
no further dinutuximab should be given that day. The antibody infusion may be restarted 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
41 
 
the following day after ensuring that the patient is volume replete. The antibody rate upon 
resumption of treatment should be 50% of the initial rate. If blood pressures are stable for 
2 hours, the infusion may be given at full rate for that day and subsequent days. If the 
patient’s blood pressures are only stable at the 50% rate and not at full rate, the remaining 
days’ doses of dinutuximab should be given at the 50% rate of infusion. 
 
For patients who require multiple volume boluses for hemodynamic stabilization, dinutuximab 
should be resumed the following day at 50% of the initial infusion rate. 
 
o 
If blood pressures are stable for 2 hours after resumption of dinutuximab at the reduced 
rate, the remainder of the antibody infusion may be given at the full rate. 
 
o 
If hypotension recurs at the reduced rate, the measures above should again be taken and 
no further dinutuximab should be given that day. The antibody infusion may be restarted 
the following day after ensuring that the patient is volume replete. The antibody rate upon 
resumption of treatment should be 50% of the initial rate. If blood pressures are stable for 
2 hours, the infusion may be given at full rate for that day and subsequent days. If the 
patient’s blood pressures are only stable at the 50% rate and not at full rate, the remaining 
days’ doses of dinutuximab should be given at the 50% rate of infusion. 
 
o 
For patients who require pressors for treatment of hypotension, if blood pressure is stable 
off pressors for at least 6 hours, administration of dinutuximab may be resumed at 50% of 
the initial infusion rate on the day following the hypotensive episode. Care should be taken 
to ensure that the patient is volume replete. Dinutuximab should not be given to patients 
who continue to require pressor support. Patients who require pressor support for ≥ 24 
hours due to treatment-related hypotension despite appropriate volume resuscitation 
should discontinue protocol therapy. Patients who again require pressor support when 
dinutuximab is resumed should discontinue protocol therapy. 
 
4.5.3     Treatment of Allergic Reactions/Infusion Reactions 
Note: Coughing may herald the onset of bronchospasm and if occurs, patients should be 
closely monitored. 
 
 
4.5.3.1 Mild allergic reactions/infusion reactions to dinutuximab infusion 
 
o 
Mild allergic reaction is limited to rash, flushing, urticaria, mild dyspnea – Grade 1 or 2 
 
o 
The following recommendations do NOT apply to Grade 3 or 4 allergic reactions, including 
anaphylaxis 
 
o 
Management 
a. Administer H1 blocker (diphenhydramine, cetirizine recommended) 
b. Administer H2 blocker 
c. Meperidine may be used for rigors 
d. Can decrease rate of dinutuximab to 50% of the full rate if clinically indicated 
e. When symptoms resolve, if the rate has been reduced, resume original infusion 
rate 
f. 
If symptoms recur when original rate is resumed (after a rate reduction), decrease 
to 50% rate again 
g. Infusion must be stopped after 20 hours (whether the full dose of dinutuximab has 
been administered or not); document total amount of drug given in the 20 hour time 
period 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
42 
 
4.5.3.2 Moderate to severe allergic reactions/infusion reactions to dinutuximab infusion 
 
o 
Moderate to severe reactions include any of the following: symptomatic bronchospasm, 
allergy-related edema/angioedema, hypotension, or anaphylaxis – Grade 3 or 4 
 
o 
The following recommendations do NOT apply to Grade 1 or 2 allergic reactions 
 
o 
Management 
a. Immediately hold dinutuximab 
b. Assess airway, breathing and circulation 
c. Follow institutional guidelines for rapid response team notification if clinically 
indicated 
 
d. For airway concerns 
• 
Administer oxygen and albuterol immediately for bronchospasm 
• 
Administer IV diphenhydramine 
• 
Administer epinephrine (1:1000 IM recommended) immediately if upper airway 
involved or if airway issues are accompanied by cardiovascular collapse 
• 
Administer IV hydrocortisone (1-2 mg/kg) if the patient has frank anaphylaxis 
with cardiorespiratory collapse OR if ≥ 2 doses of epinephrine are required OR 
if moderate to severe symptoms recur upon rechallenge with dinutuximab 
 
e. For hypotension in the setting of allergic reaction 
• 
Give normal saline bolus (20 mL/kg as rapidly as possible) 
• 
Stop or adjust doses of narcotics and sedating H1 blockers 
• 
Consider use of Trendelenberg position 
• 
See previous section for management of persistent hypotension 
 
f. 
For patients with mild bronchospasm or angioedema that does not impact 
breathing, completely resolves without the use of epinephrine and hydrocortisone 
and for patients whose hypotension resolves following volume bolus, dinutuximab 
may be resumed at 50% of the previous rate of infusion on the same day as the 
reaction occurred. If symptomatic angioedema or asymptomatic bronchospasm 
recurs when the dinutuximab is restarted, discontinue immunotherapy for that day 
and if symptoms/signs resolve completely that day, resume the next day with 
additional premedication of hydrocortisone 1-2 mg/kg IV. For this re-challenge, the 
infusion should be given in an ICU setting.  
 
g. For patients whose bronchospasm or angioedema requires the use of systemic 
epinephrine, protocol therapy should be discontinued.  
 
h. For patients with bronchospasm or angioedema that does not require systemic 
epinephrine but whose hypotension requires more extensive volume resuscitation, 
guidance in Section 4.5.2 should be followed. 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
43 
 
4.5.4 
Management of capillary leak syndrome (≥ Grade 3) due to dinutuximab 
 
 
*** Capillary leak syndrome should be managed aggressively. 
See Section 4.5.2 for management of hypotension, anemia and hypoalbuminemia 
 
o 
Hold dinutuximab infusion 
o 
Provide oxygen and fluids as needed 
o 
Consider use of albumin if albumin < 3 gm/dL, especially prior to diuretics 
o 
Consider use of PRBCs if Hb < 10 gm/dL 
o 
Do NOT resume dinutuximab therapy if symptoms of severe capillary leak syndrome persist 
on the same day or subsequent days of a given 4-day dinutuximab cycle. Only resume 
dinutuximab therapy when the capillary leak syndrome resolves or requires less significant 
intervention (Grade 2 or less). 
o 
If capillary leak resolves, may resume dinutuximab infusion at 50% rate the same day and for 
subsequent doses during a given 4-day dinutuximab cycle. The infusion may be given at the 
full rate at the start of the day 29 dose, or during course 2 when applicable. 
o 
If mechanical ventilation (any duration) or pressor support for ≥ 24 hours is required due to 
therapy-related capillary leak syndrome, the patient should discontinue protocol therapy. 
 
4.5.5 
Management of renal insufficiency (unrelated to hypotension) while receiving dinutuximab 
 
o 
Consider the possibility of renal hypoperfusion in the context of borderline hypotension; 
administer volume if appropriate 
o 
If the patient’s creatinine is elevated to ≥ 2 x the upper limit of normal for age/gender (see table 
in Section 3.2.9.2) and elevation persists despite optimized fluid management, hold 
dinutuximab 
o 
Modify dosing of concomitant medications that may contribute to or be affected by renal 
insufficiency 
o 
When creatinine returns to < 2 x upper limit of normal for age/gender, resume dinutuximab at 
50% rate. If renal function normalizes by the following day, dinutuximab may be administered 
at full rate. If renal function is not sufficiently improved (creatinine < 2x ULN for age/gender) by 
the planned end date of the 4-day dinutuximab cycle, no further dinutuximab should be given 
during that 4 day cycle of dinutuximab therapy. Subsequently, if renal function meets criteria to 
start the day 29 dinutuximab or a second course of therapy if applicable, retreatment with 
dinutuximab is permitted. 
 
4.5.6 
Management of hyponatremia (≥ Grade 3; Na < 130 mEq/L) while receiving dinutuximab 
 
o 
Change hypotonic fluids to isotonic fluids as compatibilities permit 
o 
Avoid administration of oral free water 
o 
Correct fluid losses due to diarrhea 
o 
3% saline as indicated 
o 
If Grade 4 hyponatremia occurs, discontinue dinutuximab. This will be considered a DLT and 
the patient will be taken off of protocol therapy. 
 
4.5.7 Management of fever in the absence of hypotension while receiving dinutuximab 
 
o 
Administer antipyretics 
o 
Adjust fluids to account for insensible losses if fever is persistent 
o 
For a temperature ≥ 39○ C, obtain a blood culture per institutional standards. Additional blood 
cultures are only needed for a positive blood culture or clinical decompensation (hypotension, 
concern for sepsis, etc.). 
o 
For temperature ≥ 39○ C, after drawing a blood culture, the decision whether to administer 
antibiotics will be determined by institutional guidelines. If the patient is neutropenic (ANC ≤ 
500), broad spectrum antibiotics should be administered per institutional guidelines for febrile 
neutropenia. If the patient has a positive blood culture, treat per institutional guidelines. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
44 
 
4.5.8 Management of treatment-related pain due to dinutuximab 
 
o 
No further dinutuximab therapy should be given to patients who experience treatment-related 
pain that cannot be controlled by narcotics. Treatment with gabapentin or similar agent should 
be initiated if not already being administered. If pain that is not controlled with narcotics recurs 
during a subsequent 4-day dinutuximab cycle, the patient should discontinue protocol therapy 
 
o 
For patients with treatment-related pain requiring intravenous narcotics for ≥ 48 hours following 
completion of dinutuximab therapy, gabapentin or similar agent should be initiated if not already 
being administered. If pain requiring prolonged intravenous narcotics (≥48 hours following 
completion of dinutuximab therapy) recurs during a subsequent 4-day dinutuximab cycle 
despite this intervention, the patient should discontinue protocol therapy. 
 
4.5.9 Management of visual changes due to dinutuximab 
 
Occasionally, dinutuximab may cause impaired accommodation and/or dilated pupils with sluggish 
light reflex +/- photophobia. If this occurs, no modifications, dose reductions, or changes in infusion 
rate should be made unless there is vision loss. If the patient experiences vision loss or a grade 4 
event then dinutuximab should be stopped and protocol therapy should be discontinued. 
 
4.5.10 Management of serum sickness due to dinutuximab  
 
o 
Identification of serum sickness – signs and symptoms include arthralgias/arthritis, 
splenomegaly, lymphadenopathy, glomerulonephritis in the presence of persistent fevers, 
cutaneous eruptions 
o 
Serum sickness typically develops 1 to 3 weeks after administration of the causative agent, but 
can develop within 12-36 hours in patients who have previously been sensitized to the 
causative agent 
o 
Patients with ≥ Grade 3 serum sickness should discontinue protocol therapy and receive 
appropriate treatment for this condition. 
o 
For Grade 2 serum sickness, antihistamines should be prescribed. 
 
4.5.11 Management of neurotoxicity due to dinutuximab 
o 
Patients who develop Grade 4 neurotoxicity should discontinue protocol therapy. 
o 
Dinutuximab should be discontinued for the remainder of the current treatment course (8-11 or 
29-32) of therapy for patients who develop Grade 3 sensory neuropathy or Grade 3 motor 
neuropathy. If this occurs during Days 8-11, gabapentin or a similar agent should be initiated if 
not already being administered. If abnormalities resolve by the start of the next course of 
dinutuximab (either Day 29 or the start of the second course if applicable) the patient may 
receive dinutuximab at full dose. If symptoms do not completely resolve or recur with 
dinutuximab then the patient should discontinue protocol therapy. 
 
4.5.12 Management of GM-CSF related toxicities 
 
o 
Hold GM-CSF if total white blood cell count is > 50,000/µL; resume at 50% dose when the 
count is < 20,000/µL. Administer full dose subsequently (starting with Day 29 dose or with the 
second course if applicable) and modify again if the count exceeds 50,000/µL. If GM-CSF is 
being used for neutropenia following 131I-MIBG then full dose should be used. 
o 
Localized skin reactions to GM-CSF are common, and GM-CSF can be continued when 
reactions are mild. Rotation of sites of injections is recommended rather than use of insuflon 
for subcutaneous injection when skin reactions occur. Consider use of antihistamines. If ≥ 
Grade 3 injection site reactions occur, stop GM-CSF and discontinue all subsequent GM-CSF 
doses. 
 
o 
A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, 
and/or tachycardia has been reported following the administration of the first dose of GM-CSF 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
45 
 
in a particular cycle. This syndrome generally resolves with symptomatic treatment and usually 
does not recur with subsequent doses of GM-CSF. For safety purposes in this study, if such a 
“first dose reaction” occurs, the GM-CSF dose will be reduced to 50% for the next dose (i.e., 
GM-CSF dose 125 mcg/m2). If a similar reaction occurs at the 50% dose, the GM-CSF will be 
discontinued for that patient. If the first dose at 50% does not cause any recurrent severe 
symptoms, subsequent doses can be escalated back to 100%. If recurrent severe symptoms 
are observed at 100% dose, then the dose will be reduced to 50%. If 50% is tolerated, that 
dose should be administered for all subsequent protocol treatment for that patient. If recurrent 
severe symptoms are seen at the 50% dose, the GM-CSF will be discontinued. 
 
4.6 
Dose Modifications for Vorinostat 
 
Any dose modification of vorinostat should be reported to the study chair and to the NANT Operations 
Center. Vorinostat will NOT be held for hematologic toxicity unless patients become platelet 
transfusion refractory while receiving vorinostat.  
 
4.6.1 
Patients who develop Grade 4 neutropenia while receiving vorinostat will continue to receive 
vorinostat at the prescribed dose and schedule. GM-CSF can be initiated early per Section 4.2.4.2 
once the patient clears radiation isolation. If GM-CSF is started prior to the Day 8 dinutuximab dose, 
the GM-CSF should still be continued at least until the Day 17 GM-CSF dose, i.e. the patient should 
still receive the full 10 doses of GM-CSF associated with the Day 8 dinutuximab dose. 
 
4.6.2 
Patients who develop Grade 4 thrombocytopenia while receiving vorinostat will continue to receive 
vorinostat at the prescribed dose and schedule unless they become platelet transfusion refractory. 
 
4.6.3 
Patients who experience non-hematologic DLT (Section 4.4.3) while receiving vorinostat should 
have vorinostat discontinued. 
 
4.7 
Criteria to Receive a Second Course of Therapy  
Patients who meet all of the following criteria at the end of the first course of therapy may proceed 
to a second course of therapy as long as they meet ALL of the following criteria:  
 
• 
Adequate stem cells to support a second course per Section 3.2.6;  
• 
Organ function criteria in Section 3.2.10;  
• 
No other intervening anti-cancer therapy between first course and planned second course;  
• 
Day 1 of planned second course may start no earlier than Day 57 of first course and no later 
than 4 weeks from end of Course 1 disease evaluation;    
• 
In the case of treatment delays during Course 1, Day 1 of planned second course may not 
begin earlier than 3 weeks from the start of the most recent 4 day dinutuximab infusion.  No 
protocol defined dose limiting toxicity in first course of therapy Section 4.4);  
• 
Disease response of stable disease or better at end of first course (Section 11.0); 
• 
Grade 3 vision toxicity due to pupillary dilation and/or accommodation defects must be stable 
to improved. 
 
4.8 
Concomitant Therapy 
• 
Immunosuppressive drugs (other than corticosteroids used to treat side effects of protocol 
therapy) are not allowed during protocol therapy. Dexamethasone should be avoided as an 
anti-nausea/antiemetic therapy. 
• 
Corticosteroid therapy should be utilized only for life threatening conditions. 
• 
No other cancer chemotherapy, immunomodulating agents, or biologics can be used during 
protocol therapy.  
• 
External beam radiation therapy can NOT be used during protocol therapy. 
• 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive 
care are to be used as necessary for good patient care.  
• 
No medications that interfere with MIBG uptake should be given while patient is receiving 
protocol therapy. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
46 
 
• 
IVIG should not be given while patient is receiving protocol therapy.  
• 
No other investigational agents may be given while the patient is receiving protocol therapy.  
• 
Patients on Part B may not receive valproic acid until disease re-evaluation following the last 
planned course of therapy has been completed.  
• 
Patients on Part B may not receive other medications known to prolong the QTc interval within 
1 week prior to or 1 week following vorinostat (Appendix VII; note that this list prohibits the use 
of pentamidine and cautions investigators with the use of ondansetron).  
• 
Vorinostat treatment may result in mild increases in serum creatinine. Caution should be 
exercised with the use of nephrotoxic medications while patients are receiving vorinostat. 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
47 
 
 
5.0 
SUPPORTIVE CARE 
 
5.1   
Prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) 
All patients must receive prophylaxis against Pneumocystis jiroveci pneumonia (PJP) using Bactrim 
or other appropriate agent according to institutional guidelines.  
 
5.2 
Use of Myeloid Growth Factors  
See Section 4.2.4.  It is strongly recommended that GM-CSF be the only growth factor used 
on this study.  The use of filgrastim (G-CSF) or peg-filgrastim, even if the patient experiences 
febrile neutropenia, is strongly discouraged. 
 
5.3 
Antiemetics 
 
Dexamethasone should not be used as anti-nausea / antiemetic therapy.  The use of 
 
alternative anti-emetics will be at the investigator’s discretion.  Symptomatic patients should be 
 
treated with standard anti-nausea /  
antiemetic 
therapy 
such 
as 
ondansetron 
or 
an 
 
appropriate serotonin antagonist as necessary. 
 
 
5.4 
Fever During MIBG 
Patients who develop a fever as defined by institutional guidelines during the first  
 
24 hours after the 131I-MIBG infusion should be given a single dose of ceftriaxone or appropriate 
substitute without sending a blood culture or other labs, as blood cannot be safely sent to the lab 
during this time due to radioactivity. If the patient is neutropenic, has an allergy to cephalosporins, 
or there is clinical concern for a more severe infection, alternative antibiotics can be used per 
institutional guidelines. The need for subsequent antibiotics will be determined based on blood 
culture results, clinical status, and presence/absence of neutropenia. For fever that occurs > 24 
hours after the 131I-MIBG infusion, institutional guidelines for fever in the non-neutropenic or 
neutropenic patient may be utilized.  
 
5.5  
Supportive Care During Dinutuximab Therapy  
 
 Most laboratory findings in patients receiving dinutuximab are transient during therapy and can be 
corrected with appropriate supportive care.  Consider keeping albumin > 3 g/dL by infusing with 
1gm/kg of 25% albumin. In addition, consider keeping hemoglobin >10 g/dL to help support 
intravascular volume. 
 
5.6 
Other 
 
Unless specifically excluded by the protocol, additional supportive care measures should be 
 
utilized as needed to provide good patient care. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
48 
 
6.0   
DRUG INFORMATION 
 
 
6.1 
131I-Meta-Iodo-Benzyl-Guanidine (Jubilant Radiopharma® Therapeutic 131I-MIBG) 
[Jubilant Radiopharma (JRP) IND # 76,227] 
 
 
Common name:  
 
Iobenguane sulfate (m-Iodobenzylguanidine sulfate, MIBG) 
 
Active ingredient:  
 
3-[131I]-iodobenzylguanidine Sulfate 
 
Pharmacologic class:   
Radiopharmaceutical therapeutic agent 
 
Molecular formula:  
 
[C8H10IN3]•1/2 H2SO4 
 
Molecular weight:  
 
324.13 g/mol 
 
Physical form:  
 
Colorless crystals 
 
Solubility:  
 
 
Soluble in water 
 
Melting point:   
 
Decomposition occurs between 166-167°C. 
 
Purity:   
 
 
MIBG (cold raw material): not less than 99% 
 
Formulation:  
The MIBG sulfate is synthesized by Jubilant Radiopharma (Kirkland, 
Quebec, Canada), with the following formulation: 
 
3-Iodobenzylguanidine Sulfate < 0.83 mg 
Niacinamide 16 mg 
Sodium Chloride 9 mg 
Benzyl Alcohol 9 µL 
Sodium Acetate Trihydrate 0.68 mg 
Cupric Nitrate (II) Trace 
Hydrochloric Acid Trace 
Sodium Hydroxide Pellets Trace 
Water for Injection q.s. to 1.0 mL 
 
Specific activity:  
 
Not less than 30 mCi/mg (1110 MBq/mg) MIBG at the calibration date. 
 
Radiochemical purity  
As of 10/20/21, radiochemical purity testing at clinical sites following 
receipt of 131I-MIBG from Jubilant Radiopharma is no longer required. 
Sites are still to check for discoloration and particulate matters prior to 
product administration to the patient. Additionally, if a “Temperature Alarm” 
is detected on the temperature monitor provided in the 131I-MIBG 
shipment, sites are NOT to use the product and should store the vial of 
131I-MIBG in the lead pot and call JRP Customer Service immediately for 
further instructions.  
  
Should clinical sites still wish to perform radiochemical purity testing, a 
suggested technique is provided in Appendix V.  
 
Radiolytic decay:  
131I decays by beta emission and associated gamma emission with a 
physical half-life of 8.04 days. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
49 
 
How supplied:  
131I-MIBG from Jubilant Radiopharma is supplied in a single-dose 30 mL 
glass vial or two 30-mL glass vials depending on the dose required for one 
patient. Unit dose vial may also be available. Please refer to current 
nuclear medicine manual. 
 
Storage:  
The product will be shipped frozen and should be stored at 2 °C to 8 °C 
upon arrival. 
 
Stability:  
The product is stable at 2 °C to 8 °C for 2 days with excursions permitted 
at room temperature. 
 
Distribution: 
Jubilant Radiopharma® Therapeutic 131I-MIBG will be provided by Jubilant 
Radiopharma®, Canada. Place order 4 weeks prior to infusion. If the 
procedure will be cancelled, Jubilant Radiopharma should be notified as 
soon as it becomes evident that the procedure will not proceed.  
 
Calls for drug supply are to be made to Jubilant Radiopharma Customer 
Service at: 
 
Phone: 1-888-633-5343; 8am – 5pm Eastern Time 
(514) 630-7080 
Fax: 1-866-431-4288 
Fax: 1-514-694-3865 
Email: customerservice@jubl.com 
Web: www.jubilantradiopharma.com 
 
Toxicity: 
Likely 
(happens to 21-100 children out 
of every 100 children) 
Less Likely 
(happens to 5-20 children out of 
every 100 children) 
Rare 
(happens to < 5 children out of 
every 100 children) 
• 
Myelosuppression (anemia, 
thrombocytopenia, 
leukopenia, neutropenia) 
• 
Nausea 
• 
Dry mouth 
• 
Hyperamylasemia 
• 
Hypothyroidism 
• 
Sterility 
• 
Hair thinning 
• 
Vomiting 
• 
Fatigue 
• 
Infection 
• 
Bleeding/bruising 
• 
Anorexia 
• 
Changes in blood pressure 
during and after MIBG 
infusion (hypotension & 
hypertension) 
• 
Pain in salivary glands or 
mouth 
• 
Decreased function of 
adrenal gland 
• 
Decreased heart function 
• 
Hepatotoxicity 
• 
Secondary leukemia 
• 
Pneumocystis pneumonia 
• 
Bronchiolitis obliterans with 
organizing pneumonia 
(BOOP) 
• 
Hyperthyroidism 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
50 
 
6.2 
Dinutuximab (Chimeric Monoclonal Antibody 14.18; Chimeric MOAB 14.18; human/murine 
 
anti-GD2 monoclonal  antibody; chimeric anti-GD2; chimeric mAb 14.18; ch14.18; 
 
Unituxin®) NSC# 764038 
 
6.2.1 
Source and Pharmacology 
Dinutuximab is an anti-GD2 monoclonal antibody composed of the variable region heavy and light 
chain genes of the murine mAb 14.G2a and the human constant region genes for heavy chain IgG1 
and light chain kappa. Dinutuximab exerts its antitumor effect by binding specifically to the 
disialoganglioside GD2, an antigen found in human tumors of neuroectodermal origin such as 
melanoma and neuroblastoma. This chimeric antibody has been shown to lyse melanoma and 
neuroblastoma cells through the process of antibody-dependent cell-mediated cytotoxicity (ADCC) 
and complement-dependent cytotoxicity (CDC). By targeting the GD2 antigen on the cell surface, 
dinutuximab may also prevent attachment of circulating malignant cells to the extracellular matrix. 
Additionally, dinutuximab mediates lysis of several melanoma and neuroblastoma cell lines in a 
dose dependent manner in the presence of potent mediators of ch14.18-dependent cytotoxicity, 
such as human peripheral blood mononuclear cells and granulocytes. This is most profound with 
neutrophils, especially in the presence of recombinant human granulocyte-macrophage colony-
stimulating factor. 
 
The PK profile of ch14.18 has been determined in adults with melanoma and children with 
neuroblastoma. Although the plasma clearance for both groups of patients follow a two-
compartment model, circulating antibody is cleared from the plasma at a much faster rate in 
children than adults (mean t½β = 66.6 ± 27.4 hours in children versus 123 ± 29 hours and 181 ± 73 
hours in two adult trials, respectively). Maturation of the hepatic and renal systems with age is 
thought to impact on drug metabolism and elimination and could account for these differences. In 
general, the mAb half-life following the first course of treatment was longer than the half-lives 
following subsequent courses in a given patient. 
 
6.2.2 
Toxicity 
The expected adverse reactions of dinutuximab: 
Likely 
Happens to 21-100 children out of 
every 100 
Occasional 
Happens to ≤ 20 children out of 
every 100 
Rare 
Happens to < 3 children out of every 
100 
Blood and Lymphatic System Disorders 
 
Anemia 
Hemolytic uremic syndrome1 
 
Disseminated Intravascular 
Coagulation 
 
Cardiac Disorders 
 
Sinus tachycardia 
Cardiac arrest 
 
 
Sinus bradycardia 
Eye Disorders 
 
 
Eye disorders – Other (eye disorders)2 
Gastrointestinal Disorders 
 
Abdominal pain 
 
 
Diarrhea 
 
 
Nausea 
 
 
Vomiting 
 
General Disorders and Administration Site Conditions 
Fever 
Edema limbs 
Infusion related reaction 
Pain 
 
Sudden death NOS 
Immune System Disorders 
 
Allergic reaction 
Anaphylaxis 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
51 
 
 
Serum sickness 
 
Infections and Infestations 
 
Infection3 
 
Investigations 
Investigations – Other (elevated c-
reactive proteins) 
Increased alanine aminotransferase 
(ALT) 
 
 
Increased aspartate aminotransferase 
(AST) 
 
 
Increased blood creatinine 
 
 
Decreased lymphocyte count 
 
 
Decreased neutrophil count 
 
 
Decreased platelet count 
 
 
Decreased white blood cell count 
 
Metabolism and Nutrition Disorders 
 
Decreased appetite 
 
 
Hyperkalemia 
 
 
Hypoalbuminemia 
 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
Hyponatremia 
 
 
Back pain 
 
 
Pain in extremity 
 
Nervous System Disorders 
 
Neuralgia 
Tranverse myelitis/myelitis 
 
Peripheral sensory neuropathy4 
Peripheral motor neuropathy 
 
 
Reversible Posterior encephalopathy 
syndromeb 
Renal and Urinary Disorders 
 
Proteinuria 
Renal and urinary disorders-other (atonic 
urinary bladder)4 
 
Urinary retention4 
 
Respiratory, Thoracic and Mediastinal Disorders 
Cough 
Bronchial obstruction 
 
 
Dyspnea 
 
 
Hypoxia 
 
 
Stridor 
 
Skin and Subcutaneous Tissue Disorders 
Maculo-papular rash 
Pruritus 
 
 
Urticaria 
 
Vascular Disorders 
 
Capillary Leak Syndrome 
 
 
Hypertension 
 
 
Hypotension 
 
1There have been rare instances of a typical hemolytic uremic syndrome in the absence of documented 
infection and resulting in renal insufficiency, electrolyte abnormalities, anemia and hypertension 
2Neurological disorders of the eye including blurred vision, diplopia, cycloplegia, mydriasis, photophobia, 
optic nerve disorder, eyelid ptosis, and fixed pupils have been observed. 
3Infection includes all 75 sits of infection under the Infections and Infestations SOC 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
52 
 
4Acute urinary retention may occur during therapy and is though to be due to fluid shifts and narcotic 
administration that accompanies dinutuximab administration.  Atonic urinary bladder may result in 
chronic urinary retention (CUR) that requires intermittent urethral catheterization days to weeks following 
dinutuximab administration 
 
6.2.3 
Formulation and Stability 
Dinutuximab is provided as a sterile solution in single-dose vials containing 17.5 mg/5 mL (3.5 
mg/mL) in 20 mM Histidine, 150 mM NaCl, 0.05% Tween 20 at pH 6.8. Intact vials should be stored 
in the refrigerator (2ºC to 8ºC) in the outer carton to protect from light. Stability studies of the intact 
vials are ongoing.  
 
Withdraw the required volume of dinutuximab from the single-use vial and inject the exact volume 
into a 100 mL bag of 0.9% Sodium Chloride injection, USP.  Mix by gentle inversion.  DO NOT 
SHAKE.  Discard unused content of the vial.  Discard diluted dinutuximab solution > 4 hours after 
preparation. 
 
The use of a filter during preparation is not required.  Do not freeze or shake vials. 
 
The final prepared product of dinutuximab in Normal Saline is stable at room temperature for 24 
hours when diluted to a concentration between 0.044 and 0.56 mg/mL; however, the final dosage 
form should be prepared immediately prior to administration as there is a maximum infusion time 
of 20 hours. The minimum infusion time for the antibody infusion is 10 hours.  
 
6.2.4 
Guidelines for Administration: See Treatment, Dose Modifications and/or Supportive Care sections 
of the protocol. 
 
 
6.2.5 
Supplier 
Manufactured and supplied by United Therapeutics. Dinutuximab will be distributed by Almac, Inc. 
for this study.  All drug orders will be submitted to Almac from the NANT Operations Center.  Refer 
to the NANT website for ordering information. Do NOT use commercial supply. 
 
The drug supply must be stored in a locked limited access area. Dinutuximab is for investigational 
use only, and is to be used only within the context of this study. Under no circumstances should 
the investigator or other site personnel supply study drug to other investigators, subjects, or clinics, 
or allow supplies to be used other than directed by this protocol. 
 
6.2.6 
Agent Accountability 
Accountability for the study drug at the trial site is the responsibility of the investigator. The 
investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the investigator may choose to assign drug accountability responsibilities to a pharmacist 
or other appropriate individual. Drug accountability records indicating the drug’s delivery date to 
the site, inventory at the site, use by each patient, and disposal or return of the drug, will be 
maintained by the clinical site. These records will adequately document that the patients were 
provided the doses as specified in the protocol and should reconcile all study drug received from 
Almac. Accountability records will include dates, quantities, batch/serial numbers, expiration dates 
(if applicable), and patient numbers. All unused, unopened, Dinutuximab should be held until 
confirmation that the last patient registered into the study has completed the treatment period.  The 
site will maintain detailed records of the drug reconciliation with the study files, and all material 
containing study drug will be treated as hazardous waste in accordance with governing regulations. 
 
 
 


 
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6.3 
SARGRAMOSTIM (Granulocyte Macrophage Colony Stimulating Factor, rhu GM-CSF, rGM-
 
CSF, GM-CSF, Leukine®) NSC #613795 
 
6.3.1 
Source and Pharmacology 
Sargramostim (recombinant human GM-CSF) is a glycoprotein produced in yeast (S. cerevisiae) 
by recombinant DNA technology. rGM-CSF is a hematopoietic growth factor which supports 
survival, clonal expansion, and differentiation of hematopoietic progenitor cells. rGM-CSF induces 
partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage 
pathways. rGM-CSF stimulates the production of monocytes, granulocytes, erythrocytes, and 
sometimes, megakaryocytes in the bone marrow. It also induces mature neutrophil and monocytes 
to increase phagocytosis, superoxide generation, ADCC, tumoricidal killing and cytokine production 
(IL-1 and tumor necrosis factor). Recombinant human GM-CSF is a glycoprotein of 127 amino 
acids characterized by three primary molecular masses of 15500, 16800, and 19500 daltons. The 
amino acid sequence differs from the natural sequence by a substitution of leucine at position 23 
and the CHO moiety may be different from the native protein. After subcutaneous administration of 
sargramostim, peak levels were obtained in 1-4 hours and were detectable at therapeutic levels for 
12-16 hours post injection. The elimination t½ ranges from 1.5-2.7 hours after SQ or IV 
administration. 
 
6.3.2 
Toxicity 
 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens 
to 
5-20 
children out of every 
100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: Within 
1- 
2 
days 
of 
receiving drug 
Headache, malaise, 
fatigue, 
rash, 
pruritus, bone pain, 
myalgia, arthralgia, 
fever, chills 
Abdominal 
pain, 
weakness, anorexia, 
nausea, 
local 
injection reactions 
Anaphylaxis, 
“first 
dose 
reaction” (hypoxia, dyspnea, 
hypotension, 
fever, 
tachycardia, 
diaphoresis, 
flushing, 
back 
pain), 
vomiting, diarrhea, phlebitis, 
SVT, pericardial effusion 
Prompt:  
Within 2- 3 weeks, 
prior to the next 
course 
 
Weight gain 
In high doses: capillary leak 
syndrome: 
(pleural effusion, peripheral 
edema, 
ascites, 
weight 
gain, 
hypotension), 
pneumonitis, 
peripheral 
edema, 
elevation 
of 
creatinine, 
bilirubin and 
hepatic enzymes in patients 
with preexisting 
renal or hepatic dysfunction 
Delayed:  
Any time later during 
therapy 
 
Thrombocytopenia 
 
Unknown 
Frequency 
and 
Timing: 
Fetal and teratogenic toxicities: It is not known whether sargramostim 
can cause fetal harm or affect reproduction capacity when administered to 
a pregnant woman. It is unknown whether the drug is excreted in breast 
milk. 
 
 
 


 
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6.3.3 
Formulation and Stability 
Sargramostim is available as a lyophilized sterile, white, preservative free powder with 250 mcg 
(1.4 million International Units) per vial and as a sterile, preserved injectable solution in a 500 
mcg/mL (2.8 million International Units/mL) 1 mL vial. The sargramostim reconstituted lyophilized 
vial contains 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL tromethamine, USP, 
as excipients. The liquid formulation also contains 1.1% benzyl alcohol (11 mg/mL). Store 
refrigerated at 2-8°C (36-46°F). Do not freeze or shake. 
 
6.3.4 
Guidelines for Administration 
See Treatment, Dose Modifications, and Supportive Care sections of the protocol. 
 
Reconstitute lyophilized powder for injection with 1 mL SWFI or 1 mL Bacteriostatic Water for 
Injection. Use SWFI without benzyl alcohol for neonates, infants, and children < 2 years of age or 
patients with hypersensitivity to benzyl alcohol. During reconstitution, direct the diluent at the side 
of the vial and gently swirl the contents to avoid foaming during dissolution. Avoid excessive or 
vigorous agitation; do not shake. Reconstituted solutions prepared with Bacteriostatic Water for 
Injection (0.9% benzyl alcohol) or the liquid preserved solution may be stored for up to 20 days 
following the first entry into the vial at 2°-8°C (36°-46°F). Discard reconstituted solution after 20 
days have elapsed. Reconstituted solutions prepared with SWFI (without preservative) should be 
administered as soon as possible and within 6 hours following reconstitution. 
 
Use sargramostim for subcutaneous injection without further dilution. Perform dilution for IV infusion 
in NS. If the final concentration is < 10 mcg/mL, add albumin (human) at a final concentration of 
0.1% to the saline prior to addition of sargramostim to prevent adsorption to the components of the 
drug delivery system. For a final concentration of 0.1% albumin (human), add 1 mg albumin 
(human) per 1 mL NS. For example, for a final volume of 50 mL NS, add 50 mg (or 1 mL) of 5% 
albumin [human]. Intravenous dilutions are stable for up to 48 hours at room temperature or 
refrigerated but should be used within 6 hours due to microbiological concerns. Do not use an in-
line membrane filter for IV infusion. 
 
6.3.5 
Supplier 
Sargramostim is commercially available in the U.S and so will be obtained from commercial supply. 
See package insert for more detailed information. Only sargramostim (yeast-derived recombinant 
human GM-CSF) will be used in this study. The Escherichia coli-derived product (molgramostim) 
will not be used. 
 
 
 
 


 
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6.4 
POTASSIUM IODIDE (KI, SSKI) 
 
Formulation: Oral solution 1 gram / milliliter.  
 
Therapeutic MIBG Treatment:  Loading dose of 6 mg/kg by mouth 8-12 hours prior to infusion of MIBG 
on Day 1, and then 1 mg/kg/dose by mouth starting 4-6 hours after completion of MIBG infusion and 
continuing every 4 hours on protocol Days 1 to 7 and then 1 mg/kg/dose by mouth once daily on protocol 
Days 8-45. 
 
Storage:  Room temperature 
 
Toxicity: 
Likely  
(happens to 21-100 children 
out of every 100 children) 
Less Likely 
(happens to 5-20 children out of 
every 100 children) 
Rare 
(happens to < 5 children out of 
every 100 children) 
 
 
 
 
• 
Gastrointestinal distress 
(nausea / vomiting / 
diarrhea / stomach pain) 
 
• 
Vasculitis 
• 
Flare up of adolescent 
acne 
• 
Irregular heartbeat 
• 
Confusion 
• 
Tiredness 
• 
Fever 
• 
Hypersensitivity (hives) 
• 
Burning of mouth / throat 
• 
Metallic taste 
• 
Rash 
• 
Hypothyroidism with 
overuse 
• 
Swelling of lymph glands 
 
6.5 
VORINOSTAT (ZOLINZA™) 
 
6.5.1 Structure and Molecular Weight  
The chemical names for vorinostat are N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide or N-
hydroxylN’-phenyl (9CI) octanediamide. The molecular formula is: C14H20N203. The molecular weight is 
264.32.  
 
6.5.2 Description  
Vorinostat is a histone deacetylase (HDAC) inhibitor. HDACs are a group of proteins that regulate gene 
transcription by affecting the acetylation status of histones. Vorinostat binds to the catalytic pocket of HDAC 
enzymes and inhibits their activity.  
 
6.5.3 Supplier  
Vorinostat is commercially available in the U.S. and so will be obtained from commercial supply. See 
package insert for more detailed information. 
 
6.5.4 Guidelines for Administration and Compounding  
Vorinostat is administered orally or via NG tube or G-tube. Vorinostat should be taken with food or within 
30 minutes after a meal. The dose should be taken in the morning whenever possible. Altered taste and 
decreased food and liquid intake are associated with vorinostat administration. These toxicities can be 
actively managed with fluid management and nutritional consult and support. During the period of vorinostat 
administration, patients are recommended to consume adequate fluid daily to prevent dehydration. Patient 


 
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56 
 
may require electrolyte replacement. Early use of anti-emetics is encouraged. If a patient vomits within 15 
minutes of vorinostat dose administration, the patient should be re-dosed. If the patient vomits after the 
second dose, the patient should not be re-dosed again. If a patient vomits more than 15 minutes from dose 
administration, the patient should not be re-dosed. If patients experience dysgeusia, popsicles or Gatorade 
may be successful in maintaining oral intake. Missed doses may be made up provided there is at least 24 
hours between vorinostat and infusion of stem cells, and stem cell infusion is not delayed beyond Day 17. 
Vorinostat should not be administered after stem cell infusion regardless of the number of doses received. 
Patients should not exceed 14 total doses of vorinostat for any reason. Patients should not double-up on 
missed doses during treatment.  
 
Patients will receive vorinostat as a liquid suspension or as capsules. Capsules can be used only for 
patients with a calculated dose within +/- 10% of a 100 mg dosing increment (e.g. 100 mg, 200 mg, 300 
mg, or 400 mg).  
 
The COG phase I study of vorinostat, NANT 2007-03, and NANT 2011-01 all used the following formula for 
preparing a liquid suspension with a final vorinostat concentration of 50 mg/mL.  
 
Required components  
Vorinostat 100 mg capsules (20)  
OraPlus or Suspensol S 20 mL  
OraSweet 20 mL  
 
Instructions  
Add 20 mL of Suspensol S or OraPlus into an amber or clear glass 4 ounce bottle. Place the contents of 
20 capsules of vorinostat 100 mg into the same bottle and shake to disperse. Shaking may take up to 3 
minutes. Once dispersed, add 20 mL of OraSweet to achieve a total volume of 40 mL. Shake again to 
disperse. Final concentration is 50 mg/mL. Store at room temperature. The suspension is stable for 4 weeks 
when stored at room temperature, away from excessive heat and humidity. The suspension should not be 
mixed with food or beverages.  
If there are any issues with ability to compound, please contact NANT Operations at nantcrf@chla.usc.edu. 
 
The maximum daily dose of vorinostat on this protocol is 400 mg.  
 
6.5.5 Potential Drug Interactions  
The major pathways of vorinostat metabolism involve glucuronidation and β-oxidation. As vorinostat is not 
eliminated via CYP450 pathways, no drug-drug interactions are expected with known CYP450 inhibitors or 
inducers.  
 
Although vorinostat is not a potent reversible CYP450 inhibitor, studies performed to monitor gene 
expression changes indicated some potential for CYP2C9 and CYP3A4 activity suppression. However, 
these changes were observed at concentrations higher than the pharmacologically relevant concentration.  
 
6.5.6 Special Handling  
Vorinostat is an anticancer drug. Clean powder spills from broken or damaged vorinostat capsules carefully 
minimizing inhalation. Wash spill area at least 3 times with ethyl alcohol, followed by water.  
 
6.5.7 Patient Care Implications  
Because vorinostat’s dose limiting toxicities in previous studies included anorexia, dehydration, diarrhea, 
and fatigue, patients should maintain adequate fluid and food intake. 
 
6.5.8 Toxicity 
The most common drug-related adverse reactions can be classified into 4 symptom complexes: 
gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), 
constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and 
taste disorders (dysgeusia, dry mouth). The most common serious drug-related adverse reactions were 
pulmonary embolism and anemia. 


 
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57 
 
 
Serious Adverse Reactions 
The most common serious adverse reactions in the 86 Cutaneous T Cell Lymphoma patients in two 
clinical trials were pulmonary embolism reported in  4.7% (4/86)  of  patients, squamous cell  carcinoma 
reported in  3.5% (3/86)  of  patients and anemia  reported in  2.3%  (2/86)  of  patients. There were single 
events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, 
exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, 
ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, 
T-cell lymphoma, thrombocytopenia and ureteric obstruction. 
 
 
Likely  
(happens to 21-100 children 
out of every 100 children) 
Less Likely 
(happens to 5-20 children out of 
every 100 children) 
Rare 
(happens to < 5 children out of 
every 100 children) 
 
• 
Thrombocytopenia 
• 
Fatigue 
• 
Diarrhea 
• 
Nausea 
• 
Dysgeusia 
• 
Anorexia 
 
• 
Weight loss  
• 
Muscle spasms 
• 
Alopecia 
• 
Dry mouth 
• 
Blood creatinine 
increased 
• 
Hyperglycemia 
• 
Electrolyte abnormalities 
(hypocalcemia, 
hypophosphatemia,  
Hypomagenesemia, 
hyponatremia) 
• 
Elevated Liver enzymes 
(AST, ALT, Alk phos and 
bilirubin) 
• 
Proteinuria 
• 
Lymphopenia 
• 
 
• 
Chills 
• 
Vomiting 
• 
Constipation 
• 
Dizziness 
• 
Anemia 
• 
Heartburn 
• 
Dehydration 
• 
Peripheral edema 
• 
Headache 
• 
Pruritis 
• 
Cough 
• 
Infection 
• 
Pyrexia with and without 
neutropenia 
• 
Thrombosis  
• 
Squamous Cell 
Carcinoma 
• 
Skin necrosis 
• 
PT Prolongation 
• 
Gastrointestinal Bleeding 
 
 
• 
Prolonged QTc  
 (Low-grade prolonged QTc 
interval has rarely been reported 
in patients receiving vorinostat, 
though the relationship to 
vorinostat remains 
undetermined)  
 
Based on its mechanism of action and findings from animal studies, ZOLINZA can cause fetal harm 
when administered to a pregnant woman 
 
Note: Vorinostat in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 


 
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58 
 
7.0    
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
7.1 
Clinical and Laboratory Assessments 
All clinical and laboratory examinations must be obtained within 14 days of study registration except 
for β-HCG pregnancy test if applicable which must be done within 7 days of study registration.  If 
more than 7 calendar days elapse between the date laboratory studies to determine eligibility were 
obtained and the start date of treatment, then the following studies must be repeated prior to 
initiating protocol therapy: 
• 
CBC with differential 
• 
Total bilirubin 
• 
ALT 
• 
Serum Creatinine 
Labs not meeting eligibility criteria if repeated after study registration may again be repeated within 
48 hours up to 7 days after the initial result not meeting eligibility criteria was obtained.  Please note 
that β-HCG pregnancy test if applicable must be performed within 7 days of study registration and 
may need to be repeated if there is a week delay.  Subjects will be off protocol therapy if repeated 
laboratory values have not met eligibility criteria by 7 days after the initial result not meeting 
eligibility criteria was obtained. 
 
Tumor disease evaluation (including appropriate imaging studies and bilateral bone marrow 
aspirate and biopsy for standard histology) and echo are required within 28 days prior to study 
enrollment and subsequent to any prior therapy. All patients regardless of marrow disease status 
at study registration are REQUIRED to have repeat bone marrow evaluations at each subsequent 
disease evaluation. Initiation of protocol therapy is required within 7 days of study registration. 
 
 OBTAIN OTHER STUDIES AS NEEDED FOR GOOD PATIENT CARE. 
 


 
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59 
 
Studies 
Screening 
for study 
entry 
Day 1-56 Part A 
Day 0-56 Part B 
Courses 1 & 2 
Day 57/  
Prior to 
Course 26 
Day 57/  
End of 
Therapy6 
History, physical exam, vital signs, 
height, weight and BSA1,3 
X 
Days 011, 112, 8, 153, 29, 363, 433 
Daily during dinutuximab administration 
X 
X 
Performance Status1 
X 
 
X 
X 
CBC3, differential, platelets1 
X 
Twice weekly until engraftment then weekly1,4 
X 
X 
Electrolytes, calcium, albumin, BUN, 
creatinine1 
X 
Weekly;  
Daily during dinutuximab administration 
X 
X 
AST, ALT1, total bilirubin1  
X 
Weekly9  
X 
X 
Direct bilirubin, PO4, and Mg2+ 
X 
Obtain weekly ONLY if abnormal at screening 
X 
 
PT, INR 
X 
Weekly 
X 
 
Serum or urine β-HCG1,5 
X 
 
X 
 
TSH, Free T4 
X 
 
X 
X 
Echocardiogram1, 6 
X 
 
X 
X 
Electrocardiogram (Part B only)1, 6 
X 
One time between Days 4 and 810 
X 
X 
Urine HVA and VMA6 
X6 
 
X6 
X6 
Bilateral BM aspirate + biopsy for 
morphology1,2 
X 
 
X 
X 
Tumor imaging (CT or MRI scan)1, 2 
X 
 
X 
X 
MIBG diagnostic scan  
WITH SPECT (REQUIRED)1,2  
Use same isotope with each scan 
X 
 
X 
X 
MIBG whole body scan  
(SPECT NOT required) 
 
Upon release from radiation isolation 
 
 
Whole body dosimetry 
 
Days 1-58 
 
 
Radiation level monitoring7 
 
Beginning ~24 hours after MIBG infusion and 
continuing at least daily until cleared7 
 
 
Correlative biology studies 
(blood/tumor) 
Refer to Section 8.0 
 
Blood and bone marrow for N04-05 
X 
 
X 
X 
 
1. 
Required for verification of eligibility. An eligibility checklist is available and may be used as a source document with PI 
signature or by uploading directly into patient EMR. 
2. 
Tumor imaging = CT and/or MRI (Chest, abdomen, pelvis) plus CT/MRI imaging of any other sites with MIBG uptake for 
optimum visualization of all areas of bulk tumor (primary & metastasis) excluding extremities.  If patient has a history of 
tumor lesions in the skull, orbits or brain, OR if MIBG scan shows uptake in these same areas, then a CT or MRI of the 
brain/orbits is strongly suggested. MRI is the recommended imaging technique for patients with epidural or hepatic tumor 
lesions.  FDG-PET is required if used at baseline to document evaluable soft tissue tumor lesion(s) for response.  123I-
MIBG scans are preferred for disease status evaluation. SPECT is required on this study. All patients are required to 


 
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60 
 
have a diagnostic bone marrow sent with each disease evaluation.  All disease status tests must be performed within 28 
days prior to study entry and subsequent to any intervening therapy 
3. 
Vital signs should be done more frequently when indicated per Section 4.2 and for good patient care. Examinations may 
be performed +/- 2 days for D15, D36 and D43. Height and BSA only needed at screening, Day 29 of Course 1 and 2, 
and prior to Course 2. 
4. 
Continue twice weekly (required once during week of 131I-MIBG infusion (Day 1 – Day 7) until ANC > =500 cells/μL and 
platelet  
count > = 20,000 cells/μL x 3 days without transfusion, and then obtain weekly through the end of the course.    
5. 
Obtain for females 10 years of age and older or post-pubertal.  Women of childbearing potential require a negative 
pregnancy test prior to starting treatment (Course 1 & Course 2).  Male and female subjects of reproductive age and 
childbearing potential must agree to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-
uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) or to abstain from heterosexual 
intercourse for the duration of their participation in the study. 
6. 
The end of course evaluations (clinical labs, echocardiogram, electrocardiogram, correlative studies) are to be performed 
between Days 46 - 57 except for disease status evaluation (tumor imaging by CT/MRI and bilateral bone marrow 
aspirate/biopsy) which may be performed between Days 43 and 57 of each course. In case of treatment delays with 
dinutuximab during Course 1, the time interval between performing end of Course 1 disease evaluation and administration 
of Course 2 131I-MIBG is not to exceed 4 weeks. Urine catecholamines are no longer required as part of patient disease 
status evaluation submitted to NANT Operations Center and may be obtained at investigator discretion. 
7. 
The patient will remain in a radiation protected isolation room until radiation emissions meet institutional/state guidelines, 
but at least until the radiation level is < 7 mRem/hr at 1 meter. Radiation levels will be measured at least once daily until 
the patient is cleared by Radiation Safety using a handheld monitor standing at a distant of one meter from the patient.  
8. 
See Section 4.2.1.7 for dosimetry guidelines.   
9. 
If total bilirubin result ≥ Grade 3 then fractionate and obtain a direct bilirubin along with total bilirubin until total bilirubin ≤ 
Grade 2. 
10. One EKG to be obtained prior to Day 8 dinutuximab dose. Patient must have a QTc interval ≤ 480 msec prior to proceeding 
with Day 8 dinutuximab dose (Part B only; see Section 4.2.3.3). 
11. Part B only 
12. Part A only 
 
7.2 
Recommended Follow-Up Observations 
 
The following are recommendations only, but may be altered at discretion of treating physician. 
Repeat the following if abnormal on a monthly basis until stable or normalized after the end of 
therapy. If normal at the end of therapy then repeat only as clinically indicated:  
• 
History, physical exam (Ht, Wt, VS)  
• 
CBC/Differential, Platelets, AST, ALT, Bilirubin, BUN, Creatinine  
• 
T4, TSH and MIBG scan every 3 months until 1 year post treatment, then every 6 months until 
progression, death or other therapy.  
 
 
 
After completion of protocol therapy, the disease status, sites of relapse, and last alive date will be 
recorded until first relapse/progression or until patient receives another non-protocol therapy, after 
which only last alive date will be reported, as well as date of death and cause of death (if applicable).  
 
 
7.3  
Documentation of Tumor Response  
 
Patients will undergo complete disease re-staging between Day 43 and Day 57 of each course of 
therapy.  If there are treatment delays during Course 1, disease restaging after Course 1 may be 
delayed.  This delay is not to exceed 4 weeks before the start of Course 2.  It is recommended that 
all scans and tests previously done to document tumor lesions be performed in subsequent 
evaluations of disease status.  
 
 
All patients will have diagnostic bone marrows performed with each disease evaluation, regardless 
of involvement at study registration.  To confirm a bone marrow response of CR, an additional bone 
marrow examination for morphology (for a total of 2 bone marrow exams) must be done a minimum 
of three weeks apart (Section 11.0).  
 
 
Once a patient receives therapy other than prescribed on this protocol, no further scans or bone 
marrow evaluations will be required for this protocol since the patient will no longer be evaluable for 
response to dinutuximab and 131I-MIBG.  


 
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8.0 
CORRELATIVE BIOLOGY STUDIES (See Appendix II) 
Collection of samples for correlative biology studies is to be performed during the first course of 
therapy only. If the scheduled start of the first day of dinutuximab infusions on Day 8 and/or Day 
29 are delayed, then the corresponding Day 8 and/or Day 29 biologic correlate sampling should 
also be delayed until the first day of dinutuximab infusion is given. The Day 15 biologic correlates 
should be obtained BEFORE stem cell infusion. 
 
NOTE:  It is strongly encouraged to begin 131I-MIBG on Tuesday – Thursday to allow biologic 
correlates to be received at the processing laboratory on a Wednesday – Friday.  Please 
contact the NANT Operations Center/Study Chairperson if treatment is delayed and will not 
start on a Tuesday – Thursday schedule. 
 
 
 
8.1 
Characterization of Immune and Cytokine Profile Following 131I-MIBG Therapy (Required) 
We will obtain preliminary data regarding the number of T, B, and NK cells present in the circulation 
at baseline and after treatment with 131I-MIBG, and will also perform a more detailed analysis of NK 
cells. This T-B-NK panel quantifies these cells using flow cytometry. We will also freeze additional 
peripheral blood mononuclear cells (PBMCs) for future immunophenotyping studies. The additional 
PBMCs will be obtained from the blood collected for the cytokine profiling studies as detailed below 
in Section 8.1.2.2. 
 
Below is the panel that we will test by flow cytometry: 
 
Lineage 
Panel 
Live/Dead (L/D), CD45, CD3, CD4, CD8, CD19, CD14, CD45RA, 
CD197, CD25, CD127, HLA-DR 
NK 
Cell 
Panel 
L/D, CD45, CD3, CD8, CD16, CD56, CD57, CD107a, CD158, 
CD314, CD335 
 
We will also evaluate the pro-inflammatory cytokines that may augment the effects of 
immunotherapy, stimulate an immune-mediated anti-tumor response, and help establish the TME. 
The key cytokines and chemokines that will be analyzed are included below. This testing will be 
performed using a multiplex cytokine array on a Luminex platform. 
 
39-plex: IL-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 
(p70), IL- 13, IL-15, IL-17, EGF, Eotaxin, FGF-2, Flt-3-ligand, Fractalkine, G-CSF, GM-CSF, GRO, 
IFN-α2, INF-γ, IP-10, MCP-1, MCP-3/CCL7, MDC/CCL22, MIP-1α, MIP-1β, TNFα, TNFβ, VEGF, 
sCD40L, TGFas, IL-2R   
 
Single-plex: sIL6-R 
 
 
8.1.1 
Sampling Requirements and Schedule (COURSE 1 ONLY) 
 
 
Samples are to be collected Tuesday through Thursday only for delivery Wednesday 
through Friday. 
 
 
 
 A.  Immune Profiling by Flow Cytometry  
• 
Collect 5 mL of peripheral blood into a sodium heparin (green top) tube 
 
B.  Cytokine Profiling and Future Immunophenotyping Studies  
• 
Collect 8 mL of peripheral blood into a sodium heparin cell preparation tube (CPT) tube  
 
 
 
 
 


 
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62 
 
 
Part A: Samples (A & B) should be obtained at the following time points:  
• 
After study registration through Day 1 but before 131I-MIBG infusion%. 
• 
Day 8:  prior to starting dinutuximab infusion# 
• 
Day 15:  prior to stem cell infusion# 
• 
Day 29:  prior to dinutuximab infusion#,% 
• 
End of Course 1#,% 
 
#If start of dinutuximab infusion is delayed, delay blood draw accordingly.  Stem cell infusion 
may take place +/- 2 days of Day 15, draw blood to correspond with stem cell infusion date. 
Day 15 samples must be drawn prior to stem cell infusion. End of course sample may be 
drawn with corresponding end of course blood work. 
 
%A single sample at this time point will be used to analyze both cytokine and HACA/ADA 
levels. 
 
Part B: Samples (A & B) should be obtained at the following time points:  
• 
After study registration through Day 0 but before vorinostat is given. 
• 
Day 1, before MIBG infusion% 
• 
Day 8:  prior to starting dinutuximab infusion# 
• 
Day 15:  prior to stem cell infusion# 
• 
Day 29:  prior to dinutuximab infusion#,% 
• 
End of Course 1#,% 
 
#If start of dinutuximab infusion is delayed, delay blood draw accordingly.  Stem cell infusion 
may take place +2 days/ - 1 day of Day 15, draw blood to correspond with stem cell infusion 
date. Day 15 samples must be drawn prior to stem cell infusion. End of course sample may 
be drawn with corresponding end of course blood work. 
 
%A single sample at this time point will be used to analyze both cytokine and HACA/ADA 
levels. 
 
8.1.2 
Sample Processing  
 
8.1.2.1 Immune Profiling by Flow Cytometry – Fresh whole blood (Sample 8.1.1 A) 
 
• 
Samples should be kept at room temperature until shipped. Sample should not be refrigerated 
or frozen.  Specimen will be shipped at room temperature for overnight delivery.  Refer to 
Sections 8.1.3 / 8.3 for labeling and shipping instructions. 
 
o 
For subjects enrolled at Children’s Healthcare of Atlanta (CHOA), this specimen will 
be taken directly to the Children’s Clinical and Translational Discovery Core (CCTDC).  
A specimen transmittal form must be created for these specimens using the NANT 
Specimen Transmittal Form application. 
 
8.1.2.2 Cytokine Profiling and Future Immunophenotyping Studies – Frozen plasma and viably frozen 
 
PBMCs (Sample 8.1.1 B) 
 
• 
Samples must be processed within 30 MINUTES OF COLLECTION.  The specimen will be 
spun down and the plasma will be aliquotted and frozen for future cytokine analysis and HACA 
and ADA analysis (refer to Section 8.2).  The PBMCs obtained from processing this blood draw 
will be viably frozen for future flow cytometry studies. Refer to Appendix VI for the 
recommended procedure for isolating and storing plasma and PBMCs. Alternative methods 
may be used if first approved by the study chair and CCTDC. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
63 
 
Frozen specimens (aliquotted plasma and PBMCs) will be batch shipped at the completion of 
the study. Refer to Sections 8.1.3 / 8.3 for labeling and shipping instructions.    
 
8.1.3 
Sample Labeling and Shipment 
 
Label tubes in the following manner:  
• 
Patient’s NANT Registration Number (N0xxx)  
• 
Study identifier: 
o 
Flow:  for flow cytometry samples (fresh whole blood) 
o 
Cytokine: for cytokine profiling samples (frozen plasma) 
o 
Immune: for future immunephenotyping samples (frozen PBMCs) 
• 
Date and time blood was drawn  
• 
Protocol sampling time point (ie: Day 8 etc.) 
 
Refer to Section 8.3 for shipping instructions.   
 
For the immune profiling studies (refer to Section 8.1.2.1), each sample should be sent on the same 
day it was obtained. The sample should be shipped at room temperature via Fed Ex Priority 
Overnight Delivery.  
 
Frozen specimens for cytokine profiling (plasma) and future flow cytometry (PBMCs) [refer to 
section 8.1.2.2] will be stored at the treating NANT site and batch shipped on dry ice via Fed Ex 
Priority Overnight Delivery at the end of Course 1.   
 
• 
For sites that don’t have liquid nitrogen storage for PBMCs, refer to Section 8.3 /Appendix 
VI. 
 
8.2 
Human anti-Chimeric Antibody (HACA) and Neutralizing Anti-Drug Antibody (ADA) Levels 
 
(Required) 
 
8.2.1 
Sampling Requirements and Schedule (COURSE 1 ONLY) 
 
The peripheral blood drawn per Section 8.1.1 B (cytokine profiling) and processed per section 
8.1.2.2 will provide the frozen plasma to be used in performing HACA/ADA levels on Day 0 (Part 
B) or Day 1 (Part A), 29 and at end of course.  Two additional samples (8 mL into a sodium heparin 
CPT tube) will be collected on Day 11 and Day 32 to analyze HACA/ADA levels. Please refer to 
Appendix II for overview of specimen collection time points.  
 
 
 
Part A: Samples should be obtained at the following time points:  
• 
After study registration through Day 1 but before 131I-MIBG infusion%. 
• 
Day 11: prior to dinutuximab infusion# 
• 
Day 29:  prior to dinutuximab infusion#,% 
• 
Day 32:  prior to dinutuximab infusion# 
• 
End of Course 1#,% 
 
#If start of dinutuximab infusion is delayed, delay blood draw accordingly.  End of course 
sample may be drawn with corresponding end of course blood work. 
%A single sample at this time point will be used to analyze both cytokine and HACA/ADA 
levels 
 
Part B: Samples should be obtained at the following time points:  
• 
After study registration through Day 0 but before vorinostat is given%. 
• 
Day 11: prior to dinutuximab infusion# 
• 
Day 29:  prior to dinutuximab infusion#,% 
• 
Day 32:  prior to dinutuximab infusion# 
• 
End of Course 1#,% 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
64 
 
 
#If start of dinutuximab infusion is delayed, delay blood draw accordingly.  End of course 
sample may be drawn with corresponding end of course blood work. 
%A single sample at this time point will be used to analyze both cytokine and HACA/ADA 
levels 
 
8.2.2 
Sample Processing  
Refer to 8.1.2.2 for specimen processing.  The specimen will be spun down and aliquotted into two 
vials of 200 µL each of plasma for HACA and neutralizing ADA levels. Store together with frozen 
plasma for cytokine analysis.  
 
 
8.2.3 
Sample Labeling and Shipment 
Label tubes in the following manner:  
• 
Patient’s NANT Registration Number (N0xxx)  
• 
Study identifier: 
o 
HACA  
• 
Date and time blood was drawn  
• 
Protocol sampling time point (ie: Day 11 etc.) 
 
These frozen specimens will be batch shipped to the CCTDC at Emory University at the end of 
Course 1.  Refer to section 8.3 for shipping instructions.   
 
8.3 
Shipping Instructions  
 
 
 
Samples should only be shipped on Mondays-Thursdays to allow for weekday delivery. 
 
Include NANT specimen transmittal form and corresponding correlative study worksheet(s) with 
each shipment. 
 
NANT Operations Center will email the Emory Lab at cctdc@emory.edu with the tracking number 
at the time of sample shipment.   
 
 
All specimens will be shipped by Federal Express Priority Overnight delivery to the 
 
following address: 
 
Emory University Children’s Clinical and Translational Discovery Core (CCTDC) 
Health Sciences Research Building – E264 
1760 Haygood Drive 
Atlanta, GA  30322 
Phone:  404-727-2342 
Email:  cctdc@emory.edu 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
65 
 
8.3.1 
Shipping Timing  
 
A.  Immune Profiling studies (fresh whole blood - refer to section 8.1.2.1) should be sent on the 
same day it was obtained.  The sample should be shipped at room temperature overnight via Fed 
Ex Priority Overnight delivery. 
 
B. Frozen specimens for cytokine profiling (plasma) and future immunophenotyping (PBMCs) [refer 
to section 8.1.2.2] will be stored at the treating NANT site and batch shipped on dry ice via Fed Ex 
Priority Overnight Delivery at the completion of Course 1.   
 
• 
For sites that don’t have liquid nitrogen storage available for PBMCs, follow these 
instructions for storing and shipping all the frozen samples.  Refer to Appendix VI. 
o 
Day 0 (Part B only), Day 1, Day 8, Day 15 PBMC samples: 
▪ 
Store in a - 800C freezer. 
▪ 
Ship these 3 samples to the Emory CCTDC (8.3) on dry ice via Fed Ex 
Priority Overnight Delivery after Day 15 draw is completed. 
 
o 
Day 29 and End of Course PBMC samples: 
▪ 
Store in a – 800C freezer 
▪ 
Ship these 2 samples PLUS batched frozen plasma samples 
(cytokine/HACA-ADA) on dry ice via Fed Ex Priority Overnight Delivery 
after the End of Course draw is completed. 
 
C.  Frozen specimens for HACA and ADA analysis (refer to Section 8.2) will be stored at the treating 
NANT site and batch shipped on dry ice via Fed Ex Priority Overnight Delivery at the completion of 
Course 1.  These specimens may be sent with the frozen specimens collected in 8.1.2.2.  Refer to 
8.3.1B above. 
 
D. Frozen PAXgene tubes for the optional RNA gene expression studies (refer to Section 8.5) will 
be stored at the treating NANT site and batch shipped on dry ice via Fed Ex Priority Overnight 
Delivery at the completion of Course 1.   
 
8.4 
Minimal Residual Disease by TaqMan low density array (NB5/TLDA) (Required) 
All patients are required to co-enroll onto the NANT Biology Study, NANT 2004-05. Patients should 
submit blood and/or bone marrow at study entry and at the time of Day 43-57 restaging studies. 
Submission of blood and bone marrow for TLDA will be according to the instructions in NANT 2004-
05. Patients can submit only bone marrow for NB5 assay if blood volumes for research do not allow 
for blood submission. 
 
8.5 
RNA Gene Expression Studies (Optional) 
In consenting patients, 2.5 mL peripheral blood will be drawn at the following time points in a 
PAXgene RNA tube for analysis of immune response related genes, future RNA profiling and 
protein expression studies. 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
66 
 
8.5.1 
Sampling Requirements and Schedule (Course 1 Only) 
 
Collect 2.5 mL of peripheral blood into a PAXgene RNA tube at each time point.    
 
 
PART A: 
• 
Screening:  After study registration through Day 1 but before 131I-MIBG infusion. 
• 
Day 8:  prior to starting dinutuximab infusion# 
• 
Day 11: prior to discharge after completion of dinutuximab 
• 
Day 15:  prior to stem cell infusion# 
• 
Day 29:  prior to dinutuximab infusion# 
• 
Day 32: prior to discharge after completion of dinutuximab 
• 
Day 36#,%  
• 
End of Course 
 
#If start of dinutuximab infusion is delayed, delay blood draw accordingly.  Stem cell infusion 
may take place +/- 2 days of Day 15, draw blood to correspond with stem cell infusion date. 
Day 15 samples must be obtained prior to stem cell infusion. End of course sample may 
be drawn with corresponding end of course blood work. 
%Day 36 labs should be collected four days post last dose of dinutuximab 
 
 
PART B: 
• 
After study registration through Day 0 but before vorinostat is given. 
• 
Day 1, before MIBG infusion% 
• 
Day 8:  prior to starting dinutuximab infusion# 
• 
Day 11: prior to discharge after completion of dinutuximab 
• 
Day 15:  prior to stem cell infusion# 
• 
Day 29:  prior to dinutuximab infusion# 
• 
Day 32: prior to discharge after completion of dinutuximab 
• 
Day 36#,%  
• 
End of Course 
 
#If start of dinutuximab infusion is delayed, delay blood draw accordingly.  Stem cell infusion 
may take place + 2 days/ - 1 day of Day 15, draw blood to correspond with stem cell infusion 
date. Day 15 samples must be obtained prior to stem cell infusion. End of course sample 
may be drawn with corresponding end of course blood work. 
%Day 36 labs should be collected four days post last dose of dinutuximab 
 
8.5.2 
Sample Processing and Labeling 
 
• 
Gently invert PAXgene tube 8-10 times after collection. Keep tube at room temperature for 2 – 
72 hours and then freeze upright in a wire rack (NOT STYROFOAM HOLDER) for 24 hrs at -
20○C and then transfer to -70○C or -80○C freezer until ready to batch ship at the completion of 
the study. 
o 
It is strongly suggested that each PAXgene tube be placed in a ziplock bag to avoid 
losing the sample if the PAXgene tube bursts during freezing.  Contact the Study 
Chairperson if this event occurs. 
 
• 
Label PAXgene tubes in the following manner:  
o 
Patient’s NANT Registration Number (N0xxx)  
o 
Study identifier: 
▪ 
RNA  
o 
Date and time blood was drawn  
o 
Protocol sampling time point (ie: Screening, Day 8 etc.) 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
67 
 
 
8.5.3 
Shipping 
 
All samples will be stored frozen at NANT site and batch shipped at the end of Course 1. 
 
Refer to Section 8.3 for shipping instructions and address. 
 
8.6 
Isolation of DNA for Future Gene Expression Studies (Optional) 
 
In consenting patients, two 250µL aliquots (approximately 0.25 mL) of whole blood previously 
 
collected for immune profiling by flow cytometry (Section 8.1.2.1) will be processed and stored at 
 
Emory University. No additional blood needs to be drawn from the patient to perform these 
 
studies. 
 
8.7 
Storage of Remaining Biologic Samples for Future Analysis (Optional) 
The NANT Biology Study (NANT 2004-05) provides a mechanism to allow for banking of biologic 
specimens collected through other NANT protocols. Consenting patients will be asked to allow 
storage/banking of samples leftover from correlative testing on this study for future analysis to 
address scientific questions related to 131I-MIBG, dinutuximab, neuroblastoma or other childhood 
cancers.  A decision to perform such exploratory research studies would be based on outcome 
data from this study or from new scientific findings related to the drugs or disease. 
 
8.8 
Evaluation of the Tumor Microenvironment (Optional) 
In consenting patients, archival tumor tissue from the most recent biopsy of a soft tissue lesion 
obtained prior to study registration will be collected from those patients who have adequate tumor 
tissue to submit. We will use this tissue to evaluate the tumor microenvironment (TME). Tumor 
samples will be evaluated for the presence of TILs and TAMs, as well as the immune checkpoint 
proteins CD274 (PDL1) and CD276 (B7H3) by immunohistochemistry. We will also perform 
RNAseq and exome sequencing to evaluate for immune response genes.  Three mL of peripheral 
blood will be drawn for germline DNA and the tumor sequencing will be interpreted in the context 
of these results. 
 
For consenting patients, in the future, if a biopsy is performed for clinical reasons prior to starting 
therapy subsequent to this protocol treatment, we will request that tumor tissue be submitted. This 
tumor tissue will be analyzed for changes in the TME that occur as a consequence of the 131I-MIBG 
+ dinutuximab therapy, and will be compared to pre-study samples when available. 
 
8.8.1 
Sample Requirements 
Coordinate to collect blood so blood and tumor may be shipped together at the same time. 
 
• 
Collect 3 mL peripheral blood in purple top (EDTA) tube.  This sample must arrive in the CHLA 
lab NO LATER THAN 48 hours after it was drawn. 
o 
Confirm there is tumor specimen available that can meet the sampling 
requirements below prior to arranging for blood to be drawn.   
• 
One FFPE block; OR 
• 
10 tissue scrolls 15 µm thick AND 10-25 unstained slides 
If scrolls AND slides are submitted, they should be cut sequentially from one 
representative block. 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
68 
 
8.8.2 
Sample Labeling  
Label blood: 
• 
Patient’s NANT Registration Number (N0xxx) 
• 
Collection date (MM/DD/YY) 
 
Label tumor samples in the following manner:  
• 
Patient’s NANT Registration Number (N0xxx)  
• 
Specimen type: P for primary or M for metastatic site 
• 
Surgical pathology ID number and block number from corresponding pathology report 
• 
Study identifier: 
o 
Tissue 
 
8.8.3 
Sample Shipment 
 
 
Samples should only be shipped on Mondays-Thursdays to allow for weekday delivery.  
NANT Operations will email Rebekah Kennedy with the tracking number at the time of sample 
shipment. 
 
Samples should be shipped at room temperature by Federal Express Priority Overnight Delivery to 
the address below: 
 
Include NANT specimen transmittal form and correlative study worksheet with each shipment. 
 
NANT Biology Specimen Bank 
Attn: Rebekah Kennedy 
Children’s Hospital Los Angeles 
Smith Research Tower, Room 506 
4650 Sunset Boulevard, MS 57 
Los Angeles, CA 90027 
Lab Phone: (323) 361-4503 
Lab FAX: (323) 361-4902 
Lab Contact: Rebekah Kennedy 
E-mail: rekennedy@chla.usc.edu or sasgharzadeh@chla.usc.edu 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
69 
 
 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
 
9.1 
Criteria for Removal from Protocol Therapy 
a. Disease progression before active treatment 
b. Disease progression, relapse during active treatment 
c. Patient/parent withdrawal/refusal before beginning protocol therapy 
d. Patient/parent withdrawal/refusal after beginning protocol therapy 
e. Unacceptable adverse events by protocol criteria# 
f. 
Other adverse event / side effects / complications 
g. Patient off treatment for other complicating disease 
h. Initiation onto another therapeutic study and/or another anti-cancer therapy 
i. 
Treatment completed per protocol criteria 
j. 
No treatment (includes patients unable to get vorinostat) 
k. Lost to follow-up 
l. 
Death while on protocol therapy 
 
#:  When determining criteria for removal from protocol therapy, Day 8 dinutuximab dose delayed beyond Day 11 and Day 29 
dinutuximab dose delayed by more than 2 weeks will be classified as unacceptable adverse events by protocol criteria. 
 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for off study.   
Patients who are removed from therapy prior to progression will be followed for progressive disease 
until they progress, die, or start another therapy (in which case the date of the new therapy and the 
type of therapy will be recorded).  All patients will be followed until death for survival analysis, unless 
consent is withdrawn or patient is lost to follow-up. Protocol follow-up forms will be completed every 
6 months after patient comes off protocol therapy for the first year and then once a year thereafter 
(see data submissions schedule for further detail).  
 
9.2 
Off Study Criteria 
 
a. Death 
b. Lost to follow-up 
c. Patient/Parent withdrawal of consent 
 
 


 
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70 
 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
Part A: This is a Phase I trial with a dose escalation portion using a Rolling 6 design, followed by a brief 
expansion cohort of 6 evaluable patients at the recommended Phase II dose (RP2D). 
 
Part B: Enrollment to Part B of the study will not begin until enrollment of the Part A expansion 
cohort is complete. Part B will test 1 dose level of vorinostat with a de-escalation dose level if needed, 
using a Rolling 6, Phase 1 trial design. This will be followed by a brief expansion cohort of 6 evaluable 
patients at the RP2D.  
 
 
10.1 
Sample Size and Study Duration 
 
10.1.1 Part A 
A maximum of four dose levels is planned for this part of the study (see Table in  
Section 4.3.1).  Dose Level 1 (12 mCi/kg dose of 131I-MIBG and 17.5 mg/m2/dose of dinutuximab) will be 
the starting dose; in Dose Levels 2 and 3, the dose of 131I-MIBG will be escalated to 15 and then 18 mCi/kg, 
with the dose of dinutuximab fixed at 17.5 mg/m2/dose.  If the starting dose level (Dose Level 1) is not 
tolerated (i.e. 2+ patients experience DLT), then 3-6 subsequent patients will be enrolled to Dose Level 0, 
which keeps the 131I-MIBG dose at 12 mCi/kg, but reduces the dinutuximab dose to 14 mg/m2/dose.  
 
A minimum of 3 (or 2 if the 1st 2 patients at a dose level experience DLT) and maximum of 6 patients 
evaluable for toxicity (as defined in Section 10.2.1) will be entered at each dose level. Once the final 
MTD/RP2D has been determined, a maximum of 6 additional DLT-evaluable patients will be enrolled at the 
MTD/RP2D. The number of evaluable patients needed during the expansion will be determined when a 
robust cohort, treated at the MTD/RP2D, has been established to describe toxicity, response, and immune 
correlated data. Thus a minimum of 4 DLT-evaluable patients (if the 1st 2 patients at Dose Level 1 
experience DLT and the 1st 2 patients at Dose Level 0 experience DLT) and a maximum of 30 DLT-
evaluable patients (if 6 DLT-evaluable patients are enrolled at all 4 dose levels and Dose Level 0 is the 
MTD:  4x6+6=30) could be enrolled on this study.  Based on NANT 17-1 enrollments to date and 20%-30% 
patients may be DLT-inevaluable, we anticipate that 30 to 32 patients will be enrolled. 
 
Review of accrual to previous NANT studies indicates that up to 15 patients per year should be accrued; 
however, given that NANT 11-01 will be open concurrently, and there will be study closures for dose level 
evaluation, we anticipate that it will take 3 years to complete this part of the study, i.e. about 10 patients per 
year accrual. 
 
10.1.2 Part B 
A maximum of two dose levels is planned for this part of the study (see Table in  
Section 4.3.2).  Dose Level 4 (180 mg/m2/dose of vorinostat, 17.5 mg/m2/dose of dinutuximab, and 18 
mCi/kg/dose 131I-MIBG) will be the starting dose. If the starting dose level (Dose Level 4) is not tolerated 
(i.e. 2+ patients experience DLT), then 3-6 subsequent patients will be enrolled to Dose Level 4a, which 
keeps the 131I-MIBG (18 mCi/kg/dose) and dinutuximab (17.5 mg/m2/dose) dose the same, but reduces the 
vorinostat dose to 150 mg/m2/dose.  
 
A minimum of 3 (or 2 if the 1st 2 patients at a dose level experience DLT) and maximum of 6 DLT-evaluable 
patients evaluable for toxicity (as defined in Section 10.2.1) will be entered at each dose level. Once the 
final MTD/RP2D has been determined, an additional 6 DLT-evaluable patients will be enrolled at the 
MTD/RP2D.  Thus a minimum of 4 DLT-evaluable patients (if the 1st 2 patients at Dose Level 4 experience 
DLT and the 1st 2 patients at Dose Level 4a experience DLT) and a maximum of 18 DLT-evaluable patients 
(if 6 DLT-evaluable patients are enrolled at both dose levels and Dose Level 4a is the MTD:  2x6+6=18) 
could be enrolled on this study.  We anticipate that 15 to 18 patients will be enrolled, based on the NANT 
17-1 enrollments to date that 20%-30% patients may be DLT-inevaluable. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
71 
 
NANT 2017-01 was opened to accrual in September of 2018, and 20 patients have been enrolled since 
that time, i.e. ~10 patients per year accrual. Based on this, we anticipate that it will take 1.5 to 2 years to 
complete this part of the study. 
 
10.2  
Definitions 
10.2.1  Evaluable for Inclusion in Dose Escalation Consideration (i.e. “DLT-Evaluable”) 
Dose escalation considerations will be based on Course 1 data only. Toxicity will be assessed and 
reported on all patients who begin protocol therapy. The definition of DLT is given in Section 4.4.   
 
Part A Dose Escalation Cohort: A patient will be considered evaluable for inclusion in dose 
escalation/expansion/de-escalation decisions if he/she has received at least 90% of the assigned 
dose of 131I-MIBG, and at least 80% of the assigned doses of dinutuximab and GM-CSF during 
Course one AND are followed until Day 57 or until platelet and neutrophil engraftment (defined in 
Section 4.5.2.1), whichever occurs last. In addition, patients who experience DLT at any time after 
the first dose of dinutuximab are evaluable for inclusion in dose escalation consideration. Toxicity 
will be assessed and reported on all patients who begin protocol therapy. 
 
Part A Dose Expansion and Part B Cohorts: A patient will be considered evaluable for inclusion 
in dose escalation/expansion/de-escalation decisions if he/she has received at least 90% of the 
assigned dose of 131I-MIBG, at least 80% of the assigned dose of dinutuximab, and at least 78% of 
the assigned doses of vorinostat (at least 11 days; Part B only) during Course one AND are followed 
without receiving any non-protocol therapy at least through 14 days after the last dose of 
dinutuximab or until platelet and neutrophil engraftment (defined in Section 4.5.2.1) or resolution of 
all non-hematologic toxicities at least possibly related to protocol therapy to ≤ Grade 2, whichever 
occurs last. In addition, patients who experience DLT at any time after the first dose of dinutuximab 
are evaluable for inclusion in dose escalation considerations. Toxicity will be assessed and reported 
on all patients who begin protocol therapy.   
 
Patients who receive less than 90% of the assigned 131I-MIBG dose, less than 80% of the assigned 
dinutuximab or GM-CSF doses (Part A dose-escalation phase only), or less than 78% of the 
assigned vorinostat doses (less than 11 days; Part B only) for reasons other than toxicity AND/OR 
are not followed through 14 days after the last dose of dinutuximab without receiving any non-
protocol therapy, or until platelet and neutrophil engraftment (defined in Section 4.5.2.1), or until 
resolution of all non-hematologic toxicities at least possibly related to protocol therapy to  
≤ Grade 2, whichever occurs last will be replaced for the purposes of evaluating the dose level for 
dose escalation/de-escalation purposes, unless they have DLT in first course.  
 
Certain adverse events associated with dinutuximab are known to occur and to be patient 
dependent. These will not be considered DLTs even if they result in treatment delays or skipped 
doses.  If doses are eliminated or treatment is terminated because of these toxicities, so that the 
patient is no longer DLT-evaluable, this patient will also be replaced. The number of these patients 
and toxicities will be evaluated by the study management committee and the incidence compared 
to standard dinutuximab therapy. 
 
Patients who do not meet definition of hematologic engraftment DLT (Section 4.5.2.1) and begin 
other therapy prior to platelet and/or neutrophil engraftment will not be fully evaluable for 
hematologic toxicity and will be replaced. 
 
10.2.2 Evaluable for Response 
Eligible patients with measurable or evaluable disease (which will include all patients since the 
trial requires that a patient have MIBG-avid disease at study entry) who (a) have received any 
dose of protocol therapy and (b) have at least one evaluation of tumor status as mandated in 
required observations OR have tumor progression demonstrated on at least one parameter 
(CT/MRI, MIBG, or bone marrow) OR have clinical evidence of progression per treating physician 
OR who die due to toxicity, will be classified as “evaluable for response”.  Patients who are not 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
72 
 
evaluable for response will NOT be replaced.  Response will be described for all patients entered 
on study.  
 
All patients who are registered onto the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned 
one of the following categories (see Section 11.6): 
 
a. Complete Response  
b. Complete Response MD  
c. Partial Response  
d. Progressive Disease  
e. Stable Disease  
f. Stable Disease-Non-Target Lesions  
g. Minor Response 
h. Minimal Disease  
i. Not Evaluable  
j. No Progression  
k. Not Done  
 
All eligible patients who receive any amount of 131I-MIBG will be included in the initial, primary 
analysis of response. Patients in groups a through c will be classified as responders; patients in 
groups d through j will be classified as non-responders. In a second analysis, the proportion of 
responders (patients in groups a through c) will be calculated from the subset of patients who are 
evaluable for response (as defined above). 
 
10.2.3 Maximum tolerated dose (MTD) 
The MTD is the highest dose level tested at which 0/6 or 1/6 patients experience DLT (that is possibly, 
probably, or definitely related to the study drug(s) as defined in Section 4.5) with at least 2/3 or 2/6 
patients encountering DLT at the next higher dose.  If 0/6 or 1/6 patients experience DLT at the 3rd 
and highest dose level, then Dose Level 3 is the highest tested dose and will be called the MTD. 
 
10.2.4  Recommended Phase II Dose (RP2D) 
The RP2D will be the MTD, pending comprehensive review of all toxicities (for example if the patient 
receives more than one course). If the RP2D is not the MTD, then the protocol will be amended to 
explain the decision. 
 
10.3 
Dose Escalation 
Toxicity will be graded using the CTCAE criteria, version 5.0 which can be downloaded from the 
CTEP home page (http://ctep.cancer.gov).  The definition of dose limiting toxicity (DLT) is given in 
Section 4.5. 
 
10.3.1   Dose Levels 0, 1-3, 4, and 4a: 
 
This study will utilize the Rolling 6 design for dose escalation (81). This design is a modification of 
the classic 3+3 dose escalation strategy.  With this design, three to six patients can be concurrently 
enrolled onto a dose level, dependent upon (1) the number of patients enrolled at the current dose 
level, (2) the number of patients who have experienced DLT at the current dose level, and (3) the 
number of patients entered but with toxicity data pending at the current dose level. Accrual at a 
dose level is suspended when a cohort of six has enrolled or when the study endpoints have been 
met. In order to facilitate the safe conduct of the Rolling 6 design, NANT operations and sites will 
remain in close contact to monitor occurrence of DLT in a timely fashion with increased reporting 
requirements from sites and study committee oversight. 
 
The rules for the Rolling 6 design are as follows: 
- 
At each dose level, up to 6 patients can be enrolled.    


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
73 
 
o 
Unless 2+ patients experience DLT, a minimum of 3 patients will be enrolled at each 
dose level. 
o 
At most 6 evaluable patients will be treated at each dose level. 
- 
At any time if 2+ patients experience DLT at a dose level, then the MTD has been exceeded. 
o 
At Dose Levels 1 and 2: dose escalation will be stopped, and the dose level will be de-
escalated, if there are fewer than 6 patients at the next lower dose level.   
o 
At Dose Levels 3 and 4: dose level will be de-escalated, if there are fewer than 6 patients 
at the next lower dose level.   
o 
At Dose Level 0 and 4a: the protocol will be terminated or amended.   
- 
If 6 patients have been enrolled and evaluated, and only 0 or 1 patients have experienced at 
DLT, the following rules apply. 
o 
At Dose Levels 1 and 2: the next patient will be enrolled at the next higher dose level.   
o 
At Dose Levels 0, 3, 4 and 4a: the current Dose Level will be labeled the MTD. 
- 
Once 3-5 patients have been treated at a dose level and only 0 or 1 have experienced a DLT, 
then the following rules will be followed as listed in the Table below. 
 
Rules for Dose Expansion/Escalation when 3-5 Patients have been Enrolled and Only 0 or 1 Patient has Experienced a DLT 
At the Current Dose Level 
 
Number of 
Patients 
Enrolled 
Number of Patients 
Who Have 
Experienced a DLT 
Number of Patients 
Who NOT Have 
Experienced a DLT 
Number of 
Patients with 
Data Pending 
Assignment of the Next Patient 
3 
0 
0 
3 
Enroll at Current Dose Level* 
3 
0 
1 
2 
Enroll at Current Dose Level* 
3 
0 
2 
1 
Enroll at Current Dose Level* 
3 
0 
3 
0 
Dose Levels 1 and 2:  Enroll at Next Dose Level 
Dose Levels 0 and 3: Phase I Part A completed 
with current Dose Level the MTD   
Dose Levels 4 and 4a: Phase I Part B completed 
with current Dose Level the MTD   
3 
1 
0 
2 
Enroll at Current Dose Level 
3 
1 
1 
1 
Enroll at Current Dose Level 
3 
1 
2 
0 
Enroll at Current Dose Level 
 
4 
0 
0 
4 
Enroll at Current Dose Level* 
4 
0 
1 
3 
Enroll at Current Dose Level* 
4 
0 
2 
2 
Enroll at Current Dose Level* 
4 
0 
3 
1 
Enroll at Current Dose Level* 
4 
0 
4 
0 
Dose Levels 1 and 2:  Enroll at Next Dose Level 
Dose Levels 0 and 3: Phase I Part A completed 
with current Dose Level the MTD   
Dose Levels 4 and 4a: Phase I Part B completed 
with current Dose Level the MTD 
4 
1 
0 
3 
Enroll at Current Dose Level 
4 
1 
1 
2 
Enroll at Current Dose Level 
4 
1 
2 
1 
Enroll at Current Dose Level 
4 
1 
3 
0 
Enroll at Current Dose Level 
 
5 
0 
0 
5 
Enroll at Current Dose Level* 
5 
0 
1 
4 
Enroll at Current Dose Level* 
5 
0 
2 
3 
Enroll at Current Dose Level* 
5 
0 
3 
2 
Enroll at Current Dose Level* 
5 
0 
4 
1 
Enroll at Current Dose Level* 
5 
0 
5 
0 
Dose Levels 1 and 2:  Enroll at Next Dose Level 
Dose Levels 0 and 3: Phase I Part A completed 
with current Dose Level the MTD   
Dose Levels 4 and 4a: Phase I Part B completed 
with current Dose Level the MTD 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
74 
 
5 
1 
0 
4 
Enroll at Current Dose Level 
5 
1 
1 
3 
Enroll at Current Dose Level 
5 
1 
2 
2 
Enroll at Current Dose Level 
5 
1 
3 
1 
Enroll at Current Dose Level 
5 
1 
4 
0 
Enroll at Current Dose Level 
*Study Committee may opt to hold accrual until all patients have been evaluated  
 
When participants are inevaluable for toxicity, they are replaced with the next available participant 
if escalation or de-escalation rules have not been fulfilled at the time the next available participant 
is enrolled onto the study. 
 
In this study, the MTD will be defined as the highest dose tested in which 0 or only 1 patient – out 
of a total of 6 patients – experiences a DLT during the first course of therapy.    
 
 
Operating Characteristics of the Rolling 6. This trial was designed to select an MIBG dose that, 
combined with dinutuximab, has a DLT rate that is 25% or less.  The operating characteristics of 
the Rolling 6 rules, in terms of the probability of DLT at the selected MTD, are very similar to those 
of the 3+3 rules.  Both tend to select an MTD with a probability of DLT in the range 0f 0.10 to 0.25.  
The tables below estimates the characteristics of the proposed design for a variety of scenario, 
using the 3+3 rules in which the dose can be escalated over 3 doses, with a single dose reduction 
if too many DLT’s are observed at Dose Level 1.  
 
Note: There are different tables for Part A and B. 
 
Operating Characteristics  Part A 
Probability of DLT at Dose Level 
Probability that 
MTD has DLT Rate 
of 10% to 25% 
Probability that 
MTD has DLT Rate 
of 30% or Greater 
No Dose 
Selected as MTD 
0 
1 
2 
3 
0.02 
0.05 
0.15 
0.25 
0.78 
0.00 
0.00 
0.02 
0.05 
0.15 
0.30 
0.44 
0.33 
0.00 
0.02 
0.05 
0.15 
0.35 
0.51 
0.25 
0.00 
0.05 
0.10 
0.20 
0.30 
0.63 
0.27 
0.00 
0.05 
0.10 
0.20 
0.35 
0.69 
0.20 
0.00 
0.05 
0.10 
0.20 
0.40 
0.75 
0.15 
0.00 
0.05 
0.15 
0.25 
0.35 
0.64 
0.16 
0.01 
0.05 
0.15 
0.25 
0.40 
0.68 
0.11 
0.01 
0.05 
0.15 
0.25 
0.45 
0.72 
0.08 
0.01 
0.05 
0.15 
0.30 
0.40 
0.44 
0.36 
0.01 
0.05 
0.15 
0.30 
0.45 
0.44 
0.35 
0.01 
0.05 
0.15 
0.30 
0.50 
0.44 
0.35 
0.01 
0.10 
0.20 
0.30 
0.40 
0.65 
0.31 
0.04 
0.10 
0.20 
0.30 
0.45 
0.66 
0.31 
0.04 
0.10 
0.20 
0.30 
0.35 
0.65 
0.31 
0.04 
0.10 
0.20 
0.35 
0.45 
0.73 
0.24 
0.04 
0.10 
0.25 
0.35 
0.40 
0.75 
0.20 
0.05 
0.10 
0.25 
0.35 
0.45 
0.75 
0.20 
0.05 
0.10 
0.25 
0.35 
0.50 
0.75 
0.20 
0.05 
0.15 
0.30 
0.40 
0.45 
0.44 
0.44 
0.13 
0.15 
0.30 
0.40 
0.50 
0.44 
0.44 
0.13 
0.15 
0.30 
0.45 
0.50 
0.44 
0.43 
0.13 
 


 
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Operating Characteristics Part B 
Probability of DLT at 
Dose Level 
Probability that 
MTD has DLT Rate 
of 10% to 25% 
Probability that 
MTD has DLT Rate 
of 30% or Greater 
No Dose 
Selected as 
MTD 
4a 
4 
0.02 
0.10 
0.89 
0.00 
0.00 
0.05 
0.10 
0.89 
0.00 
0.00 
0.05 
0.15 
0.78 
0.00 
0.01 
0.10 
0.15 
0.97 
0.00 
0.03 
0.10 
0.20 
0.96 
0.00 
0.04 
0.15 
0.20 
0.92 
0.00 
0.08 
0.15 
0.25 
0.90 
0.00 
0.10 
0.20 
0.25 
0.84 
0.00 
0.16 
0.20 
0.30 
0.38 
0.42 
0.20 
0.25 
0.30 
0.31 
0.42 
0.27 
0.25 
0.35 
0.36 
0.32 
0.32 
0.30 
0.35 
0.00 
0.61 
0.39 
  
 
10.3.2 Expansion Cohort at the RP2D/MTD 
Once the MTD of dinutuximab and 131I-MIBG in Part A and vorinostat, dinutuximab, and 131I-MIBG 
in Part B has been determined, an expansion cohort will be enrolled at the RP2D/MTD of each part 
of the study. This number of additional patients will provide a maximum of 12 DLT-evaluable 
patients (3-6 DLT-evaluable patients already treated at the RP2D/MTD plus 6-9 new DLT-evaluable 
patients in the expansion cohort) treated at the RP2D/MTD.  If one or more patients are not DLT 
evaluable and evaluable for response (see definitions above), then they will be replaced..  
 
The purpose of the expansion cohort is to provide a more precise assessment of the tolerability 
and toxicities of this regimen when dosed at the RP2D/MTD as well as provide additional biologic 
correlate data. In addition, this expansion cohort will provide preliminary data regarding the anti-
tumor activity at the RP2D/MTD. The number of DLT-evaluable patients needed during expansion 
will be determined when a robust cohort, treated at the RP2D/MTD, has been established to 
describe toxicity, response, and immune correlated data. 
 
Detailed toxicity data will be collected on patients in the expansion cohort in a manner identical to 
the toxicity data collection in the dose-escalation portion of the study. Toxicities observed in the 
expansion cohort will not alter the defined MTD from the dose-escalation portion of the study, but 
may impact on the final selection of the RP2D, and on the study committee’s recommendation for 
supportive care with this regimen and for the role of this regimen in the future.  
 
Accrual to the MTD expansion cohort will be continuous and will not depend upon completion of 
treatment of the previous patients in the expansion cohort. There will not be formal rules for 
continuing or terminating enrollment to the expansion cohort. However, we will adopt the following 
guideline: 
 
Toxicity Monitoring Guideline:  if a second DLT is observed in the patients in either expansion 
cohort, then cumulative toxicities will be reviewed prior to enrolling the next patient. The table below 
summarizes the probability of observing 2 or more patients with DLT (out of 6 in each of the two 
expansion cohorts) for a range of DLT rates. 
 
 
 


 
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Probability of Observing 2+ Patients of the 6 Enrolled in Each Expansion Cohort 
DLT Rate 
5% 
10% 
15% 
20% 
25% 
30% 
35% 
40% 
Probability of 2+ DLTs 
0.03 
0.11 
0.22 
0.34 
0.47 
0.58 
0.68 
0.77 
 
The group of all DLT-evaluable patients (dose escalation + expansion) treated at the MTD of each 
part of the study will also provide additional preliminary information regarding the anti-tumor activity 
of this regimen at the MTD. The overall response rate will be determined. In addition, MIBG 
response rates, bone marrow response rates, and CT/MRI response rates will be documented. 
 
Including the dose-expansion phase, the total number of patients treated on this study will not 
exceed 35 patients in Part A and 20 patients in Part B. 
 
10.4 
Analysis of Results 
The outcome status (in terms of toxicity, engraftment, response, reason off study, progression, and 
survival) of all registered patients will be reported.  
 
If a patient is found to be ineligible and does not receive any protocol treatment, or if an eligible 
patient refuses treatment and receives no protocol therapy, then the enrollment of that patient will 
be documented but that patient will not be included in any analyses. 
 
If a patient is found to be ineligible after he or she has begun treatment on this trial, then data from 
that patient will continue to be collected and recorded as long as he or she continues treatment and 
then for a minimum of 30 days afterwards or until resolution of toxicities – whichever comes last.  
In the reporting of results, the enrollment of that patient will be documented but that patient will not 
be included in any analyses.  For completeness, the toxicities and adverse events experienced by 
that patient will be listed separately.   
 
Finally, if an eligible patient, who began treatment, subsequently withdrew consent for further 
treatment, then data from that patient will continue to be collected and recorded as long as he or 
she continues treatment and then for a minimum of 30 days afterwards or until resolution of 
toxicities – whichever comes last.  However, if the patient consents to continued follow-up, these 
data will also be collected.  The results of this patient will be included in all analyses as with all the 
other eligible patients, unless he or she requests that his or her data not be used. 
 
10.4.1 Toxicity  
All toxicities observed will be summarized in terms of type (organ affected or laboratory 
determination), severity (by NCI CTCAE v5), and attribution. Tables will be created to summarize 
theses toxicities and side effects by dose level and by course. All eligible patients who begin 
treatment will be included in these summaries.  Ineligible patients who begin treatment will be listed 
separately. 
 
10.4.2  Response/Outcome  
All eligible patients who begin treatment will be included in the analysis of survival, time-to-failure, 
and best response. Patients with measurable or evaluable tumor who receive 131I-MIBG or who 
progress prior to completion of therapy will be included in a planned subset analysis of tumor 
response.  
 
10.4.3  Evaluation of Patients Receiving Multiple Courses of Therapy 
 
 
It is anticipated that one-third of patients will receive a second course of therapy. Therefore, toxicity 
and response from a second course of therapy will be reported descriptively. In addition, if any 
patient experiences a protocol-defined dose limiting toxicity in the second course of therapy, the 
study committee will discuss the event and determine whether future patients should continue to 
be offered a second course of therapy. 
 
 
 


 
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10.5 
Monitoring Plan for Specific Toxicities  
 
10.5.1  Monitoring plan for opportunistic infection  
Opportunistic infections are anticipated to be rare events in these patients, particularly as all 
patients will be required to receive PCP prophylaxis. Any diagnosis of an opportunistic infection 
within 90 days of stem cell infusion will be reviewed by the Study Committee and IND sponsor and 
decision will be made to close the trial, modify the trial, or continue unchanged; in addition, it will 
be determined if the event requires that new information be added to the informed consent.  
 
10.5.2  Monitoring plan in the event of death prior to engraftment or within 2 months of stem cell infusion 
(whichever occurs last)  
Any time that a patient dies while undergoing treatment prior to a stem cell infusion, or within two 
months of stem cell infusion, the status of the study will be examined. Information reviewed will 
include the specific details of the patient who died, the timing of the death, the specifics of all 
patients who experienced the same type of toxicity that did not lead to death, and all toxicities 
observed to date.  
 
Each death on study not due to tumor will be reviewed by the NANT Study Management 
Committee, reported to NANT DSMB and a decision in consultation with NANT DSMB and IND 
sponsor will be made to close the trial, modify the trial, or continue unchanged; in addition, it will 
be determined if the event requires that new information be added to the informed consent.  Each 
death occurring within 30 days of completing the last dose of dinutuximab regardless of cause will 
be reviewed and reported to the NANT DSMB and to the FDA according to standard procedure.  
 
10.6  
Analysis of Correlative Studies 
Summary statistics and descriptive plots will be generated for the correlative biology studies. The 
changes will be assessed using a paired t-test or Wilcoxon matched pairs signed rank sum test 
when appropriate. Linear mixed models (with appropriate transformation if necessary) may also be 
considered to take advantage of the repeated measurements.  All these analyses will be 
descriptive, exploratory, and hypotheses generating in nature. 
 
10.7     Inclusion of Women and Minorities 
The study is open to all participants regardless of gender or ethnicity. Review of accrual to past 
NANT studies of new agents demonstrates the accrual of both genders and all NIH-identified 
ethnicities to such studies. The small number of patients entered into this trial will obviate any 
analysis of variation in response rate with gender or ethnicity. 
 
 
 


 
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11.0 
NANT RESPONSE CRITERIA v2.0 
For evaluation of response this study will utilize the New Approaches to Neuroblastoma Therapy (NANT) 
Response Criteria v2.0. Since patients on this study must have MIBG avid tumors, any reference to 
MIBG non-avid tumors is not applicable, but the language is retained here to present the NANT 
response criteria in its entirety.  
 
Overall response will incorporate all three parameters: Soft Tissue Response, Bone Response, and Bone 
Marrow Response with Overall Response defined as outlined in Section 11.6.  Response for each 
parameter and overall response will be reported by the treating site using the criteria below. However, the 
final statistical analysis of response will utilize responses as graded by central review, using the same 
criteria below. 
 
11.1 
Soft Tissue Response Criteria 
Soft tissue lesions will be evaluated by CT/MRI, using the definitions of measurable disease from 
the Response Evaluation Criteria in Solid Tumors (RECIST 1.1; European Journal Cancer 45: 228-
247, 2009) modified per the criteria below to define target lesions (lesions which are measurable 
AND evaluable for response). 
 
Note that the response criteria for lymph nodes measured by short axis will only be applied to 
discrete lymph nodes (i.e. cervical, axillary) that are not adjacent to the primary site and are not 
composed of a coalesced mass of multiple lymph nodes. Coalesced masses of lymph nodes should 
be assessed using non-lymph node criteria and measured using longest dimension. 
 
11.1.1 DEFINITION OF SOFT TISSUE TARGET LESIONS: 
. 
Soft tissue target lesions that will be followed for response must meet criteria 1 and 2, OR criteria 3 below: 
1. A target lesion must be measurable, defined as a soft tissue lesion that can be accurately 
measured in at least one dimension with a longest diameter ≥ 10mm, or for discrete lymph 
nodes ≥ 15mm on short axis.  (The short axis is measured after identifying the longest diameter 
of a lymph node, and then measuring the longest perpendicular diameter to that as the short 
axis). For coalesced masses of multiple lymph nodes, the longest diameter will be used. 
2. A target lesion must also be MIBG avid OR FDG-PET avid (if tumor known to be MIBG non-
avid), and have a biopsy if required in the eligibility criteria.  If one avid soft tissue or bone 
lesion present at enrollment is biopsied showing neuroblastoma or ganglioneuroblastoma at 
any time point prior to enrollment, then all other avid soft tissue lesions present at enrollment 
are considered target lesions.   
3. A lesion that is measurable but does not have either MIBG or FDG-PET uptake will be 
considered a target lesion if a biopsy done at any time prior to enrollment demonstrates 
neuroblastoma and/or ganglioneuroblastoma. 
 
NOTE: Soft tissue components of bone lesions will be considered measurable soft tissue lesions if 
> 10mm in at least one dimension, and target lesions evaluable for response if MIBG avid (or FDG-
PET-avid if tumor known to be MIBG non-avid). 
 
Serial measurements of target lesions are to be done with the same method of assessment (either 
CT or MRI) used to characterize each lesion reported at baseline.  The sum of diameters (longest 
for non-nodal lesions and coalesced masses of multiple lymph node, short axis for discrete nodal 
lesions) for all target soft tissue lesions will be calculated and reported as the sum of diameters. 
 
11.1.2 DEFINITION OF NON-TARGET SOFT TISSUE LESIONS: 
 
a. Leptomeningeal tumor and tumor in cerebrospinal fluid cytology. 
b. Lesions that are considered likely to be active tumor by the treating physician based on clinical 
correlation (for example, hepatic and pulmonary nodules) 
 


 
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11.1.3   The following lesions will NOT be followed to evaluate response either as target lesions or non-
target lesions, if they meet the criteria below AND the treating physician feels they are unlikely to 
represent active tumor (an exception for active tumor will be made for c. below): 
a. Measurable non-lymph node and coalesced masses of lymph node soft tissue lesions ≥ 10mm 
and discrete lymph nodes >15 mm that are not MIBG avid or FDG-PET avid (if tumor known to 
be MIBG non-avid) and if biopsied did not show neuroblastoma or ganglioneuroblastoma. 
b. Non-measurable non-lymph node soft tissue lesions < 10mm or non-measurable discrete 
lymph nodes (defined as lymph nodes >10 to <15mm on short axis). 
c. Intramedullary bone lesions will not be followed for CT/MRI response even though they are felt 
to represent active tumor since they will be evaluated with MIBG scans (or FDG-PET scans if 
MIBG non-avid), and since bone changes on CT/MRI are known to persist after resolution of 
active tumor.   
 
11.1.4  SOFT TISSUE RESPONSE CRITERIA: 
 
11.1.4.1 Complete Response (CR) 
All target and non-target soft tissue lesions have longest diameter < 10 mm. Discrete lymph nodes 
identified as target lesions must decrease to a short axis < 15 mm. Resolution of all MIBG uptake 
(FDG-PET uptake if tumor known to be MIBG non-avid). 
 
11.1.4.2 Partial Response (PR) 
At least a 30% decrease in sum of diameters of target soft tissue lesions (using longest diameter 
for non-nodal and coalesced masses of lymph node lesions and short axis for discrete lymph node 
lesions), taking as reference the measurement of target lesions performed at study enrollment. 
Non-target soft tissue lesions must be stable to smaller in size.  No new lesions.  MIBG (FDG-PET 
for MIBG non-avid tumors) uptake may still be present in lesions positive at enrollment. 
 
11.1.4.3 Progressive Disease (PD) 
At least a 20% increase in sum of diameters of target soft tissue lesions (using longest dimension 
for non-nodal and coalesced masses of lymph node lesions and short axis for discrete lymph node 
lesions) taking as reference the smallest sum of diameters while on study (this includes the baseline 
if that is the smallest while on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of 5 mm. A new target or non-target soft tissue lesion seen on 
CT/MRI without MIBG or PET uptake is considered PD, but may be biopsied to rule out PD.  An 
overall substantial worsening of non-target soft tissue lesions is also considered as a criteria for 
PD (guidance for substantial includes a 73% increase  in volume, or sufficient worsening of overall 
non-target disease such that the treating physician feels a change in therapy is indicated).     
 
New uptake of MIBG (or FDG-PET for MIBG non-avid tumors) at target and/or non-target soft tissue 
lesions which are stable in size, will also be considered PD.  Biopsy of such lesions can be done 
to rule out PD for the MIBG (or FDG-PET) response.   
 
11.1.4.4  Stable disease (SD)  
(Applies only to patients with target soft tissue lesions) 
Neither sufficient shrinkage in sum of diameters to qualify for PR nor does the patient meet any 
criteria for PD. No new soft tissue lesions.  Non-target soft tissue lesions must be stable to smaller 
in size. 
 
11.1.4.5 Stable disease-no target lesions (SD-NTL) (Applies to patients with non-target soft tissue 
lesions only) 
Non-target soft tissue lesions are still present; may be smaller or stable in size, and do not meet 
criteria for PD.  No new soft tissue lesions and no new uptake of MIBG (FDG-PET if tumor known 
to be MIBG non-avid) at existing non-target soft tissue lesions.  New lesions or lesions with new 
MIBG (FDG-PET) uptake may be biopsied to rule out PD. 
 
 


 
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80 
 
11.1.4.6  Not involved (NI):  No target or non-target soft tissue lesions 
 
11.1.4.7  Not evaluable (NE) 
CT/MRI scans and/or MIBG scans (FDG-PET if tumor known to be MIBG non-avid) are of 
inadequate quality as assessed by central reviewer, or scans are not repeated of all anatomic sites 
with tumor documented at entry. (Note that patients not evaluable at a given time point may be 
evaluable for response at later time points if all scans done with adequate quality at later time point) 
or if based on Study Management Committee / PI review it is deemed that there is insufficient data 
to grade response. 
 
11.1.4.8  Not done (ND) 
No CT/MRI scans were done at the given time point.  
 
 
11.2 
Bone Marrow Response Criteria  
 
Methodology:   
1. Routine morphology with immunohistochemistry will be used for all bone marrow evaluations.  
Immunohistochemistry (with antibodies that are used per local site’s standard procedure) is 
recommended for evaluating percentage of tumor but it is not required.  If immunohistochemistry 
is not done on the baseline bone marrow, then BM response should be graded based on routine 
morphology only at all time points. 
2. The percentage of tumor in the bone marrow at study entry (baseline) and all subsequent time 
points reported will use the highest tumor percentage noted among the four samples (bilateral 
aspirates and biopsies).   
3. The percentage of tumor in an aspirate will be calculated as the number of tumor cells divided by 
the number of total nucleated cells.   
4. The percentage of tumor in a biopsy will be calculated as the percent of tumor cells (including 
neuroblasts, mature and maturing ganglion cells) based on the bone marrow parenchymal surface 
area examined. Schwannian stroma only is considered negative. 
 
Bone marrow response will be graded using the bone marrow done at study entry as the reference 
point.  The baseline bone marrow must include an attempt to obtain bilateral aspirates and biopsies, 
and will be considered as evaluable if at least one biopsy sample is adequate to determine the 
percentage tumor involvement. At baseline, or any subsequent time point, the percentage tumor 
from the unilateral evaluable biopsy will be used to grade bone marrow response. Patients with ≤ 
5% tumor (including patients with tumor seen by immunohistochemistry only) on all samples of the 
bilateral bone marrow aspirate and biopsies at the baseline evaluation will be evaluable for bone 
marrow response, but defined separately from patients with > 5% at study entry as outlined below.  
 
Central review will be performed on bilateral biopsies only, unless BM tumor is seen only on 
aspirates.  If a patient meets protocol criteria for central review of BM response, morphology slides 
will be requested.     
 
11.2.1 Complete Response (CR) 
Greater than 5% tumor at study entry, with no tumor seen at one subsequent time point 
 
11.2.2 Complete Response Minimal Disease (CR-MD)  
 ≤ 5% tumor at study entry, with no tumor seen at one subsequent time point.  
 
11.2.3 Partial Response (PR) 
Greater than 20% tumor at study entry, with >0 to < 5% tumor at a subsequent time point.  
 
 
 
 


 
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11.2.4  Minimal Disease (MD) 
One of the following: 
A. No tumor at study entry, with >0 to <5% tumor at a subsequent time point 
B. >0 to <5% tumor at study entry, with >0 to <5% tumor at a subsequent time point 
C. >5-<20% tumor at study entry, with > 0 to <5% at a subsequent time point. 
 
11.2.5 Progressive Disease (PD) 
Patients with any amount of tumor in the bone marrow at study entry will be considered to have PD if one 
subsequent evaluation shows >20% tumor on any one bone marrow sample AND there is a greater than 2 
times increase in the amount of tumor compared to study entry. 
 
Patients with ≤ 5% tumor at study entry must increase to > 20% tumor to have PD; a patient with 30% tumor 
at study entry must increase to >60% tumor.  If patients have an increase in tumor amount which is less 
than the amount specified for PD, the response will be classified as SD.  
 
Patients with no tumor at study entry will be considered PD if ONE subsequent evaluation shows >5% 
tumor.   
 
Patients who are deemed to have bone marrow progression based on review of prior bone marrows by 
physician assessment and confirmed by the study management committee.   
 
 
11.2.6 Stable Disease (SD) 
Persistence of an amount of tumor in the bone marrow that does not meet criteria for progressive disease 
or PR or MD, and is > 5%. .  
 
11.2.7  Not Evaluable (NE) 
Patients for whom follow-up bone marrow evaluations do not include an attempt to obtain bilateral aspirates 
and biopsies and do not have at least one adequate biopsy sample, as assessed by local site’s pathology 
report for that time point or if based on Study Management Committee / PI review it is deemed that there is 
insufficient data to grade response.    
 
11.2.8  Not involved (NI) 
Patients with no evidence of neuroblastoma in the bone marrow at study entry, and bone marrow remains 
negative on subsequent evaluations.   
 
11.2.9  Not done (ND) 
Bone marrow evaluation not done at a given time point. 
 
 
11.2.10 EXAMPLES OF GRADING BONE MARROW RESPONSE: 
 
BASELINE 
TP 1 or any subsequent timepoint* 
BM Response 
0 
0 
NI 
0 
>0-<=5 
MD 
0 
>5 
PD 
>0-<=5 
0 
CR-MD 
>0-<=5 
>0-<=5 
MD 
>0-<=5 
>5-20 
SD 
>0-<=5 
>-20 
PD 


 
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82 
 
>5-20 
0 
CR 
>5-20 
>0-<=5 
MD 
>5-20 
>5-20 
SD 
>5-20 
>-20 and doubled compared to baseline 
PD 
>20 
0 
CR 
>20 
>0-<=5 
PR 
>20 
>5-20 
SD 
>20 
>20 but not doubled compared to baseline 
SD 
>20 
>-20 and doubled compared to baseline 
PD 
 
11.3. 
Bone Response Criteria Using MIBG Scans (for MIBG avid tumors) 
 
Bone response will be evaluated using MIBG scans for MIBG avid tumors.  FDG-PET scans (see 
section 11.4) may be substituted for MIBG scans to assess bone response only if the tumor is 
known to be MIBG non-avid.  Bone response will be graded using a modification of the Curie 
scoring scale (Eur J Cancer 1995;31A:256-261). The treating site will report the Bone Response 
using MIBG scoring done at local site, however the statistical endpoint of Bone Response will utilize 
the MIBG score from the central reviewer. 
 
MIBG scans will be scored for 9 anatomic regions for bone metastases only, MIBG uptake in soft 
tissue disease will NOT be included, since this uptake is utlized as part of evaluating Soft Tissue 
Response.  SPECT scans are strongly encouraged to be used for MIBG scoring, if SPECT is 
available at baseline and subsequent time points.  If SPECT scans are not available at all time 
points, then conjugate planar imaging alone should be used to score each region, and SPECT may 
be used only as an adjunct  to help delineate the location of the MIBG avid lesion. 
 
Table 7: Scoring of Bone Disease 
Regions 1 – 9 
Scoring 
MIBG uptake 
0 
No MIBG uptake 
1 
1 focal lesion 
2 
> 1 focal lesion 
3 
> 50% of a region 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
83 
 
 
The absolute extension score is obtained by adding the scores of all nine regions.  The presence of a 
MIBG avid lesion, and NOT the “intensity” of MIBG-avidity, determines the scoring within a particular region. 
 
REGIONS 1 – 9 / BONE DISEASE:  Cranio-facial disease is scored in Region 1, cervico-thoracic spine in 
Region 2, ribs / sternum / clavicles / scapula in Region 3, lumbar-sacral spine in Region 4, pelvis in Region 
5, humeri in Region 6, distal upper extremities in Region 7, femurs in Region 8, and distal lower extremities 
in Region 9 (see figure above). 
 
The relative score is calculated by dividing the absolute score of bone lesions at each time by the 
corresponding pre-treatment overall absolute score. The relative score of each patient is calculated at each 
response assessment and classified as below:  
a. Complete response:  all areas of bone uptake on MIBG scan completely resolved. 
b. Partial response: Relative score > 0.1 to < 0.5 
c. Stable disease: Relative score  0.5 to < 1.2  
d. Progressive disease:  New bone lesions on MIBG scan compared to most recent prior MIBG 
scan OR a relative score > 1.2.  Biopsy of new lesions may be done to rule out progressive 
disease. If biopsy is negative for tumor (neuroblastoma and/or ganglioneuroblastoma), patient 
will not meet definition of PD.   
e.   Not evaluable (NE):  MIBG scan of inadequate quality as assessed by central reviewer. 
f.  Not involved (NI): No MIBG avid bone lesions at study entry and subsequent response time 
points. 
g. Not done (ND): MIBG scan not done at a given response time point 
 
11.4 
Bone Response Criteria Using FDG-PET Scans (only for MIBG non-avid tumors) 
Patients known to be non-avid for MIBG should have FDG-PET scans performed for monitoring bone 
response. FDG-PET avid bone lesions will be scored by the presence or absence of a lesion with uptake that 
is two times above background.  For MIBG non-avid patients, uptake of FDG-PET in soft tissue lesions will 
be utilized in the Soft Tissue Response (see section 11.1). 
 
11.4.1 Complete response (CR) 
Resolution of all FDG-PET uptake in all FDG-PET avid bone lesions identified at baseline and no new FDG-
PET avid bone lesions. 
 


 
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11.4.2  Partial response (PR) 
Reduction of number of bone lesions by FDG-PET by ≥50%.  No new FDG-PET avid bone lesions. 
 
11.4.3  Stable disease (SD) 
Changes that do not meet the criteria for PR or PD.   
 
11.4.4  Progressive disease (PD) 
New bone lesions on FDG-PET scan.  Note: biopsy may be done to exclude causes of FDG-PET uptake 
other than tumor.  If biopsy of the new lesion is negative for tumor (neuroblastoma and/or 
ganglioneuroblastoma), patient will not meet definition of PD.   
 
11.4.5  Not evaluable (NE) 
FDG-PET scan of inadequate quality to evaluate bone response or if based on Study Management Committee 
/ PI review it is deemed that there is insufficient data to grade response. 
 
11.4.6  Not involved (NI) 
No FDG-PET uptake in bone sites that is two times above background.   
 
11.4.7  Not done (ND) 
FDG-PET scan not done at a given time point. 
 
On central review, FDG-PET avid bone lesions will be evaluated by both the MIBG scoring method outlined 
in Section 11.3 and also by enumeration of lesions to grade bone response. 
 
11.5 
Urine Catecholamines 
Due to variance with diet and concomitant medications, frequently missing dopamine levels, and lack of 
standardized methodology for this assay, urine catecholamines will not be utilized in grading response.  
Results of urine catecholamines will not be requested. 
 
 
 
11.6 
Definition of Overall Response 
 
The criteria below will be used to define the overall response for each patient, with consideration of all three 
individual response parameters: Soft tissue Response, Bone Response, and Bone Marrow Response. 
 
11.6.1 Complete Response (CR) 
Response of CR or NI for soft tissue and bone, soft tissue with bone marrow response of CR or CR-MD.   
 
11.6.2 Complete Response MD (CR-MD) 
Soft tissue and bone response are both NI, with BM response of CR-MD  
 
11.6.3 Partial Response (PR) includes any one of the following: 
a. Response of PR for soft tissue, bone response of PR, and BM response of CR, CR-MD, PR, MD, 
or NI. 
b. Response of CR, SD-NTL or NI for soft tissue, with bone response of PR, and BM response of CR, 
CR-MD, PR, MD, or NI.   
c. Soft tissue response of PR; with bone response of CR or NI; and BM response of CR, CR-MD, PR, 
MD, or NI. 
d. CR for soft tissue and bone response, with MD for bone marrow response  
 
11.6.4 Progressive Disease (PD) includes either one of the following: 
a. PD for at least one response parameter, including soft tissue, bone, and bone marrow response.  
If PD is found by one parameter, the other two parameters are not required to be evaluated to 
define an overall response of PD. 


 
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85 
 
b. Treating physician grades patient as progressive disease based on clinical assessment without 
radiographic or bone marrow evaluations. 
  
11.6.5 Stable disease (SD)   
Response of stable disease for at least one parameter, with response of SD, NI, MD, or SD-NTL for other 
parameters.   
 
11.6.6  Stable disease-Non-target lesions (SD-NTL) 
Response of SD-NTL for soft tissue, with response of NI for bone and bone marrow.  
 
11.6.7  Minor response (MR) 
Complete response, Complete-MD response, and/or partial response for one parameter (i.e. soft tissue, 
bone, or bone marrow), with response of stable disease for a second parameter and any response other than 
PD for third parameter. 
 
11.6.8  Minimal disease (MD) 
Soft tissue and bone marrow responses are both NI, with bone marrow response of MD. 
 
11.6.9 Not evaluable (NE) 
Response of Not evaluable for one or more response parameters including soft tissue, bone, or bone marrow 
for any parameter that had sites evaluable for response at study enrollment.  However, if one parameter is 
done and demonstrates PD this is defined as an overall response of PD.  The SMC will review all patients 
where one or more parameters were graded as not evaluable, and make the final determination if the overall 
response is evaluable at that time point.  In addition, response may be declared not evaluable if review by the 
Study Management Committee (SMC) that there is insufficient data to grade response.  The SMC may also 
declare response at a given time point evaluable if only one parameter is missing and was not involved at 
study enrollment. 
 
11.6.10 No progression  
Baseline status at enrollment was NI for soft tissue response, NI for bone marrow response, NI for bone 
response, and there has NOT been PD for any of the three parameters since on protocol therapy 
 
11.6.11 Not done (ND) 
Response not assessed at this time point.  If only one parameter is not done at a given response time point, 
the SMC and PI will review and make the final determination if the overall response is evaluable at that time 
point. 
 
11.6.12   Summary 
The overall response as assessed at any particular time point based on consideration of each of the three 
parameters as defined above is summarized in the following table: 
 
TABLE 8: RESPONSE CATEGORIZATION 
SOFT TISSUE RESPONSE 
BONE RESPONSE 
BONE MARROW RESPONSE 
OVERALL RESPONSE 
CR 
CR 
CR 
CR 
NI 
CR 
CR 
CR 
CR 
NI 
CR 
CR 
NI 
NI 
CR 
CR 
CR 
CR 
CR-MD 
CR 
NI 
CR 
CR-MD 
CR 
CR 
NI 
CR-MD 
CR 
CR 
CR 
NI 
CR 
NI 
CR 
NI 
CR 
CR 
NI 
NI 
CR 
NI 
NI 
CR-MD 
CR-MD 
PR 
CR 
CR 
PR 
SD-NTL 
CR 
CR 
PR 
CR 
PR 
CR 
PR 
SD-NTL 
PR 
CR 
PR 


 
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86 
 
NI 
PR 
CR 
PR 
PR 
NI 
CR 
PR 
SD-NTL 
NI 
CR 
PR 
PR 
CR 
CR-MD 
PR 
SD-NTL 
CR 
CR-MD 
PR 
CR 
PR 
CR-MD 
PR 
PR 
PR 
CR-MD 
PR 
SD-NTL 
PR 
CR-MD 
PR 
NI 
PR 
CR-MD 
PR 
PR 
NI 
CR-MD 
PR 
SD-NTL 
NI 
CR-MD 
PR 
CR 
CR 
PR 
PR 
PR 
CR 
PR 
PR 
SD-NTL 
CR 
PR 
PR 
PR 
PR 
CR 
PR 
NI 
CR 
PR 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
PR 
PR 
SD-NTL 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
CR 
NI 
PR 
PR 
PR 
NI 
PR 
PR 
SD-NTL 
NI 
PR 
PR 
NI 
NI 
PR 
PR 
CR 
CR 
MD 
PR 
PR 
CR 
MD 
PR 
SD-NTL 
CR 
MD 
PR 
NI 
CR 
MD 
PR 
CR 
PR 
MD 
PR 
PR 
PR 
MD 
PR 
SD-NTL 
PR 
MD 
PR 
NI 
PR 
MD 
PR 
CR 
NI 
MD 
PR 
PR 
NI 
MD 
PR 
PR 
CR 
NI 
PR 
PR 
PR 
NI 
PR 
SD-NTL 
CR 
NI 
PR 
CR 
PR 
NI 
PR 
SD-NTL 
PR 
NI 
PR 
NI 
PR 
NI 
PR 
PR 
NI 
NI 
PR 
SD 
CR 
CR 
MINOR 
SD 
PR 
CR 
MINOR 
CR 
SD 
CR 
MINOR 
PR 
SD 
CR 
MINOR 
SD 
SD 
CR 
MINOR 
SD-NTL 
SD 
CR 
MINOR 
NI 
SD 
CR 
MINOR 
SD 
NI 
CR 
MINOR 
SD 
CR 
CR-MD 
MINOR 
SD 
PR 
CR-MD 
MINOR 
CR 
SD 
CR-MD 
MINOR 
PR 
SD 
CR-MD 
MINOR 
SD 
SD 
CR-MD 
MINOR 
SD-NTL 
SD 
CR-MD 
MINOR 
NI 
SD 
CR-MD 
MINOR 
SD 
NI 
CR-MD 
MINOR 
SD 
CR 
PR 
MINOR 
SD 
PR 
PR 
MINOR 
CR 
SD 
PR 
MINOR 
PR 
SD 
PR 
MINOR 
SD 
SD 
PR 
MINOR 
SD-NTL 
SD 
PR 
MINOR 
NI 
SD 
PR 
MINOR 
SD 
NI 
PR 
MINOR 
SD 
CR 
MD 
MINOR 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
87 
 
SD 
PR 
MD 
MINOR 
CR 
SD 
MD 
MINOR 
PR 
SD 
MD 
MINOR 
CR 
CR 
SD 
MINOR 
PR 
CR 
SD 
MINOR 
SD 
CR 
SD 
MINOR 
SD-NTL 
CR 
SD 
MINOR 
NI 
CR 
SD 
MINOR 
CR 
PR 
SD 
MINOR 
PR 
PR 
SD 
MINOR 
SD 
PR 
SD 
MINOR 
SD-NTL 
PR 
SD 
MINOR 
NI 
PR 
SD 
MINOR 
CR 
SD 
SD 
MINOR 
PR 
SD 
SD 
MINOR 
CR 
NI 
SD 
MINOR 
PR 
NI 
SD 
MINOR 
SD 
CR 
NI 
MINOR 
SD 
PR 
NI 
MINOR 
CR 
SD 
NI 
MINOR 
PR 
SD 
NI 
MINOR 
NI 
NI 
MD 
MD 
SD 
SD 
MD 
SD 
SD-NTL 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
SD-NTL 
NI 
MD 
MD 
SD 
SD 
SD 
SD 
SD-NTL 
SD 
SD 
SD 
NI 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
SD-NTL 
NI 
SD 
SD 
NI 
NI 
SD 
SD 
SD 
SD 
NI 
SD 
SD-NTL 
SD 
NI 
SD 
NI 
SD 
NI 
SD 
SD 
NI 
NI 
SD 
SD-NTL 
NI 
NI 
SD-NTL 
NI 
NI 
NI 
NO PROGRESSION 
PD 
ANY 
ANY 
PD 
ANY 
PD 
ANY 
PD 
ANY 
ANY 
PD 
PD 
NOT EVALUABLE 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT EVALUABLE* 
ANY EXCEPT PD 
NOT EVALUABLE 
ANY EXCEPT PD 
NOT EVALUABLE* 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT EVALUABLE 
NOT EVALUABLE* 
NOT EVALUABLE 
NOT EVALUABLE 
NOT EVALUABLE 
NOT EVALUABLE* 
NOT DONE 
NOT DONE 
NOT DONE 
NOT DONE* 
NOT DONE (and required at 
this time point) 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT DONE* 
ANY EXCEPT PD 
NOT DONE (and 
required at this time 
point)  
ANY EXCEPT PD 
NOT DONE* 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT DONE (and required at this 
time point) 
NOT DONE* 
** The Study Management Committee will review patients with overall response of Not Evaluable and/or 
Not Done to make the final determination of overall response.   
 
 
 


 
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12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
12.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Adverse events are reported in a routine manner at scheduled times 
during a trial. (Please follow directions for routine reporting provided in the data collection packet 
for this protocol). Additionally, certain adverse events must be reported in an expedited manner to 
allow for timelier monitoring of patient safety and care. The following sections provide information 
about expedited reporting through the use of a written IND safety report (MedWatch) to the Food 
and Drug Administration (FDA). 
 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.  A copy of the CTCAEv5 can be downloaded from the CTEP home 
page (http://ctep.cancer.gov).   
 
12.2 
Definitions 
 
Adverse Event (AE): An adverse event means any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. 
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the adverse event. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse event 
or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not available, is not consistent with the risk information described in the general 
investigational plan. 
 
Serious Adverse Events (SAE) or Serious Suspected Adverse Reactions: An adverse event 
or suspected adverse reaction is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
 
Table 9: Severe Adverse Events or Reactions 
Death of Patient 
An event that results in the death of a patient. 
Life-Threatening 
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal 
if it had occurred in a more severe form. 
Hospitalization 
An event that results in an admission to the hospital for any length 
of time.  This does not include an emergency room visit or 
admission to an outpatient facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and 
prolongs the patient’s hospital stay. 
Congenital Anomaly 
An anomaly detected at or after birth or any anomaly that result in 
fetal loss. 


 
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Persistent or Significant 
Disability/ Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study patient.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle). 
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome 
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the patient and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent 
or significant disability/incapacity). Examples of such events 
include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
12.3 
Expedited Serious Adverse Event Reporting to NANT Operations 
 
For any serious adverse event, both expected and unexpected: 
 
o 
Contact the Study Chairperson and the NANT Operations Center to alert them to the 
existence of the serious adverse event within 24 hours of learning of the event. 
o 
Within 48 hours of learning of the event, complete the NANT SAE form online through 
Medidata Rave.  If access to Medidata Rave is unavailable for some reason, use the paper 
SAE form found on the NANT website (see NANT website (www.nant.org) and email to 
NANTstaff@chla.usc.edu.  
 
o 
Follow-up information should be submitted online in an updated report through Medidata 
Rave as soon as relevant information is available. 
 
Copies of all serious adverse event reports will be kept on file in the NANT Operations Center. All 
NANT institutions are to file SAE reports with their Institutional Review Boards according to local 
institutional policy.   
 
12.4 
Expedited Adverse Event Reporting to the FDA 
Per CFR 312.32 (c), the sponsor of the IND, Araz Marachelian, MD, must notify the FDA and all 
participating investigators in a written IND safety report of any adverse experience associated with 
use of the drug that is both serious and unexpected.  Each written notification shall be made as 
soon as possible, and in no event later than 15 calendar days after the sponsor’s initial receipt of 
the information.  Each written notification may be submitted on FDA Form 3500A (MedWatch) or 
in a narrative format and must bear prominent identification of its contents, i.e., “IND Safety Report”.  
Follow-up information to a safety report should be submitted as soon as the relevant information is 
available. 
 
The sponsor must also notify FDA by telephone or by facsimile transmission of any unexpected 
fatal or life-threatening experience associated with use of the drug in the clinical studies 
conducted under the IND as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. 
 


 
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Each telephone call or facsimile transmission to the FDA shall be transmitted to the FDA division that 
has responsibility for review of the IND; a specific contact person is assigned to each IND at the time 
the application is filed, and this will be included in the FDA’s correspondence acknowledging receipt 
of the IND application.   
 
12.5 
NANT Operations Center Role in Expedited Adverse Event Reporting to the FDA and  
Participating Sites   
For purposes of this protocol, the MedWatch Report Form (FDA 3500A) will be submitted to the FDA 
by NANT on behalf of the IND sponsor, Araz Marachelian, MD.  These forms will be submitted to the 
appropriate FDA division and will serve as the written IND safety report.  The NANT Operations 
Center will file all expedited adverse event reports as well as other adverse events with the FDA and 
other relevant authorities or investigators.  The IND sponsor, Araz Marachelian, MD, has also 
delegated to the NANT Operations Center the telephone/facsimile FDA notification responsibilities 
for unexpected fatal or life-threatening experiences.  All IND submissions will be maintained in a 
master file at the NANT Operations Center. 
 
For Adverse Events associated with the use of the drug that are both Serious and Unexpected: 
• 
The MedWatch form will be drafted by the NANT Operations Center based on the SAE form within 
10 days of the adverse event and reviewed with PI at treating site and the study chair.  Final 
MedWatch form will be submitted to FDA by NANT Operations Center.  Electronic version of 
MedWatch form is 
available from NANT Operations Center 
or MedWatch 
website 
www.fda.gov/medwatch. NANT will forward the completed report to the FDA and other relevant 
authorities or investigators on behalf of the IND Sponsor, Araz Marachelian, MD.  
• 
Follow-up information should be submitted as soon as relevant information is available. 
 
For Adverse Events associated with the use of the drug that are Unexpected or Life Threatening: 
• 
Notify the NANT Operations Center (who will notify the FDA and other relevant authorities and 
investigators) by telephone or fax as soon as possible but no later than 7 calendar days from the 
occurrence of the event. 
 
FDA PHONE: 
1-800-332-1088 
FDA FAX: 
1-800-332-0178 
 
• 
The MedWatch form will be drafted by the NANT Operations Center based on the SAE form within 
10 days of the adverse event and reviewed with PI at treating site and the study chair.  Final Medwatch 
form will be submitted to FDA and other relevant authorities or investigators by NANT Operations 
Center on behalf of the IND Sponsor, Araz Marachelian, MD.   
• 
Follow-up information should be submitted as soon as relevant information is available. 
 
A cover letter to accompany the MedWatch report will be prepared by the NANT Operations Center in 
collaboration with the IND sponsor, Araz Marachelian, MD. The cover letter will be submitted with MedWatch 
report to the FDA and other NANT institutions and relevant authorities.  Contents will include: 
 
1. An assessment of the adverse event and its significance/relevance to the study. And the impact on 
the risk/benefit ratio of the study. 
2. A statement as to whether this adverse event has been reported previously, and if so, whether the 
frequency is considered unusually high. 
3. A statement as to whether the protocol and/or informed consent should reflect changes in the 
potential risks involved. 
 
Copies of all adverse event reports will be kept on file in the NANT Operations Center.  All NANT institutions 
are to file AE reports with their Institutional Review Boards according to local institutional policy.  
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
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12.6  
Adverse Event Reporting Requirements for United Therapeutics Corporation 
 
NANT will notify United Therapeutics Corporation (UT) of all serious adverse events, both expected 
and unexpected, and copy all forms and related correspondence to UT within seven (7) days after 
initial notification from NANT site. 
 
12.7  
Adverse Event Reporting Requirements for Jubilant Radiopharma  
 
NANT will notify Jubilant Radiopharma of all serious adverse events, both expected and 
unexpected, and copy all forms and related correspondence to Jubilant Radiopharma within twenty 
four (24) hours after initial notification from NANT site. 
 
 
12.8 
Reporting Secondary AML/MDS 
Within two weeks of an AML/MDS diagnosis or other secondary malignancy following treatment for 
cancer, submit the following to the NANT Operations Center: 
 
o 
A completed NANT SAE Form 
o 
A copy of the pathology report confirming the AML/MDS or other malignancy 
o 
A copy of the cytogenetics report (if applicable) 
 
The NANT Operations Center will submit the form and accompanying reports to the FDA via 
MedWatch and to Araz Marachelian, MD (IND Sponsor). All NANT institutions are to file the 
secondary malignancy reports with their Institutional Review Boards according to local institutional 
policy. 
 
12.9   
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and must permanently discontinue study drug(s).  All 
pregnancies and suspected pregnancies will be reported to by the NANT Operations Office (see 
Section 3.1.1 for contact information) immediately.  If a female partner of a male patient becomes 
pregnant during the male patient’s participation in this study, this must be reported to by the NANT 
Operations Office immediately.  
 


 
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13.0 
RECORDS AND REPORTING 
See separate Data Forms Packet which includes the data submission schedule in the member section on 
the NANT web site (www.NANT.org). 
 
The following are required to be submitted for all patients entered: 
 
1. Study case report forms, bone marrow reports (including aspirate and biopsy reports), , and 
radiology reports (CT/MRI/MIBG/PET scans). Study case report form data is collected and 
accessed remotely through Medidata Rave. Disease response reports detail reports (CT/MRI, 
MIBG/PET, Bone marrow) are sent by email as electronic files to NANTCRF@chla.usc.edu at the 
end of each course of therapy or as delineated in the Required Observations section 7.0 of this 
document.   
2. For all patients on study, CT/MRI and MIBG/PET scans done as baseline tumor evaluation at study 
entry and for determination of over overall response will be submitted for central review.   
3. For all patients who report an overall response of CR, PR, minor response, or who have SD for at 
least 4 courses will submit all CT/MRI scans, MIBG scans, PET scans, and bone marrow aspirate 
and biopsy slides done, during therapy and at end of protocol therapy for central review upon 
request by NANT Operations Center. Additional scans may also be requested by the NANT 
Operations Center to clarify response.   
4. Radiology scans are submitted into NANT PACS electronic repository, which is managed by the 
ICL (Imaging Core Lab) at Children’s Hospital Los Angeles.  The Imaging CoreGrid DICOM 
Dropbox software is functional at all NANT sites and is used for all NANT clinical trials for central 
review of tumor response. (See NANT SOP regarding Central Review of Response Procedures for 
details).    
5. For all patients, slides from bone marrow aspirates done at the time of study entry, during therapy 
and at end of therapy, are required to be submitted upon request to NANT Operations Center.   
 


 
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14.0 
REFERENCES 
 
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Survival among Children and Adolescents: United States SEER Program 1975-1995, National 
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2. 
Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat mortality
 
database: total U.S. (1969-2006). Bethesda, MD: National Cancer Institute. 
3. 
Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive 
chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N 
Engl J Med 1999; 341:1165-1173. 
4. 
Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk 
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5. 
Yanik GA, Parisi MT, Shulkin BL, et al. Semiquantitative mIBG scoring as a prognostic indicator in 
patients with stage 4 neuroblastoma: a report from the Children's Oncology Group. J Nucl Med 
2013; 54:541-548.  
6. 
London WB, Castel V, Monclair T, et al. Clinical and biologic features predictive of survival after 
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7. 
Glowniak JV, Kilty JE, Amara SG, Hoffman BJ, Turner FE. Evaluation of metaiodobenzylguanidine 
uptake by the norepinephrine, dopamine and serotonin transporters. J Nucl Med 1993; 34:1140-
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8. 
DuBois SG, Geier E, Batra V, et al. Evaluation of norepinephrine transporter expression and 
metaiodobenzylguanidine avidity in neuroblastoma: a report from the children's oncology group. Int 
J Mol Imaging 2012; 2012:250834. 
9. 
Treuner J, Feine U, Niethammer D, et al. Scintigraphic imaging of neuroblastoma with [131-
I]iodobenzylguanidine. Lancet 1984;1:333–334. 
10. 
Garaventa A, Bellagamba O, Lo Piccolo MS, et al. 131I-metaiodobenzylguanidine (131I-MIBG) 
therapy for residual neuroblastoma: a mono-institutional experience with 43 patients. Br J Cancer 
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16. 
Matthay 
KK, 
DeSantes 
K, 
Hasegawa 
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targets more efficiently than m1 cells in vitro. J Immunol 2009;182:4415-4422. 
 
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in children with high-risk neuroblastoma. Cancer Chemother Pharmacol 2014;74(5):1047-55.  
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Marachelian A, Villablanca JG, Liu CW, et al. Expression of five neuroblastoma genes in bone 
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Borriello L, Seeger RC, Asgharzadeh S, et al. More than the genes, the tumor microenvironment 
in neuroblastoma. Cancer Letters 2015;380:304-314. 
 
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de Ruijter AJ, Kemp S, Kramer G, et al. The novel histone deacetylase inhibitor BL1521 inhibits 
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75. 
 Keshelava N, Houghton PJ, Morton CL, et al. Initial testing (stage 1) of vorinostat (SAHA) by the 
pediatric preclinical testing program. Pediatr Blood Cancer 2009;53:505–508. 
 
76.  
More SS, Itsara M, Yang X, Geier EG, Tadano MK, Seo Y, et al. Vorinostat increases expression 
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Cancer Res 2011;17:2339–2349. 
 
77.  
Mueller S, Yang X, Sottero TL, Gragg A, Prasad G, Polley MY, et al. Cooperation of the HDAC 
inhibitor vorinostat and radiation in metastatic neuroblastoma: efficacy and underlying 
mechanisms. Cancer Lett 2011;306:223–229. 
 
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van den Bijgaart RJE, Kroesen M, Wassink M, et al. Combined sialic acid and histone deacetylase 
(hdac) inhibitor treatment up-regulates the neuroblastoma antigen GD2. J Biol Chem 
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DuBois SG, Granger M, Groshen S, et al. Randomized phase II trial of MIBG vs. 
MIBG/vincristine/irinotecan vs. MIBG/vorinostat for relapsed/refractory neuroblastoma:  A report 
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consortium. 
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Pinto N, DuBois SG, Marachelian A, et al. Phase I study of vorinostat in combination with 
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Neuroblastoma Therapy (NANT) trial. Pediatr Blood Cancer 2018;65(7):e27023. 
 
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rolling six design. J Clin Oncol 2008;26:190-195. 


 
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15.0 
SAMPLE INFORMED CONSENT 
 
There are separate sample informed consent documents for Part A and B. 
 
15.1 
Part A 
 
NANT 
2017-01: 
 
A 
PHASE 
I 
STUDY 
OF 
131I-MIBG 
WITH 
DINUTUXIMAB 
FOR 
RELAPSED/REFRACTORY NEUROBLASTOMA 
 
FOR PATIENTS ON PART A 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
The word “you” used throughout this document refers to you or your child. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find the highest safe dose of 131I-MIBG that can be given with dinutuximab to children with 
refractory or recurrent neuroblastoma without causing severe side effects 
• 
To find out what side effects there are from giving 131I-MIBG and dinutuximab together on this 
schedule at different dose levels 
• 
To see if your tumor gets smaller after treatment with 131I-MIBG and dinutuximab 
• 
To learn what happens to your immune system and other proteins that cause inflammation when 
giving different doses of 131I-MIBG with dinutuximab. 
• 
To see what effect giving different doses of 131I-MIBG has on your body in making an antibody to 
the dinutuximab 
• 
To see what effect treatment with 131I-MIBG in combination with dinutuximab has on the cells of 
your immune system that surround and invade your tumor 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The research is being done because: 
Currently there is no known effective treatment for neuroblastoma that has returned or that has not 
responded to treatment.  
 
This study will use a chemical agent called metaiodobenzylguanidine (MIBG) together with an intravenous 
(IV) drug called dinutuximab. MIBG is taken up by neuroblastoma tumor cells. MIBG can be combined with 
radioactive iodine (131I) in the laboratory to form the radioactive compound 131I-MIBG. 131I-MIBG delivers 
radiation to the neuroblastoma cancer cells and causes them to die. 131I-MIBG lowers the number of blood 
forming cells (called stem cells) in the bone marrow when it is given at higher doses as in this study. 
Because of this, all patients will get back their own stem cells to help the bone marrow recover from this 
therapy.   
 


 
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Dinutuximab works differently than most standard chemotherapy drugs. Dinutuximab is a monoclonal 
antibody. Monoclonal antibodies are proteins made in the lab, designed to attach to specific targets on 
cancer cells. When dinutuximab attaches to neuroblastoma cells, the body’s immune system is stimulated 
to attack and kill the neuroblastoma cells. Dinutuximab represents a new kind of cancer therapy called 
immunotherapy which, unlike chemotherapy and radiation, targets the cancer cells without destroying 
nearby healthy cells. 
 
Laboratory studies have shown greater anti-cancer effects when radiation is given before an 
immunotherapy treatment.  Some clinical responses have been seen in adults when radiation has been 
combined with different types of immunotherapy in treating their cancers. 
 
Giving dinutuximab together with 131I-MIBG may help the 131I-MIBG kill more neuroblastoma cells. This is 
the first study to test giving dinutuximab together with 131I-MIBG.   We want to find out if giving increasing 
doses of 131I-MIBG along with dinutuximab can be tolerated.  We also want to see how effective this drug 
combination is against relapsed or refractory neuroblastoma.  
 
Dinutuximab is a drug that has been approved by the Food and Drug Administration (FDA) for treating 
newly diagnosed patients with neuroblastoma. The use of dinutuximab in combination with 131I-MIBG for 
the treatment of relapsed or refractory neuroblastoma is considered experimental. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be a maximum of 30 patients enrolling to this part of the study. Between 9 and 24 people will 
take part in the dose escalation part of the study. When you join the study, you will be assigned a certain 
131I-MIBG and dinutuximab dose. This study will test up to three 131I-MIBG doses in groups of 3-6 patients.  
The starting 131I-MIBG dose for the first group of patients is about 2/3 of the standard dose when 131I-MIBG 
is given alone as treatment.  The dose of dinutuximab is the standard dose used for patients with 
neuroblastoma.  The dinutuximab dose will not be increased during the study.  If the first dose level is 
tolerated without serious side effects, then the 131I-MIBG dose will be increased (“dose escalation”) in 
groups of 3-6 patients until the third dose level or until serious side effects are seen.  At that point, 
investigators will have found the highest dose of 131I-MIBG that can be given in combination with 
dinutuximab without bad side effects (called maximum tolerated dose).  This part of the trial is called the 
dose escalation phase. 
 
  
Once the maximum tolerated dose is determined, a group of 6 more patients will be enrolled and treated at 
this dose of 131I-MIBG and dinutuximab, known as the dose expansion part of the study.  The purpose of 
the dose expansion part of the study is to gather more information about side effects seen in patients treated 
at the maximum tolerated dose of 131I-MIBG in combination with dinutuximab. The dose expansion cohort 
will not enroll patients until the dose escalation part of the study is completed and the highest dose of 131I-
MIBG that can be safely given in combination with dinutuximab without serious side effects is found. 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Before you can get treatment on this study, blood stem cells must be available that meet the study 
requirements. We will check your child’s previously stored stem cells to make sure that they can be used 
for the stem cell infusion. 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These tests will also be done at various times throughout the study and at the end of the 
study.  The purpose of these tests is to see how well the treatment works and to measure the status of your 
neuroblastoma.   If you have had some of them recently, they may not need to be repeated. This will be up 
to your doctor. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
100 
 
 
A medical history & physical exam 
Bone marrow tests2 to check your tumor 
Blood tests 
Various scans3 to check your tumor 
Pregnancy test (urine or blood)1 
Echocardiogram to check the heart function 
Urine tests 
 
 
1If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins.  You will 
be informed of a positive pregnancy test. Reporting of a positive pregnancy test to your parent or guardian 
will depend on local and/or state regulations.  All men and women who could have children must either 
agree to practice abstinence from heterosexual intercourse or use two effective methods of birth control for 
as long as they participate in this study.  
 
2Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
3Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG scans. We will recommend scans specific for your case and we 
will answer your questions about these scans. 
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 131I-
MIBG will be given on Day 1 and dinutuximab will be given on Days 8-11 and Days 29-32 of each treatment 
course.  The growth factor GM-CSF is given on the same days as the dinutuximab and continues after the 
dinutuximab has finished for a total of 10 doses (days 8-17 and days 29-38).  All patients will be given an 
infusion of their stem cells on Day 15 of each course. Each course is 57 days long and you may receive up 
to two treatment courses of 131I-MIBG and dinutuximab as long as you are benefiting from the treatment 
and meet the criteria to continue the treatment safely. 
 
DAY 
1 
2-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18-28 
131I-MIBG (M) 
M 
GM-CSF (G) 
 
 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
DINUTUXIMAB 
(D) 
 
D 
D 
D 
D 
Stem Cell 
Infusion (HSC) 
 
 
 
HSC 
+/- 2d 
 
 
 
 
 
 
 
 
DAY 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
43-57 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
101 
 
GM-CSF (G) 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
 
DINUTUXIMAB (D) 
D 
D 
D 
D 
 
 
 
  
Disease Evaluation 
(Eval) 
 
 
 
Eval 
 
Treatment with 131I-MIBG 
Patients will be assigned a certain dose level of 131I-MIBG at time of study registration.  If you are enrolled 
early in this study you may get a lower dose than those who are enrolled later.  Whatever 131I-MIBG dose 
you start at, this dose will not be increased during the study.   Dosing is done this way because we do not 
yet know the best dose to use in children when it is used together with dinutuximab.   
 
Treatment with 131I-MIBG will be done at a hospital that is set up to take care of patients that are treated 
with radioactive substances.  This means that you may need to travel some distance to another hospital to 
get this treatment.  Your health care team will talk with you and help you plan for the trip to get this treatment. 
 
Patients will be admitted to an 131I-MIBG treatment center one day before starting 131I-MIBG therapy. On 
the following day (Day 1), 131I-MIBG is given into a temporary IV or in your central venous catheter over 90-
120 minutes.  IV fluids for hydration and other medicines will be given through your central venous catheter.  
 
Patients who get 131I-MIBG are considered to be “hot” or radioactive and you will stay in the special room 
until your radiation measurement reaches a safe level, usually 3 - 5 days, since you could expose others 
to radiation.  Special care precautions include: 
 
• 
A single room in a bed surrounded by a lead shield to keep family and the staff who take care of you 
from being exposed to radiation from the 131I-MIBG treatment. This usually takes about 5 days. 
 
• 
The length of time family can visit inside the room in front of the protective lead shield that is around 
your bed will depend on how much radiation is measured in the room each day by the radiation 
specialist. Usually family can visit for a total of 30-45 minutes on the first day and longer on the days 
after that because there will be less radiation measured in the room each day. 
 
• 
Family may visit anytime outside of the room or behind a lead shield. You will be able to see who is 
visiting over this shield.  
 
• 
No one will be able to spend the night in this special room with you during this time. 
 
Your urine will be radioactive after treatment with 131I-MIBG. A urinary catheter will be inserted to drain the 
radioactive urine from your body. A urinary catheter is a soft tube that is inserted into your urethra (the hole 
where urine comes out of your body) and up into the bladder (the place where urine waits inside your body 
until you go to the bathroom). The catheter is strongly recommended for all patients but is required for 
patients < 12 years of age. If the catheter comes out for any reason, it will most likely have to be replaced. 
The catheter will be removed at the time of discharge (3-5 days).  
 
You will also take a medicine by mouth [potassium iodide (SSKI)] to prevent thyroid damage from the 
radioactive iodine contained in the 131I-MIBG compound. The medicine will be taken together by mouth 
beginning before treatment and continuing for a total of 6 weeks. This will be taken every 4 hours for the 
first 7 days after the MIBG infusion and then daily for the remainder of the 6 weeks. 
 
 
Treatment with Dinutuximab and GM-CSF 
All patients on this study will receive the same dose of dinutuximab. It will be administered IV over 10-20 
hours, once daily for four consecutive days in the hospital. Patients will also receive GM-CSF beginning 


 
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102 
 
with dinutuximab and continuing for a total of 10 doses. GM-CSF is a substance that is similar to one made 
by the body. Under normal circumstances, the body makes small amounts of GM-CSF that help it to 
produce normal infection fighting white blood cells. It is now possible to make GM-CSF outside of the body 
and give humans much higher doses than their own bodies make. There is some evidence that, in the lab 
and in animals, GM-CSF increases the anti-cancer effect of monoclonal antibodies like dinutuximab. GM-
CSF is administered under the skin [subcutaneously (SQ)] except in special circumstances when it can be 
given IV 
 
Stem Cell Infusion 
All patients on this study will receive an autologous stem cell infusion on Day 15.  You will receive your 
stored stem cells back by vein two weeks after the 131I-MIBG infusion. This may be done as a day visit to 
the hospital or may require a brief (one night) stay in the hospital.  The stem cells can be given at any NANT 
hospital.  
 
If you develop a low white blood count, you may receive GM-CSF (Leukine/sargramostim), G-CSF 
(Neupogen), or pegfilgrastim (Neulasta) in order to help your white blood cells recover faster after treatment, 
though it is strongly recommended that GM-CSF be the only growth factor used. GM-CSF, G-CSF, or 
pegfilgrastim will be given under the skin (SQ). You may also get a dose (or doses) of one of these 
medicines after you have received your stem cells, even if your blood counts are not low yet.  
 
You can receive this therapy two times as part of this study, as long as: 
• 
your tumor is not getting worse; 
• 
you have not had any other anti-cancer treatments since the first course; 
• 
you have enough stem cells to get a second course; and 
• 
you have not had any bad side effects from the first course. 
 
The second course cannot start earlier than 8 weeks from the date of the first 131I-MIBG infusion.  The 
following tests and procedures will be done during the study.  They are part of regular cancer care. 
 
A medical history & physical exam 
Bone marrow tests to check your tumor 
Blood tests 
Various scans to check your tumor 
Pregnancy test (urine or blood) 
Echocardiogram to check the heart function 
Urine tests 
 
 
NANT Biology Study (NANT 2004-05) 
You will also be expected to join a companion NANT biology study to collect blood, bone marrow and tumor 
tissue (if available) and reports from radiology scans from patients with neuroblastoma. The biology study 
also provides a place (called NANT biorepository) where any leftover samples of tumor tissue or bone 
marrow and blood collected on this study could be transferred and stored. While you will be asked to join 
the Biology Study (NANT 2004-05), the decision to store/bank any leftover samples is optional and will not 
affect your ability to participate in this treatment study with 131I-MIBG and dinutuximab.  Your doctor will talk 
with you in detail about the NANT biology study and have you sign a separate consent form. 
 
When You Have Finished Treatment with 131I-MIBG and Dinutuximab  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ function, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
 
Medical Tests after the Study: 
 
Physical exam 
Bone marrow tests & various scans to check your tumor1 


 
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103 
 
Blood tests 
 
1Bone marrow tests and various scans (CT/MRI, MIBG) are done for checking the response of your tumor 
to treatment.  These tests will be done at the end of a course and at certain times following treatment to 
monitor your tumor status. 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this consent. 
 
 
Additional Tests in this Study 
We would like to do some extra tests called correlative biology studies.  These tests will help us learn more 
about treatment with 131I-MIBG and dinutuximab and may help children and adolescents who receive this drug 
in the future.  The information learned would not change the way you are treated and the results of these tests 
will not be given to you.  Some of these tests are required but others are optional meaning you can decide 
whether you want to do them or not. All of these tests (required and optional) will be done only during the first 
course. 
 
Evaluation of Immune Function – Required  
During this study blood samples will be collected to look at changes in your immune function before and after 
treatment with 131I-MIBG and dinutuximab. We will look at changes in the number and function of certain cells 
of the immune system, as well as measure levels of certain proteins that cause inflammation in the body. We 
will collect 13 mL (~2.5 teaspoons) of blood with each sample at 5 different time points during course 1 ONLY. 
The total amount of blood drawn for testing will be 65 mL (13 teaspoons). If you have a central line (such as 
a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein in 
your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to Children’s 
Healthcare of Atlanta for testing. 
 
Testing for Antibodies Against Dinutuximab – Required 
During this study blood samples will be collected to look for antibodies that attach to dinutuximab, and also to 
look at how many of these antibodies make it so the dinutuximab can’t attack your neuroblastoma. The amount 
of blood required for this test is < 1 mL (less than ¼ teaspoon) and it will be taken from the amount collected 
as part of the immune functions studies at 3 of the 5 time points, and two additional time points. We will collect 
8 mL (~1.5 teaspoon) of blood at each of these two additional time points, both to test for the antibodies 
against dinutuximab and to save for future testing of changes in your immune function. 
 
Other Biology Research Tests in this Study - Optional 
You will be asked if you want to participate in other optional research tests.  You can decide not to let the 
doctors do these tests and still be able to be treated as part of this study. Your care will be unaffected even if 
you say “no” to participating in any or all of these optional research studies. There are checkboxes at the end 
of this form to mark whether you are willing to participate in these voluntary studies. The results of these 
research tests will not be shared with you or become part of your medical record.  These results would also 
not be used to make decisions about your care while enrolled on this study.     
 
• 
Using extra blood to look for proteins and genetic changes in your cells. 
Part of the research goal for this study is to look for the presence of and changes in certain proteins 
and genes in the blood that might affect your response to treatment. We would like to collect this 
blood before, during, and after treatment on this study.  
 
o 
For the tests looking at the genes in your cells (DNA), no additional blood draw is required. 
The sample would be obtained from the blood that is collected for the testing of the cells of 
your immune system at the 5 time points described above.  
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
104 
 
o 
For the tests looking at proteins or at certain genes that affect your body’s immune response, 
an additional 2.5 mL (1/2 teaspoon) of blood will be collected at 8 different time points during 
course 1. The total amount of blood drawn for this testing will be 20 mL (4 teaspoons). If 
you have a central line (such as a port or a Broviac) these samples can be drawn through 
that line or through a small tube placed in a vein in your hand or arm.  This amount of blood 
is considered safe to donate. Samples will be sent to Children’s Healthcare of Atlanta for 
testing.  
 
• 
Evaluate tumor tissue for immune system cells that surround and invade your tumor. 
Part of the research goal for this study is to learn more about the cells of your immune system that 
surround and invade your tumor, and learn how these cells change after treatment with 131I-MIBG 
and dinutuximab. We would also like to perform genetic studies on a small amount of your blood in 
addition to the tumor tissue to better understand your immune response. These tumor samples and 
tests would be used to see whether we can predict response to treatment based on the kinds of cells 
we see around and inside your tumor.  
 
o 
If you agree we would ask for three mL (approximately 1/2 teaspoon) of peripheral blood to 
be drawn and leftover tumor tissue from the most recent time point in the past when tumor 
tissue was removed (removal of primary tumor or removal of tumor at a relapse) to be sent 
together to a research laboratory for testing.  The laboratory uses the blood sent with your 
tumor for determining the genetic make-up of your normal cells (known as germline testing) 
that is used to compare to the genetic make-up of your tumor.  The researchers will look for 
any changes in the genetic make-up of the tumor that are different from those changes found 
in your normal genetic material obtained from your blood sample. 
o 
To see how treatment with MIBG and dinutuximab affects the immune cells around and in 
your tumor, if you agree, we would also like to ask for tumor tissue that might be collected  in 
the future if your doctor thinks it is in your best interest to have more of your tumor removed 
for any reason. This would happen after you have finished treatment on this study, but before 
you receive any additional therapy for your neuroblastoma.  
 
We will not remove tissue just for these additional studies. The tissue will be sent to a research 
laboratory at Children’s Hospital of Los Angeles for testing.   
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get two treatment courses with 131I-MIBG and dinutuximab as long as you are not having bad side 
effects and as long as your tumor is not getting worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 
or whether you have developed any additional cancer. Your doctor will give the researchers this information 
at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely. There are certain time points in the 
study where it would be strongly recommended that you complete the medical supportive care required to 
avoid very bad and/or fatal side effects. 
 
• 
Once you have gotten 131I-MIBG treatment, you will stay in the special room until you are no longer 
radioactive (usually 5 days), since you could expose others to radiation. 
 
• 
Once you have gotten 131I-MIBG treatment, it would be strongly recommended that you complete the 


 
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105 
 
medical supportive care needed to avoid very bad and/or fatal side effects. This includes the stem cell 
infusion and the potassium iodide for thyroid protection.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest, if you do not follow study rules, or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of 131I-MIBG 
in combination with dinutuximab. Though subjects will be assigned to different dose levels of 131I-MIBG, all 
doses of 131I-MIBG being tested have been shown to be effective against neuroblastoma.  
 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable (such as for nausea, headache, itching). Many side 
effects go away soon after you stop taking the study medications but it is always possible that side effects 
can be serious, long lasting or may never go away. There is also a risk of death. Patients are watched 
carefully and treatment will be stopped if bad side effects develop. There may also be risks we do not know 
about. You should talk to your doctor about any side effects that you have while taking part in this study.  
 
While on the study, you are at risk for the side effects listed below: 
 
Possible Risks of 131I-MIBG 
 
Likely   
(happens to 21-100 children out 
of every 100 children) 
Less Likely 
(happens to 5-20 children out of every 
100 children) 
Rare 
(happens to < 5 children out of every 
100 children) 
• Decrease in the number of 
red and white blood cells 
and platelets made in the 
bone marrow.  You may 
need blood and platelet 
transfusions and sometimes 
stem cell infusions are 
necessary.  (Stem cells are 
required on this trial) The 
dose of 131I-MIBG used in 
this study will lower your 
blood counts. 
• Nausea 
• Dry mouth 
• Increase in blood marker of 
salivary gland irritation (your 
serum amylase will 
increase)  
• Decreased function of the thyroid 
gland.  This causes tiredness 
(fatigue), weight gain, constipation, 
and lower blood pressure. 
Treatment for life with a medicine 
to supplement the thyroid gland 
(i.e. Synthroid or related thyroid 
supplement) may be needed. 
•  Not being able to get pregnant or 
father a child 
• High or low blood pressure during 
or after the 131I-MIBG infusion 
• Thinning of the hair 
• Vomiting 
• Infection due to low white blood 
cells 
• Fatigue due to low red blood cells 
• Bleeding/bruising due to low 
platelets 
• Loss of appetite 
 
• Pain in salivary glands or mouth 
• Decreased function of adrenal 
gland. This affects your activity 
level and growth.  It causes 
tiredness (fatigue), weight 
changes and blood pressure 
changes.  You may need to take 
medicine to supplement the 
adrenal gland. 
• Decreased heart function 
• Irritation of the liver. Because 
some of the radioactive 131I-
MIBG is taken up by the liver, 
there is a possible risk of future 
liver damage from the 131I-MIBG 
alone. 
• Second cancer (such as 
leukemia) that is different from 
the kind of cancer you have 
now 
• Trouble breathing due to 
infection or damage to the lung 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
106 
 
• Overactive thyroid gland 
Possible risks from having a bladder catheter placed 
In order to safely receive MIBG therapy, you will need to a have a tube or catheter called a Foley catheter 
temporarily placed in your bladder. The catheter may cause you some discomfort and may increase your 
risk for getting a bladder infection.  
 
Possible Risks of Potassium Iodide  
Likely   
(happens to 21-100 children out 
of every 100 children) 
Less Likely 
(happens to 5-20 children out 
of every 100 children) 
Rare 
(happens to < 5 children out of every 100 
children) 
 
• Gastrointestinal distress 
(nausea / vomiting / 
diarrhea / stomach pain) 
• Tingling, pain or weakness in arms and 
legs 
• Flare up of acne in teenagers 
• Irregular heartbeat 
• Confusion 
• Tiredness 
• Fever 
• Allergic reaction (hives) 
• Burning of mouth / throat 
• Metallic taste 
• Rash 
• Decreased function of the thyroid gland 
with overuse 
• Swelling of lymph glands  
This medication is given for 45 days after the 131I-MIBG infusion to protect your thyroid gland.  
 
Possible Risks of Dinutuximab 
 
Likely 
(happens to 21-100 children out of 
every 100 children) 
Less Likely 
(happens to 5-20 children out of every 
100 children) 
Rare  
(happens to < 5 children out of 
every 100 children) 
• 
Fever 
• 
Anemia, kidney problems 
which may cause tiredness, 
or may require blood 
transfusion or dialysis 
• 
Blood clot 
• 
Abnormal heartbeat 
• 
Diarrhea, nausea, vomiting 
• 
Swelling of arms, legs 
• 
Allergic reaction, which may 
cause rash, low blood 
pressure, wheezing, 
shortness of breath, swelling 
• 
Heart stops beating 
• 
Vision changes which 
may include changes in 
the pupils of the eye 
• 
Death 
• 
Swelling of the spinal 
cord 
• 
Muscle weakness 
• 
Brain damage which 
may cause headache, 
seizure, blindness 
(reversible posterior 
• 
Pain 
• 
Cough 
• 
Rash 


 
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107 
 
of the face or throat and 
difficulty speaking 
• 
Infection, especially when 
white blood count is low 
• 
Bruising, bleeding 
• 
Loss of appetite 
• 
Numbness, tingling or pain of 
the arms and legs 
• 
Difficulty emptying the 
bladder, which may require 
catheterization during 
therapy, and in rare cases 
catheterization may be 
required after discharge from 
the hospital 
• 
Itching, hives 
• 
Fluid in the organs which may 
cause low blood pressure, 
shortness of breath, swelling 
of ankles 
• 
High blood pressure which 
may cause dizziness, blurred 
vision 
• 
Low blood pressure which 
may cause feeling faint 
leukoencephalopathy 
syndrome) 
 
Possible Risks of Sargramostim (GM-CSF) 
 
Likely   
(happens to 21-100 
children out of every 100 
children) 
Less Likely 
(happens to 5-20 children 
out of every 100 children) 
Rare 
(happens to < 5 children out of every 100 
children) 
• 
Headache 
• 
Bone pain 
• 
Joint pain 
• 
Muscles aches 
• 
Rash 
• 
Fever 
• 
Chills 
• 
Itching 
• 
Stomach pain 
• 
Weakness 
• 
Nausea 
• 
Reaction to 
injection site 
• 
Lack of appetite 
• 
Reaction during or following injection 
of drug which may cause fever, 
chills, rash, low blood pressure, fast 
heartbeat, shortness of breath and 
swelling of the face or throat 
• 
Vomiting  
• 
Diarrhea 
• 
Abnormally fast heartbeat 
• 
Fluid around the heart which may 
cause shortness of breath and/or 
chest pain 
• 
Inflammation of veins which may 
cause pain and swelling 
• 
In high doses: fluid in the organs 
which may cause low blood 
pressure, shortness of breath and/or 
swelling of ankles 
 
 
 
 


 
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108 
 
Possible Risks Associated with Stem Cells 
 
• 
ANY TIME BEFORE STEM CELL INFUSION:  The freezer where PBSC are stored could 
malfunction, the container holding them could break and the stem cells could be damaged so they 
could not be used. This is expected to be an extremely rare event. However, if this occurs, another 
stem cell collection may be attempted or the back-up stem cells (if available) may be used if they 
were not damaged. 
 
• 
If stem cells need to be shipped from one location to another, they could be lost or damaged during 
shipping such that they could not be used. This is expected to be an extremely rare event. If this 
occurs, another stem cell collection may be attempted or the back-up stem cells, if available, may 
be used. 
 
• 
Some patients may need extra fluids given into the vein after getting their stem cells.  This is to 
protect the kidneys from the red blood cells mixed in with the stem cells.   
 
Likely  
(happens 
to 
21-100 
children out of every 100 
children) 
Less Likely 
(happens 
to 
5-20 
children out of every 100 
children) 
Rare 
(happens to < 5 children out of every 100 children) 
 
• Fever and chills 
• Allergic reaction.  Can cause difficulty 
breathing and low blood pressure. 
• High blood pressure 
• Infection 
• Infusion of tumor cells. Tumor cells may still be 
present in the harvested stem cells and they 
could regrow after stem cells are infused. 
• Cough 
• Chest Tightness 
• Flushing 
• Nausea and/or vomiting 
• Rash 
• Irregular Heart Beat 
 
Herbs and Supplements 
Some drugs or supplements may interact with your treatment plan. Talk to your doctor, pharmacist, or study 
team before starting any new prescription drugs, over-the-counter drugs, herbals, or supplements and 
before making a significant change in your diet. Supplements may come in many forms, such as teas, 
drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be avoided. 
  
Possible Risks to Unborn Child 
Patients who agree to participate in this study should not become pregnant while on this study. Patients 
and their sexual partners should avoid sex and/or use two effective methods of contraception that are 
medically appropriate based on your personal doctor’s recommendation at that time and should be used 
for as long as you participate in this study.  If you or your partner becomes pregnant while you are 
participating in this study, please notify your doctor immediately.  For more information about risks and 
side effects, ask your doctor. 
 
Possible Risks to the Caregiver(s) of the Patient Getting 131I-MIBG Treatment 
Caregivers (example: parent, other family member, guardian, friend, partner) will be exposed to radiation 
while you are being treated with MIBG.  Caregivers who could possibly become pregnant during this time 
need to avoid contact with the patient because the radiation exposure may increase the unborn baby’s 
risk of developing cancer or other health problems.   


 
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109 
 
If your caregiver is pregnant, then special precautions should be used to avoid contact with you during 
and for 4 weeks after getting MIBG treatment.  Should your caregiver or your caregiver’s sexual partner 
be found to have been pregnant while you were getting MIBG treatment and did not know it at the time, 
please contact your doctor immediately.  
 
Possible Long Term Risk of This Treatment  
• 
Recurrence of tumor 
• 
Infection 
• 
Sterility and/or delayed onset of puberty 
• 
Increased risk of a second cancer (such as leukemia) different from the kind of cancer you have now. 
• 
Patients who have more than one 131I-MIBG treatment will have greater doses of radiation to the 
normal organs than those patients having one treatment. It is possible that there may be later damage 
to the normal function of the liver or other organs. 
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. You may also 
experience some pain or bruising at the site your blood was drawn. Experienced doctors or nurses will perform 
these blood draws to minimize this risk. You will be asked to sign a separate consent for any procedure that 
needs sedation. 
 
Possible Risks from Germline Genetic Testing   
If you agree to participation in the optional test looking at immune system cells in your tumor and immune 
response, a small amount of your blood will be collected. Researchers will use the blood sent with your tumor 
for determining the genetic make-up of your normal cells (known as germline testing) that is used as a baseline 
to compare to the genetic make-up of your tumor. This helps the laboratory in identifying the genetic changes 
they may see in your tumor tissue.  
 
The germline genetic testing is for research purposes only and is performed on de-identified samples, and so 
the information can’t be linked back to your child. Hence, the results will not be sent to you or your physician. 
 
Unknown Risks 
This treatment combination may have side effects that no one knows about yet.  The researchers will let you 
know if they learn anything that might make you change your mind about participating in the study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children or young people with solid cancers in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
 
• 
Treatment with other chemotherapy medicines, or 131I-MIBG without dinutuximab 
• 
Treatment with other experimental agents that may be available 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable 
 
Please talk about these options with your doctor. 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
110 
 
 
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
We will do our best to make sure that the personal information in your medical record will be kept private. 
However, we cannot guarantee total privacy. Your personal information may be given out if required by law. 
If information from this study is published or presented at scientific meetings, your name and other personal 
information will not be used. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA), Health Canada, or European regulatory agency(ies) involved in keeping 
research safe for people. 
• 
Jubilant Radiopharma (supplier of 131I-MIBG)  
• 
United Therapeutics Corporation (manufacturer of dinutuximab) 
 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
The 131I-MIBG will be supplied by Jubilant Radiopharma. The cost of 131I-MIBG and its administration 
costs will be billed to your/your child’s insurance company. 
 
Dinutuximab will be provided free of charge by United Therapeutics, Inc while you are taking part in this 
study.  United Therapeutics does not cover the cost of getting dinutuximab ready and giving it to you so 
your insurance company may have to pay for this. 
 
GM-CSF is a commercially available agent. You will pay for the amount of drug needed to complete this 
study.  This cost is normally covered by your insurance company. 
 
The correlative biology studies will be done at no cost to you.  However, you or your health plan may need 
to pay for the costs of the supplies and personnel who draw the blood from you for these tests. 
  
You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
 
Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
111 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)] if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from the study at any time. No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 
We will tell you about new information or changes in the study that may affect your health or your willingness 
to continue in the study.  
 
In case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
You can talk to your study doctor about any questions or concerns you have about this study. Contact your 
study doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ [name 
of center] Institutional Review Board (a group of people who review the research to protect your rights) at 
__________________ (telephone number).  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites at http://cancer.gov/ 
For NCI’s clinical trials information, go to http://cancer.gov/clinicaltrials/ 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
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CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. 
Using extra blood to look for proteins and genetic changes in your cells. 
 
Initial next to YES if you agree to let researchers use some of the blood (less than ¼ teaspoon) already 
drawn for one of the required studies to look at certain immune cell genes and how changes in these genes 
might affect how you respond to the treatment.   No extra blood needs to be drawn from you to do this 
optional test.  The results of this test will be confidential and not made available to you or your treating 
physician. 
 
Initial next to NO if you do not want researchers to use some of the blood already drawn for a required test 
to look at immune cell genes.    
 
_______Yes      _______No    
 
Initial next to YES if you agree to let researchers take an extra half teaspoon (2.5 mL) of blood 8 different 
times to look for certain proteins and changes in these proteins that might affect your response to treatment 
with 131I-MIBG and dinutuximab.  This blood would be drawn at a time when blood was being drawn for 
clinical purposes.  The results of this test will be confidential and not made available to you or your treating 
physician. 
 
Initial next to NO if you do not want researchers to take extra blood above what is needed for clinical 
purposes. 
 
_______Yes      _______No 
 
2. 
Evaluate tumor tissue for immune system cells that surround and invade your tumor and 
the genes that cause an immune response, and if possible also comparing immune system cells in 
tumor samples from before and after treatment with MIBG and dinutuximab. 
 
Initial next to YES if you agree  to let researchers collect 3 mL (about ½ teaspoon) of blood to be sent together 
with any leftover tumor (if available from an earlier procedure) to a laboratory so researchers can learn more 
about the immune system cells that surround and invade your tumor and genes that cause an immune 
response. Looking at the immune response genes involves comparing your normal genetic information gotten 
from the blood sample (called germline) to the genetic information of your tumor and determining what is 
different between the two. The results of these tests will be confidential and not made available to you or your 
treating doctor. 
 
Initial next to NO if you do not want extra blood drawn and leftover tumor from an earlier procedure, if it is 
available, to be sent to a research laboratory.  
 
_______Yes      _______No   
 
Initial next to YES if you agree to have leftover tumor sent to the research lab if a biopsy is done in 
the future for clinical care and this happens after finishing this protocol therapy and before starting the next 
treatment for your tumor.  The purpose of this part of the test is to see if the 131I-MIBG had any effect on 
the immune cells that surround and invade your tumor.   
 
Initial next to NO if you do not want leftover tumor from a future procedure to be sent to a research laboratory. 
 
_______Yes      
_______No   
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
113 
 
3.  Storage of left over specimens obtained on this study for future use in research 
The NANT Biology Study (N2004-05) provides a way to allow for banking of leftover specimens from this 
study for future research to answer questions about MIBG and dinutuximab treatment, neuroblastoma or 
other childhood cancers. 
 
Initial next to YES if you agree to storage of any specimens leftover from this study for future research. 
 
Initial next to NO if you do not want leftover specimens from this study stored for future research 
 
_______Yes      _______No 
 
 
STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments that 
were included with this informed consent document. I have asked all of my questions and I have gotten 
answers. I agree to enroll myself (my child) in this study. 
 
 
_____________________________________ 
Print Patient Name 
 
 
______________________________________  
 
_____/_____/_____ 
Print Name of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Patient (If > 7 years old) 
 
 
 
 
Date 
 
 
___________________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
114 
 
Consent Addendum I: Tests That Will Be Done On This Study 
Observation 
Before 
Entry 
Days 1 to Day 56 of Course 1 & 2 
End of treatment 
All other days during 
course 
During dinutuximab 
infusions only 
Day 8-11 and Day 29-32 
Physical Exam 
X 
Weekly 
Daily 
X 
Blood Tests 
X 
Twice weekly for blood 
counts,  
Weekly for other tests  
Daily 
 
X 
Urine tests 
 
X 
 
 
X 
Pregnancy test 
X 
 
 
X 
Heart test 
(echocardiogram) 
X 
 
 
X 
MIBG scan after MIBG 
treatment 
(no extra MIBG is given to 
you to do this scan) 
 
After you get out of your 
radiation isolation room 
 
 
Blood correlative studies 
(Required) 
 
Course 1 only 
2 times  
 
Course 1 only 
4 times   
  
Course 1 only 
1 time 
Blood for correlative 
studies 
(Optional) 
 
Course 1 only 
3 times  
 
Course 1 only 
4 times   
 
Blood & Tumor sample 
sent for research (optional) 
Blood & Tumor sample can be sent any time during the study 
Disease Evaluation Tests# 
Bone marrow 
aspirate/biopsy 
X 
Day 43 – 57 of Course 1  
X 
CT, MRI and/or MIBG 
scans 
X 
X 
# Patients enrolled in the companion biology study may have additional samples of blood and  
bone marrow collected at study entry and with each disease evaluation time point. Please look at  
the biology study N04-05 consent form for more information. 
 
 
 
 
 
 
 
 
 
 
 


 
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Consent Addendum II 
Certificate of Confidentiality Information 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects.  The Certificate protects against the involuntary release 
of information about subjects collected during the course of our covered studies.  The researchers 
involved in the studies cannot be forced to disclose the identity or any information collected in the 
study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may 
choose to voluntarily disclose the protected information under certain circumstances.  For example, 
if the subject or his/her guardian requests the release of information in writing, the Certificate does 
not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program 
evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of 
Confidentiality will not protect against the required reporting by hospital staff of information on 
suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or 
others. 
 
 


 
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15.2 
Part B 
 
NANT 2017-01:  A PHASE I STUDY OF 131I-MIBG WITH DINUTUXIMAB +/- VORINOSTAT FOR 
RELAPSED/REFRACTORY NEUROBLASTOMA 
 
FOR PATIENTS ON PART B 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
The word “you” used throughout this document refers to you or your child. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find the highest safe dose of vorinostat that can be given with 131I-MIBG and dinutuximab to 
children with refractory or recurrent neuroblastoma without causing severe side effects 
• 
To find out what side effects there are from giving vorinostat, 131I-MIBG, and dinutuximab together 
on this schedule  
• 
To see if your tumor gets smaller after treatment with vorinostat, 131I-MIBG, and dinutuximab 
• 
To learn what happens to your immune system and other proteins that cause inflammation when 
giving vorinostat and 131I-MIBG with dinutuximab. 
• 
To see what effect giving vorinostat and 131I-MIBG has on your body in making an antibody to the 
dinutuximab 
• 
To see what effect treatment with vorinostat and 131I-MIBG in combination with dinutuximab has on 
the cells of your immune system that surround and invade your tumor 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The research is being done because: 
Currently there is no known effective treatment for neuroblastoma that has returned or that has not 
responded to treatment.  
 
This study will use an intravenous (IV) chemical agent called metaiodobenzylguanidine (MIBG) together 
with an oral drug called vorinostat and an IV drug called dinutuximab. MIBG is taken up by neuroblastoma 
tumor cells. MIBG can be combined with radioactive iodine (131I) in the laboratory to form the radioactive 
compound 131I-MIBG. 131I-MIBG delivers radiation to the neuroblastoma cancer cells and causes them to 
die. 131I-MIBG lowers the number of blood forming cells (called stem cells) in the bone marrow when it is 
given at higher doses as in this study. Because of this, all patients will get back their own stem cells to help 
the bone marrow recover from this therapy.   
 
Vorinostat is a drug that is FDA-approved to treat a certain type of cancer mainly seen in adults. Vorinostat 
affects the way the DNA that carries our genes is folded in cells. In the laboratory, vorinostat causes 
neuroblastoma cells to stop growing. This effect is even greater when vorinostat is combined with radiation. 


 
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A recent clinical trial has shown that giving vorinostat together with 131I-MIBG increases the number of 
patients who respond to 131I-MIBG compared to giving 131I-MIBG by itself. Laboratory studies also show 
that dinutuximab may work better when it is given with vorinostat; however, combining vorinostat with 
dinutuximab either with or without 131I-MIBG has never been tested in a clinical trial. 
 
Dinutuximab works differently than most standard chemotherapy drugs. Dinutuximab is a monoclonal 
antibody. Monoclonal antibodies are proteins made in the lab, designed to attach to specific targets on 
cancer cells. When dinutuximab attaches to neuroblastoma cells, the body’s immune system is stimulated 
to attack and kill the neuroblastoma cells. Dinutuximab represents a new kind of cancer therapy called 
immunotherapy which, unlike chemotherapy and radiation, targets the cancer cells without destroying 
nearby healthy cells. 
 
Laboratory studies have shown greater anti-cancer effects when radiation is given before an 
immunotherapy treatment.  Some clinical responses have been seen in adults when radiation has been 
combined with different types of immunotherapy in treating their cancers. 
 
Giving dinutuximab together with vorinostat and 131I-MIBG may kill more neuroblastoma cells. This is the 
first study to test giving dinutuximab together with vorinostat and 131I-MIBG.   We want to find out if giving 
the combination of vorinostat, 131I-MIBG, and dinutuximab can be tolerated.  We also want to see how 
effective this drug combination is against relapsed or refractory neuroblastoma.  
 
Dinutuximab is a drug that has been approved by the Food and Drug Administration (FDA) for treating 
newly diagnosed patients with neuroblastoma. The use of dinutuximab in combination with vorinostat and 
131I-MIBG for the treatment of relapsed or refractory neuroblastoma is considered experimental. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
This study has two parts. In the first part of the study, the dose of 131I-MIBG and dinutuximab will be 
determined (Part A). 30 patients are expected to take part in the first part of the study.  This second part of 
the study (Part B) will add vorinostat to this combination. There will be approximately 18 patients enrolling 
on this part of the study (Part B).  You are being asked to participate in Part B of this study. When you join 
the study, you will be assigned a certain dose of vorinostat. The doses for 131I-MIBG and dinutuximab will 
be the same for all patients on Part B of this study. This study will test one dose of vorinostat in 3-6 patients. 
The starting dose of vorinostat will be the dose that has been proven safe and effective in previous trials 
giving vorinostat in combination with 131I-MIBG. The 131I-MIBG and dinutuximab doses will be the doses 
that were demonstrated to be safe to give together in Part A of the study. This dose of vorinostat will be 
given in 3 to 6 patients. If too many patients have serious side effects then a lower dose of vorinostat will 
be tested in 3 to 6 more patients. The dose level tolerated without serious side effects will be the highest 
dose of vorinostat and 131I-MIBG that can be given in combination with dinutuximab (called the maximum 
tolerated dose). 
 
  
Once the maximum tolerated dose is determined, a group of 6 more patients will be enrolled and treated at 
this dose of vorinostat in combination with 131I-MIBG and dinutuximab, known as the dose expansion part 
of the study.  The purpose of the dose expansion part of the study is to gather more information about side 
effects seen in patients treated at the maximum tolerated dose of vorinostat in combination with 131I-MIBG 
and dinutuximab.  
 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Before you can get treatment on this study, blood stem cells must be available that meet the study 
requirements. We will check your child’s previously stored stem cells to make sure that they can be used 
for the stem cell infusion. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
118 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These tests will also be done at various times throughout the study and at the end of the 
study.  The purpose of these tests is to see how well the treatment works and to measure the status of your 
neuroblastoma.   If you have had some of them recently, they may not need to be repeated. This will be up 
to your doctor. 
 
 
A medical history & physical exam 
Bone marrow tests2 to check your tumor 
Blood tests 
Various scans3 to check your tumor 
Pregnancy test (urine or blood)1 
Echocardiogram and electrocardiogram to check the heart 
function 
Urine tests 
 
 
1If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins.  You will 
be informed of a positive pregnancy test. Reporting of a positive pregnancy test to your parent or guardian 
will depend on local and/or state regulations.  All men and women who could have children must either 
agree to practice abstinence from heterosexual intercourse or use two effective methods of birth control for 
as long as they participate in this study.  
 
2Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
3Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG scans. We will recommend scans specific for your case and we 
will answer your questions about these scans. 
 
During the Study   
If the exams, tests and procedures show that you can participate in the study, and you choose to take 
part in the study, the following will be your treatment plan: 
 
• 
Vorinostat will be given on Days 0 to +13 (14 days) 
• 
131I-MIBG will be given on Day 1  
• 
Dinutuximab will be given on Days 8-11 and Days 29-32 of each treatment course.   
• 
The growth factor GM-CSF will be given on the same days as the dinutuximab and continue after 
the dinutuximab has finished for a total of 10 doses (Days 8-17 and Days 29-38).   
• 
All patients will be given an infusion of their stem cells around Day 15 of each course.    
• 
Each course is around 57 days long. 
• 
You may receive up to two treatment courses of vorinostat, 131I-MIBG, and dinutuximab as long as 
you are benefiting from the treatment and meet the criteria to continue the treatment safely. 
 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
119 
 
The following is the schematic of the days of treatment outlined above. 
 
DAY 
0 
1 
2-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18-28 
Vorinostat (V) 
dose level 
assignment 
V 
V 
V 
V 
V 
V 
V 
V 
V 
 
 
 
 
 
131I-MIBG (M) 
dose level 
assignment 
 
M 
 
 
 
 
 
 
GM-CSF (G) 
250 mcg/m
2 
 
 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
 
DINUTUXIMAB (D) 
17.5 mg/m2 
 
 
D 
D 
D 
D 
 
 
Stem Cell Infusion 
(HSC) 
 
 
 
HSC 
 
 
DAY 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
43-57 
GM-CSF (G) 
G 
G 
G 
G 
G 
G 
G 
G 
G 
G 
DINUTUXIMAB (D) 
D 
D 
D 
D 
 
 
 
  
Disease Evaluation 
(Eval) 
 
 
 
 
 
 
 
 
 
 
Eval 
 
Treatment with Vorinostat 
Patients will be assigned a certain dose level of vorinostat at time of study registration. The vorinostat dose 
you are assigned to will not be increased during the study. Dosing is done this way because we do not yet 
know the best dose of vorinostat to use in children when it is used together with 131I-MIBG and dinutuximab. 
 
The vorinostat is given by a pill or a liquid depending upon your size. If you cannot take medicines by mouth, 
the vorinostat can be given into a tube placed in the nose or stomach. You will receive vorinostat orally 
once daily for 14 days (Days 0 to +13). One day after starting vorinostat, 131I-MIBG will be given (Day 1). If 
you vomit within 15 minutes of taking the vorinostat you should retake the dose. If you vomit again with the 
second dose you should not try to take the dose again. If you vomit more than 15 minutes after taking the 
vorinostat you should not try to retake the dose.       
 
Treatment with 131I-MIBG 
Patients will be given the 131I-MIBG dose that has been shown can be safely given with dinutuximab during 
the first part of this study (Part A).  Treatment with 131I-MIBG will be done at a hospital that is set up to take 
care of patients that are treated with radioactive substances.  This means that you may need to travel some 
distance to another hospital to get this treatment.  Your health care team will talk with you and help you 
plan for the trip to get this treatment. 
 
Patients will be admitted to an 131I-MIBG treatment center one day before starting 131I-MIBG therapy. On 
the following day (Day 1), 131I-MIBG is given into a temporary IV or in your central venous catheter over 90-
120 minutes.  IV fluids for hydration and other medicines will be given through your central venous catheter.  


 
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Patients who get 131I-MIBG are considered to be radioactive and you will stay in the special room until your 
radiation measurement reaches a safe level, usually 3 - 5 days, since you could expose others to radiation.  
Special care precautions include: 
 
• 
A single room in a bed surrounded by a lead shield to keep family and the staff who take care of you 
from being exposed to radiation from the 131I-MIBG treatment.  
 
• 
The length of time family can visit inside the room in front of the protective lead shield that is around 
your bed will depend on how much radiation is measured in the room each day by the radiation 
specialist. Usually family can visit for a total of 30-45 minutes on the first day and longer on the days 
after that because there will be less radiation measured in the room each day. 
 
• 
Family may visit anytime outside of the room or behind a lead shield. You will be able to see who is 
visiting over this shield.  
 
• 
No one will be able to spend the night in this special room with you during this time. 
 
Your urine will be radioactive after treatment with 131I-MIBG. A urinary catheter may be inserted to drain the 
radioactive urine from your body. The catheter is strongly recommended for all patients but is required for 
patients < 12 years of age. If the catheter comes out for any reason, it will most likely have to be replaced. 
The catheter will be removed at the time of discharge (3-5 days).  
 
You will also take a medicine by mouth [potassium iodide (SSKI)] to prevent thyroid damage from the 
radioactive iodine contained in the 131I-MIBG compound. This medicine will be taken by mouth or by tube 
before beginning treatment and will continue to be taken for a total of 6 weeks. This will be taken every 4 
hours for the first 7 days after the 131I-MIBG infusion and then daily for the remainder of the 6 weeks. 
 
Treatment with Dinutuximab and GM-CSF 
All patients on this study will receive the same dose of dinutuximab. It will be administered IV over 10-20 
hours, once daily for four consecutive days in the hospital. Patients will also receive GM-CSF beginning 
with dinutuximab and continuing for a total of 10 doses. GM-CSF is a substance that is similar to one made 
by the body. Under normal circumstances, the body makes small amounts of GM-CSF that help it to 
produce normal infection fighting white blood cells. It is now possible to make GM-CSF outside of the body 
and give humans much higher doses than their own bodies make. There is some evidence that, in the lab 
and in animals, GM-CSF increases the anti-cancer effect of monoclonal antibodies like dinutuximab. GM-
CSF is administered under the skin [subcutaneously (SQ)] except in special circumstances when it can be 
given IV. 
 
Stem Cell Infusion 
All patients on this study will receive an autologous stem cell infusion (an infusion of your previously collected 
stem cells) at about Day 15 which is around 2 weeks from the 131I-MIBG infusion.  You will receive your 
stored stem cells back by vein. This may be done as a day visit to the hospital or may require a brief (one 
night) stay in the hospital. The stem cells can be given at any NANT hospital.  
 
If you develop a low white blood count, you may receive GM-CSF (Leukine/sargramostim), G-CSF 
(Neupogen), or pegfilgrastim (Neulasta) in order to help your white blood cells recover faster after treatment, 
though it is strongly recommended that GM-CSF be the only growth factor used. GM-CSF, G-CSF, or 
pegfilgrastim will be given under the skin (SQ). You may also get a dose (or doses) of one of these 
medicines after you have received your stem cells, even if your blood counts are not low yet.  
 
 
 
 
 


 
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121 
 
You can receive this therapy two times as part of this study, as long as: 
• 
your tumor is not getting worse; 
• 
you have not had any other anti-cancer treatments since the first course; 
• 
you have enough stem cells to get a second course; and 
• 
you have not had any bad side effects from the first course. 
 
The second course cannot start earlier than 8 weeks from the date of the first 131I-MIBG infusion.  The 
following tests and procedures will be done during the study.  They are part of regular cancer care. 
 
A medical history & physical exam 
Bone marrow tests to check your tumor 
Blood tests 
Various scans to check your tumor 
Pregnancy test (urine or blood) 
Echocardiogram and electrocardiogram to check the heart 
function 
Urine tests 
 
 
NANT Biology Study (NANT2004-05) 
You will be required to join a companion NANT biology study to collect blood, bone marrow and tumor 
tissue (if available) and reports from radiology scans from patients with neuroblastoma. The biology study 
also provides a place (called NANT biorepository) where any leftover samples of tumor tissue or bone 
marrow and blood collected on this study could be transferred and stored. While you will be required to join 
the Biology Study (NANT 2004-05), the decision to store/bank any leftover samples is optional and will not 
affect your ability to participate in this treatment study with vorinostat, 131I-MIBG, and dinutuximab.  Your 
doctor will talk with you in detail about the NANT biology study and have you sign a separate consent form. 
 
When You Have Finished Treatment with Vorinostat, 131I-MIBG, and Dinutuximab  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to see 
how you are doing. If test results show you have abnormal organ function, tests are recommended by the 
study to be repeated monthly until test results are stable or normal. You doctor will tell you how often these 
tests and evaluations will be done. 
 
Medical Tests after the Study: 
 
Physical exam 
Bone marrow tests & various scans to check your tumor1 
Blood tests 
 
1Bone marrow tests and various scans (CT/MRI, MIBG) are done for checking the response of your tumor 
to treatment.  These tests will be done at the end of a course and at certain times following treatment to 
monitor your tumor status. 
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this consent. 
 
Additional Tests in this Study 
We would like to do some extra tests called correlative biology studies. These tests will help us learn more 
about treatment with vorinostat, 131I-MIBG, and dinutuximab and may help children and adolescents who 
receive this drug in the future. The information learned would not change the way you are treated and the 
results of these tests will not be given to you.  Some of these tests are required but others are optional meaning 
you can decide whether you want to do them or not. All of these tests (required and optional) will be done only 
during the first course. 
 
 
 


 
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122 
 
Evaluation of Immune Function – Required  
During this study blood samples will be collected to look at changes in your immune function before and after 
treatment with vorinostat, 131I-MIBG, and dinutuximab. We will look at changes in the number and function of 
certain cells of the immune system, as well as measure levels of certain proteins that cause inflammation in 
the body. We will collect 13 mL (~2.5 teaspoons) of blood with each sample at 6 different time points during 
Course 1 ONLY. The total amount of blood drawn for testing will be 78 mL (~15.5 teaspoons). If you have a 
central line (such as a port or a Broviac) these samples can be drawn through that line or through a small tube 
placed in a vein in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent 
to Children’s Healthcare of Atlanta for testing. 
 
Testing for Antibodies Against Dinutuximab – Required 
During this study blood samples will be collected to look for antibodies that attach to dinutuximab, and also to 
look at how many of these antibodies make it so the dinutuximab can’t attack your neuroblastoma. The amount 
of blood required for this test is < 1 mL (less than ¼ teaspoon) and it will be taken from the amount collected 
as part of the immune functions studies at 3 of the 5 time points, and two additional time points. We will collect 
8 mL (~1.5 teaspoons) of blood at each of these two additional time points, both to test for the antibodies 
against dinutuximab and to save for future testing of changes in your immune function. 
 
Other Biology Research Tests in this Study - Optional 
You will be asked if you want to participate in other optional research tests.  You can decide not to let the 
doctors do these tests and still be able to be treated as part of this study.  There are checkboxes at the end 
of this form to mark whether you are willing to participate in these voluntary studies. The results of these 
research tests will not be shared with you or become part of your medical record.  These results would also 
not be used to make decisions about your care while enrolled on this study.     
 
• 
Using extra blood to look for proteins and genetic changes in your cells. 
Part of the research goal for this study is to look for the presence of and changes in certain proteins 
and genes in the blood that might affect your response to treatment. We would like to collect this 
blood before, during, and after treatment on this study.  
 
o 
For the tests looking at the genes in your cells (DNA), no additional blood draw is required. 
The sample would be obtained from the blood that is collected for the testing of the cells of 
your immune system at the 6 time points described above.  
 
o 
For the tests looking at proteins or at certain genes that affect your body’s immune response, 
an additional 2.5 mL (1/2 teaspoon) of blood will be collected at 9 different time points during 
course 1. The total amount of blood drawn for this testing will be 22.5 mL (4.5 teaspoons). 
If you have a central line (such as a port or a Broviac) these samples can be drawn through 
that line or through a small tube placed in a vein in your hand or arm.  This amount of blood 
is considered safe to donate. Samples will be sent to Children’s Healthcare of Atlanta for 
testing.  
 
• 
Evaluate tumor tissue for immune system cells that surround and invade your tumor. 
Part of the research goal for this study is to learn more about the cells of your immune system that 
surround and invade your tumor, and learn how these cells change after treatment with vorinostat, 
131I-MIBG, and dinutuximab. We would also like to perform genetic studies on a small amount of 
your blood in addition to the tumor tissue to better understand your immune response. These tumor 
samples and tests would be used to see whether we can predict response to treatment based on 
the kinds of cells we see around and inside your tumor. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
123 
 
o 
To see how treatment with vorinostat, 131I-MIBG, and dinutuximab affects the immune cells 
around and in your tumor, if you agree, we would also like to ask for tumor tissue that might 
be collected in the future if your doctor thinks it is in your best interest to have more of your 
tumor removed for any reason. This would happen after you have finished treatment on this 
study, but before you receive any additional therapy for your neuroblastoma.  
o 
If you agree we would ask for 3 mL (approximately 1/2 teaspoon) of peripheral blood to be 
drawn and leftover tumor tissue from the most recent time point in the past when tumor tissue 
was removed (removal of primary tumor or removal of tumor at a relapse) to be sent together 
to a research laboratory for testing.  The laboratory uses the blood sent with your tumor for 
determining the genetic make-up of your normal cells (known as germline testing) that is 
used to compare to the genetic make-up of your tumor.  The researchers will look for any 
changes in the genetic make-up of the tumor that are different from those changes found in 
your normal genetic material obtained from your blood sample 
 
We will not remove tissue just for these additional studies. The tissue will be sent to a research 
laboratory at Children’s Hospital of Los Angeles for testing.   
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get two treatment courses with vorinostat, 131I-MIBG, and dinutuximab as long as you are not 
having bad side effects and as long as your tumor is not getting worse and your insurance allows you to 
get vorinostat and GM-CSF.    
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 
or whether you have developed any additional cancer. Your doctor will give the researchers this information 
at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely. There are certain time points in the 
study where it would be strongly recommended that you complete the medical supportive care required to 
avoid very bad and/or fatal side effects. 
 
• 
Once you have gotten 131I-MIBG treatment, you will stay in the special room until you are no longer 
radioactive (usually 5 days), since you could expose others to radiation. 
 
• 
Once you have gotten 131I-MIBG treatment, it would be strongly recommended that you complete the 
medical supportive care needed to avoid very bad and/or fatal side effects. This includes the stem cell 
infusion and the potassium iodide for thyroid protection.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest, if you do not follow study rules, or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
124 
 
In this study, researchers will be looking at side effects seen in patients taking vorinostat and 131I-MIBG in 
combination with dinutuximab. The dose of 131I-MIBG you will receive has been shown to be effective 
against neuroblastoma, and a recent study has shown that giving vorinostat with 131I-MIBG increases the 
number of patients who will respond to 131I-MIBG. 
 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable (such as for nausea, headache, itching). Many side 
effects go away soon after you stop taking the study medications but it is always possible that side effects 
can be serious, long lasting or may never go away. There is also a risk of death. Patients are watched 
carefully and treatment will be stopped if bad side effects develop. There may also be risks we do not know 
about. You should talk to your doctor about any side effects that you have while taking part in this study.  
 
While on the study, you are at risk for the side effects listed below: 
 
Possible Risks of Vorinostat 
Likely   
(happens to 21-100 children out 
of every 100 children) 
Less Likely 
(happens to 5-20 children out of every 
100 children) 
Rare 
(happens to < 5 children out of every 
100 children) 
• 
Low 
blood 
counts, 
including low red blood 
cells (which can cause 
fatigue 
or 
pale 
appearance) 
and 
platelets 
(which 
can 
cause 
bruising 
or 
bleeding).  
• 
Fatigue  
• 
Anorexia  
• 
Diarrhea  
• 
Nausea  
• 
Change in taste 
 
• 
Decrease in specific types of 
blood cells (white blood cells 
which can cause increased 
risk of infection  
• 
Weight loss  
• 
Decreased kidney function 
• 
High blood sugar  
• 
Fever, with or without low 
blood counts  
• 
Chills  
• 
Hair loss  
• 
Vomiting 
• 
Constipation  
• 
Dehydration  
• 
Dry mouth  
• 
Heartburn  
• 
Infection  
• 
Headache 
• 
Changes in liver blood tests 
• 
Changes in blood salts 
• 
Muscle spasm or weakness 
• 
Dizziness 
• 
Cough 
• 
Blood clot 
• 
Protein in the urine 
• 
Blood creatinine increased 
• 
Lymphopenia 
• 
Anemia 
• 
Swelling in the hands and 
feet 
• 
Pruritis 
• 
Skin breakdown 
• 
Changes in a specific part 
of the heart tracing known 
as an EKG. (Mild changes 
in a specific part of the 
heart tracing known as an 
EKG has been rarely 
reported in patients treated 
with vorinostat, though it is 
not clear whether vorinostat 
caused these changes or 
not.) 
• 
A kind of skin cancer called 
Squamous cell carcinoma 
• 
Bleeding from GI tract 
• 
An increase in the time it 
takes for your blood to clot 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
125 
 
Possible Risks of 131I-MIBG 
 
Likely   
(happens to 21-100 children out 
of every 100 children) 
Less Likely 
(happens to 5-20 children out of every 
100 children) 
Rare 
(happens to < 5 children out of every 
100 children) 
• Decrease in the number of 
red and white blood cells 
and platelets made in the 
bone marrow.  You may 
need blood and platelet 
transfusions and sometimes 
stem cell infusions are 
necessary.  (Stem cells are 
required on this trial) The 
dose of 131I-MIBG used in 
this study will lower your 
blood counts. 
• Nausea 
• Dry mouth 
• Increase in blood marker of 
salivary gland irritation (your 
serum 
amylase 
will 
increase)  
• Decreased function of the thyroid 
gland.  This causes tiredness 
(fatigue), weight gain, constipation, 
and lower blood pressure. 
Treatment for life with a medicine 
to supplement the thyroid gland 
(i.e. Synthroid or related thyroid 
supplement) may be needed. 
•  Not being able to get pregnant or 
father a child 
• High or low blood pressure during 
or after the 131I-MIBG infusion 
• Thinning of the hair 
• Vomiting 
• Infection due to low white blood 
cells 
• Fatigue due to low red blood cells 
• Bleeding/bruising due to low 
platelets 
• Loss of appetite 
 
• Pain in salivary glands or mouth 
• Decreased function of adrenal 
gland. This affects your activity 
level and growth.  It causes 
tiredness (fatigue), weight 
changes and blood pressure 
changes.  You may need to take 
medicine to supplement the 
adrenal gland. 
• Decreased heart function 
• Irritation of the liver. Because 
some of the radioactive 131I-
MIBG is taken up by the liver, 
there is a possible risk of future 
liver damage from the 131I-MIBG 
alone. 
• Second cancer (such as 
leukemia) that is different from 
the kind of cancer you have 
now 
• Trouble breathing due to 
infection or damage to the lung 
• Overactive thyroid gland 
 
Possible risks from having a bladder catheter placed 
In order to safely receive 131I-MIBG therapy, you will need to a have a tube or catheter called a Foley 
catheter temporarily placed in your bladder. The catheter may cause you some discomfort and may 
increase your risk for getting a bladder infection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
126 
 
Possible Risks of Potassium Iodide  
Likely   
(happens to 21-100 children out 
of every 100 children) 
Less Likely 
(happens to 5-20 children out 
of every 100 children) 
Rare 
(happens to < 5 children out of every 100 
children) 
 
• Gastrointestinal distress 
(nausea / vomiting / 
diarrhea / stomach pain) 
• Tingling, pain or weakness in arms and 
legs 
• Flare up of acne in teenagers 
• Irregular heartbeat 
• Confusion 
• Tiredness 
• Fever 
• Allergic reaction (hives) 
• Burning of mouth / throat 
• Metallic taste 
• Rash 
• Decreased function of the thyroid gland 
with overuse 
• Swelling of lymph glands  
This medication is given for 45 days after the 131I-MIBG infusion to protect your thyroid gland.  
 
Possible Risks of Dinutuximab 
 
Likely 
(happens to 21-100 children out of 
every 100 children) 
Less Likely 
(happens to 5-20 children out of every 100 
children) 
Rare  
(happens to < 5 children out of every 
100 children) 
 
• 
Fever 
• 
Anemia, kidney problems 
which may cause tiredness, 
or may require blood 
transfusion or dialysis 
• 
Blood clot 
• 
Abnormal heartbeat 
• 
Diarrhea, nausea, vomiting, 
abdominal pain 
• 
Swelling of arms, legs 
• 
Allergic reaction, which may 
cause rash, low blood 
pressure, wheezing, 
shortness of breath, swelling 
of the face or throat and 
difficulty speaking 
• 
Infection, especially when 
white blood count is low 
• 
Bruising, bleeding 
• 
Loss of appetite 
• 
Numbness, tingling or pain of 
the arms and legs 
• 
Difficulty emptying the 
bladder, which may require 
catheterization during 
therapy, and in rare cases 
catheterization may be 
• 
Heart stops beating 
• 
Vision changes which 
may include changes in 
the pupils of the eye 
• 
Death 
• 
Swelling of the spinal 
cord 
• 
Muscle weakness 
• 
Brain damage which 
may cause headache, 
seizure, blindness 
(reversible posterior 
leukoencephalopathy 
syndrome) 
• 
Pain 
• 
Cough 
• 
Rash 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
127 
 
required after discharge from 
the hospital 
• 
Itching, hives 
• 
Fluid in the organs which may 
cause low blood pressure, 
shortness of breath, swelling 
of ankles 
• 
High blood pressure which 
may cause dizziness, blurred 
vision 
• 
Low blood pressure which 
may cause feeling faint 
• 
Back pain 
 
 
Possible Risks of Sargramostim (GM-CSF) 
 
Likely   
(happens to 21-100 
children out of every 100 
children) 
Less Likely 
(happens to 5-20 children 
out of every 100 children) 
Rare 
(happens to < 5 children out of every 100 
children) 
• 
Headache 
• 
Bone pain 
• 
Joint pain 
• 
Muscles aches 
• 
Rash 
• 
Fever 
• 
Chills 
• 
Itching 
• 
Stomach pain 
• 
Weakness 
• 
Nausea 
• 
Reaction to 
injection site 
• 
Lack of appetite 
• 
Weight gain 
• 
Reaction during or following injection 
of drug which may cause fever, 
chills, rash, low blood pressure, fast 
heartbeat, shortness of breath and 
swelling of the face or throat 
• 
Vomiting  
• 
Diarrhea 
• 
Abnormally fast heartbeat 
• 
Fluid around the heart which may 
cause shortness of breath and/or 
chest pain 
• 
Inflammation of veins which may 
cause pain and swelling 
• 
In high doses: fluid in the organs 
which may cause low blood 
pressure, shortness of breath and/or 
swelling of ankles 
 
Possible Risks Associated with Stem Cells 
 
• 
ANY TIME BEFORE STEM CELL INFUSION: The freezer where PBSC are stored could 
malfunction, the container holding them could break and the stem cells could be damaged so they 
could not be used. This is expected to be an extremely rare event. However, if this occurs, another 
stem cell collection may be attempted or the back-up stem cells (if available) may be used if they 
were not damaged. 
 
• 
If stem cells need to be shipped from one location to another, they could be lost or damaged during 
shipping such that they could not be used. This is expected to be an extremely rare event. If this 
occurs, another stem cell collection may be attempted or the back-up stem cells, if available, may 
be used. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
128 
 
• 
Some patients may need extra fluids given into the vein after getting their stem cells.  This is to 
protect the kidneys from the red blood cells mixed in with the stem cells.   
 
Likely  
(happens 
to 
21-100 
children out of every 100 
children) 
Less Likely 
(happens 
to 
5-20 
children out of every 100 
children) 
Rare 
(happens to < 5 children out of every 100 children) 
 
• Fever and chills 
• Allergic reaction.  Can cause difficulty 
breathing and low blood pressure. 
• High blood pressure 
• Infection 
• Infusion of tumor cells. Tumor cells may still be 
present in the harvested stem cells and they 
could regrow after stem cells are infused. 
• Cough 
• Chest Tightness 
• Flushing 
• Nausea and/or vomiting 
• Rash 
• Irregular Heart Beat 
 
Herbs and Supplements 
Some drugs or supplements may interact with your treatment plan. Talk to your doctor, pharmacist, or study 
team before starting any new prescription drugs, over-the-counter drugs, herbals, or supplements and 
before making a significant change in your diet. Supplements may come in many forms, such as teas, 
drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be avoided. 
  
Possible Risks to Unborn Child 
Patients who agree to participate in this study should not become pregnant while on this study. Patients 
and their sexual partners should avoid sex and / or use two effective methods of contraception that are 
medically appropriate based on your personal doctor’s recommendation at that time and should be used 
for as long as you participate in this study. If you or your partner becomes pregnant while you are 
participating in this study, please notify your doctor immediately.  For more information about risks and 
side effects, ask your doctor. 
 
Possible Risks to the Caregiver(s) of the Patient Getting 131I-MIBG Treatment 
Caregivers (example: parent, other family member, guardian, friend, partner) will be exposed to radiation 
while you are being treated with 131I-MIBG.  Caregivers who could possibly become pregnant during this 
time need to avoid contact with the patient because the radiation exposure may increase the unborn 
baby’s risk of developing cancer or other health problems.   
 
If your caregiver is pregnant, then special precautions should be used to avoid contact with you during 
and for 4 weeks after getting 131I-MIBG treatment.  Should your caregiver or your caregiver’s sexual 
partner be found to have been pregnant while you were getting 131I-MIBG treatment and did not know it 
at the time, please contact your doctor immediately.  
 
Possible Long-Term Risks of This Treatment  
• 
Recurrence of tumor 
• 
Infection 
• 
Sterility and/or delayed onset of puberty 
• 
Increased risk of a second cancer (such as leukemia) different from the kind of cancer you have now. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
129 
 
• 
Patients who have more than one 131I-MIBG treatment will have greater doses of radiation to the 
normal organs than those patients having one treatment. It is possible that there may be later damage 
to the normal function of the liver or other organs. 
 
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk. You will be asked to sign a separate 
consent for any procedure that needs sedation. 
 
Possible Risks from Germline Genetic Testing   
If you agree to participation in the optional test looking at immune system cells in your tumor and immune 
response, a small amount of your blood will be collected. Researchers will use the blood sent with your tumor 
for determining the genetic make-up of your normal cells (known as germline testing) that is used as a baseline 
to compare to the genetic make-up of your tumor. This helps the laboratory in identifying the genetic changes 
they may see in your tumor tissue.  
 
The germline genetic testing is for research purposes only and is performed on de-identified samples, and so 
the information can’t be linked back to your child. Hence, the results will not be sent to you or your physician. 
 
Unknown Risks 
This treatment combination may have side effects that no one knows about yet.  The researchers will let you 
know if they learn anything that might make you change your mind about participating in the study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children or young people with solid cancers in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
 
• 
Treatment with other chemotherapy medicines, or 131I-MIBG without dinutuximab 
• 
Treatment with other experimental agents that may be available 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable 
 
Please talk about these options with your doctor. 
 
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
We will do our best to make sure that the personal information in your medical record will be kept private. 
However, we cannot guarantee total privacy. Your personal information may be given out if required by law. 
If information from this study is published or presented at scientific meetings, your name and other personal 
information will not be used. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA), Health Canada, or European regulatory agency(ies) involved in keeping 
research safe for people. 
• 
Jubilant Radiopharma (supplier of 131I-MIBG)  
• 
United Therapeutics Corporation (manufacturer of dinutuximab) 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
130 
 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
The costs of vorinostat will be billed to your/your child’s insurance company. If your insurance company 
will not pay for the vorinostat you/your child may not continue on study.  Your physician will speak with 
you about other options that are available for future treatment. 
 
The 131I-MIBG will be supplied by Jubilant Radiopharma. The cost of 131I-MIBG and its administration 
costs will be billed to your/your child’s insurance company. 
 
Dinutuximab will be provided free of charge by United Therapeutics, Inc while you are taking part in this 
study.  United Therapeutics does not cover the cost of getting dinutuximab ready and giving it to you so 
your insurance company may have to pay for this. 
 
GM-CSF is a commercially available agent. You will pay for the amount of drug needed to complete this 
study.  This cost is normally covered by your insurance company. 
 
The correlative biology studies will be done at no cost to you.  However, you or your health plan may need 
to pay for the costs of the supplies and personnel who draw the blood from you for these tests. 
  
You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
 
Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)] if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
131 
 
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from the study at any time. No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 
We will tell you about new information or changes in the study that may affect your health or your willingness 
to continue in the study.  
 
In case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
You can talk to your study doctor about any questions or concerns you have about this study. Contact your 
study doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ [name 
of center] Institutional Review Board (a group of people who review the research to protect your rights) at 
__________________ (telephone number).  
 
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites at http://cancer.gov/ 
For NCI’s clinical trials information, go to http://cancer.gov/clinicaltrials/ 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
132 
 
CONSENT FOR OPTIONAL RESEARCH STUDIES 
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. Using extra blood to look for proteins and genetic changes in your cells. 
 
Initial next to YES if you agree to let researchers use some of the blood (less than ¼ teaspoon) already 
drawn for one of the required studies to look at certain immune cell genes and how changes in these genes 
might affect how you respond to the treatment. No extra blood needs to be drawn from you to do this 
optional test. The results of this test will be confidential and not made available to you or your treating 
physician. 
 
Initial next to NO if you do not want researchers to use some of the blood already drawn for a required test 
to look at immune cell genes.    
 
_______Yes      _______No    
 
Initial next to YES if you agree to let researchers take an extra half teaspoon (2.5 mL) of blood 9 different 
times to look for certain proteins and changes in these proteins that might affect your response to treatment 
with vorinostat, 131I-MIBG, and dinutuximab.  This blood would be drawn at a time when blood was being 
drawn for clinical purposes. The results of this test will be confidential and not made available to you or 
your treating physician. 
 
Initial next to NO if you do not want researchers to take extra blood above what is needed for clinical 
purposes. 
 
_______Yes      _______No 
 
2. 
Evaluate tumor tissue for immune system cells that surround and invade your tumor and 
the genes that cause an immune response, and if possible also comparine immune system cells in 
tumor samples from before and after treatment with vorinostat, 131I-MIBG and dinutuximab. 
 
Initial next to YES if you agree  to let researchers collect 3 mL (about ½ teaspoon) of blood to be sent together 
with any leftover tumor (if available from an earlier procedure) to a laboratory so researchers can learn more 
about the immune system cells that surround and invade your tumor and genes that cause an immune 
response. Looking at the immune response genes involves comparing your normal genetic information gotten 
from the blood sample (called germline) to the genetic information of your tumor and determining what is 
different between the two. The results of these tests will be confidential and not made available to you or your 
treating doctor. 
 
Initial next to NO if you do not want extra blood drawn and leftover tumor from an earlier procedure, if it is 
available, to be sent to a research laboratory.  
 
_______Yes      _______No   
 
Initial next to YES if you agree to have leftover tumor sent to the research lab if a biopsy is done in 
the future for clinical care and this happens after finishing this protocol therapy and before starting the next 
treatment for your tumor.  The purpose of this part of the test is to see if the 131I-MIBG had any effect on 
the immune cells that surround and invade your tumor.   
 
Initial next to NO if you do not want leftover tumor from a future procedure to be sent to a research laboratory. 
 
_______Yes      
_______No   
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
133 
 
3.  Storage of left over specimens obtained on this study for future use in research 
The NANT Biology Study (NANT2004-05) provides a way to allow for banking of leftover specimens from 
this study for future research to answer questions about vorinostat, 131I-MIBG, and dinutuximab treatment, 
neuroblastoma or other childhood cancers. 
 
Initial next to YES if you agree to storage of any specimens leftover from this study for future research. 
 
Initial next to NO if you do not want leftover specimens from this study stored for future research 
 
_______Yes      _______No 
 
 
 
STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments that 
were included with this informed consent document. I have asked all of my questions and I have gotten 
answers. I agree to enroll myself (my child) in this study. 
 
 
_____________________________________ 
Print Patient Name 
 
 
______________________________________  
 
_____/_____/_____ 
Print Name of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Patient (If > 7 years old) 
 
 
 
 
Date 
 
 
___________________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
134 
 
Consent Addendum I: Tests That Will Be Done On This Study 
Observation 
Before 
Entry 
Days 0 to Day 56 of Course 1 & 2 
End of treatment 
All other days during 
course 
During dinutuximab 
infusions only 
Day 8-11 and Day 29-32 
Physical Exam 
X 
Weekly 
Daily 
X 
Blood Tests 
X 
Twice weekly for blood 
counts,  
Weekly for other tests  
Daily 
 
X 
Urine tests 
 
X 
 
 
X 
Pregnancy test 
X 
 
 
X 
Heart tests 
[echocardiogram and 
electrocardiogram (EKG)] 
X 
EKG once between 
Days 4-8  
 
X 
MIBG scan after MIBG 
treatment 
(no extra MIBG is given to 
you to do this scan) 
 
After you get out of your 
radiation isolation room 
 
 
Blood correlative studies 
(Required) 
 
Course 1 only 
3 times  
 
Course 1 only 
4 times   
  
Course 1 only 
1 time 
Blood for correlative 
studies 
(Optional) 
 
Course 1 only 
4 times  
 
Course 1 only 
4 times   
 
Blood & Tumor sample 
sent for research (optional) 
Blood & Tumor sample can be sent any time during the study 
Disease Evaluation Tests# 
Bone marrow 
aspirate/biopsy 
X 
Day 43 – 57 of Course 1  
X 
CT, MRI and/or MIBG 
scans 
X 
X 
# Patients enrolled in the companion biology study may have additional samples of blood and  
bone marrow collected at study entry and with each disease evaluation time point. Please look at  
the biology study N04-05 consent form for more information. 
 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
135 
 
 
Consent Addendum II 
Certificate of Confidentiality Information 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects.  The Certificate protects against the involuntary release 
of information about subjects collected during the course of our covered studies.  The researchers 
involved in the studies cannot be forced to disclose the identity or any information collected in the 
study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may 
choose to voluntarily disclose the protected information under certain circumstances.  For example, 
if the subject or his/her guardian requests the release of information in writing, the Certificate does 
not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program 
evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of 
Confidentiality will not protect against the required reporting by hospital staff of information on 
suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or 
others. 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
136 
 
 
16.0 
SAMPLE INFORMED ASSENT 
 
There are separate sample assent documents for Part A and B. 
 
16.1 
Part A 
 
NANT 2017-01: A PHASE I STUDY OF 131I-MIBG WITH DINUTUXIMAB +/- VORINOSTAT FOR 
RELAPSED/REFRACTORY NEUROBLASTOMA 
 
FOR PATIENTS ON PART A 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol 
 
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1.  Dr. _______________ is doing a research study about the treatment of neuroblastoma.  
 
2.  You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. It 
may be that your cancer went away for a while but has come back. Or it may be that it has never 
gone away. We are asking you to take part in a research study because doctors want to learn more 
about treating neuroblastoma with two medicines called MIBG and dinutuximab to see what effects 
(both good and bad) this medicine has on patients and their cancer. The doctors think that giving 
MIBG with dinutuximab may kill more neuroblastoma cancer cells.  They also want to find out what 
the side effects are when MIBG is given together with dinutuximab. 
 
3. If you agree to be in this study this is what will happen: 
 
You can get up to two courses of this therapy as long as your tumor doesn’t get worse and you don’t 
have too bad of side effects. 
 
131I-MIBG 
131I-MIBG is a radioactive medicine given into an IV over 2 hours on the first day.   Because of this 
radiation treatment you will need to stay in your hospital room until you go home.   This is usually about 
5 days. Your parents cannot sleep in your room but they will be able to stay just outside your room 
and you will be able to see and talk to them anytime you want.  They can visit inside your room for a 
short time each day. 
 
Because not all hospitals can give the 131I-MIBG, you might have to go with your parents to another 
hospital to get the MIBG part.  Your doctor will talk with you and your parents about the different 
hospitals that can give the MIBG, and which one will be the best for you. 
 
You may need to have a urinary catheter placed to help drain your urine while you are getting the 
131I-MIBG treatment. A soft tube will be put inside your urethra (the hole where urine comes out of our 
bodies), and up into your bladder (the place where urine waits inside our bodies until we go to the 
bathroom). Because the 131I-MIBG will be in your urine, and can cause damage to your bladder, the 
catheter is necessary to prevent this from happening by keeping your bladder completely empty all 
the time.    
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
137 
 
 
Stem Cells 
 
131I-MIBG is a medicine that can lower the numbers of your normal blood cells.  Stem cells make all 
the normal blood cells your body needs to be healthy. This includes white blood cells that fight 
infection, platelets that stop you from bleeding, and red blood cells that carry oxygen to your body.  
When 131I-MIBG is given at higher doses it can damage stem cells so they don’t make enough of the 
normal blood cells we need to live. Your stem cells which were collected during your initial visit will be 
given back to you like a blood transfusion after the 131I-MIBG and other treatments are finished.  This 
is called Stem Cell Infusion or Stem Cell Rescue.  Two weeks after getting 131I-MIBG, we will give the 
stem cells back through your central line either in the hospital or in the clinic. It is a lot like getting a 
platelet transfusion – the stem cells look like watery blood. 
 
Dinutuximab 
 
You will get dinutuximab in your IV once a day for 4 straight days on Days 8-11 and Days 29-32. The 
dinutuximab is given over 10-20 hours.  You will be in the hospital when dinutuximab is given. 
 
Sargramostim/GM-CSF 
 
The GM-CSF helps the dinutuximab work better and also helps the blood cells grow back faster after 
treatment.  GM-CSF is given through your IV or as an injection (shot) from a very small needle into your 
leg that your parents will learn how to give you. It is given one time a day. You will get GM-CSF during 
the 4 days you are receiving dinutuximab and then for 6 days afterwards (total of 10 days with each 
dinutuximab; Days 8-17 and 29-38). You may also get GM-CSF if your blood cells are low after getting 
131I-MIBG, or your doctor may choose to give you a different medicine such as G-CSF or pegfilgrastim. 
If you are given GM-CSF because your blood cells are low it will be continued until your blood cells have 
started to grow back. We will know when the blood counts are high enough to stop the GM-CSF by doing 
a blood test. 
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who are 
taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked so far. 
The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often) 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Tests for your heart and your kidneys 
• 
Check your urine 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having. 
• 
You may have to come to the clinic to have blood and platelet transfusions when the blood counts 
are low or stay in the hospital if you have a fever with low blood counts. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything is 
going well.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happen to kids in research studies that may make them feel bad.  These are called 
“risks”.  Some of the risks of this study are:  
• 
You may feel sick to your stomach and you may throw up.   
• 
You may feel tired. 
• 
You may have a bad appetite. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
138 
 
• 
You may have pain or your body may hold onto too much fluid when you are getting the 
dinutuximab. 
• 
You might have a fever and maybe an infection where you will need to be in the hospital to get 
medicines to treat the infection.   
• 
You may feel tired and weak and need a blood transfusion or you may get bruises or have 
bleeding (most often a nosebleed) and need a platelet transfusion. 
• 
During 131I-MIBG, the urinary catheter may be uncomfortable, and some people feel 
embarrassed having it – but you will only need it for a few days.  It may also be hard to be in a 
room for a long time by yourself until the radiation levels are low enough that it is safe for your 
parents and everyone else to be around you all the time. 
• 
The treatments may not work, and your tumor may grow, or it might come back again after the 
treatment has finished. If this happens we will try other ways to stop the tumor from growing. 
• 
You could get a different kind of cancer, this doesn’t happen often, but can happen years later. 
• 
It is possible that you could die from the treatment or cancer. 
• 
Not all of these things may happen to you. Or things may happen that the doctors don’t know 
about yet. 
 
5. Things that happen to children in research studies that are good are called “benefits”.  Some of the good 
things for this research study could be: 
• 
This treatment might make your neuroblastoma tumor stay the same size or get smaller for some 
time. 
• 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
6. We will do everything possible to keep your information private and prevent people outside of the study 
from seeing information about you.  
 
7. Please talk this over with your parents before you decide whether or not to be in this study. We will 
also ask your parents to give their permission for you to take part in this study.  But even if your parents 
say “yes” you can still decide not to do this.   
 
8. Being in this study is up to you. You do not have to be in this study if you don’t want to. You may stop 
being in this study at any time but there are two times where you would be at more risk for being sick 
or having side effects or being dangerous to other people if you stopped being in the study.   
1)  If you got 131I-MIBG and left the special room before the doctors said it was ok to leave, then you 
would still be radioactive and this would be dangerous to everyone who was around you since 
you would give them radiation from your body.    
 
2)  If you decided to stop treatment after getting 131I-MIBG but before you were given your stem cells 
back, the high dose of 131I-MIBG could kill your blood cells so they would not grow back on their 
own without getting back your stem cells.  In this case you would not be able to make your own 
blood cells and could have bad infections or bleeding, and you could die from not having enough 
normal blood cells. 
 
9. You can ask any questions that you have about the study. If you have a question later that you didn’t 
think of now, you can call me or ask me next time you see me.   
• 
Study doctor’s phone number: __________________ 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
139 
 
10. Special Study Tests:  
You will have blood tests done to measure changes in the number and function of certain cells of your 
immune system, as well as to measure levels of certain proteins that cause inflammation in the body. 
You will also have blood tests done to look for antibodies that attach to the dinutuximab and make it so 
it can’t attack your neuroblastoma. These blood tests will be done 7 times over the first course of 
treatment. A central line can be used to draw these blood samples.  Otherwise you may need to have 
a needle poke or a small plastic tube placed in a vein of your hand or arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study.   These extra tests are done for research only so the results won’t 
be told to your doctor or to you. 
 
#1:   
Check YES if it is ok for us to take 1/2 teaspoon of extra blood at different 8 times to learn 
more about how the body responds to this treatment. There will be no extra blood draw. We 
will draw this blood at the same time blood is being drawn to take care of you.  
 
 
 
Check NO if it is not ok for us to take this extra blood. 
 
____________ 
YES,   you can draw the extra blood 
 
____________ 
NO,    I don’t want to have the extra blood drawn 
 
 
#2:  
Check YES if it is ok to use a little bit of blood (less than half a teaspoon) that was drawn to do 
another test on this study to look at the genes in charge of how your immune system responds 
to this treatment.  No extra blood draws are needed to do this test.  
 
____________ 
YES,   you can do this test.   
____________ 
NO,    I don’t want this test done. 
 
#3  
Check YES if it is OK to let us look at some leftover tumor collected from a surgery you had 
before as part of your treatment to learn more about the immune cells that are inside your tumor 
and outside surrounding it, and the genes that are in charge of your body’s immune response.  
In order to do this test, researchers also need to collect a small about of blood (half teaspoon) 
that would be sent to the laboratory at the same time as the tumor sample. 
 
____________ 
YES,    you can use my tumor samples and draw the extra blood 
 
____________ 
NO,    I don’t want my tumor samples to be used or have extra 
blood drawn for this test. 
 
 
 
#4 
Check YES if you agree to let researchers have a tumor sample if you have tumor surgery 
sometime after you finish treatment with MIBG on this study. Researchers want to see if the 
MIBG had any effect on the immune cells that are around and invade your tumor.   
 
____________ 
YES,    you can use my tumor samples collected in the future 
 
____________ 
NO,    I don’t want my tumor samples to be used 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
140 
 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
Name of Patient: _________________________ 
 
 
 
 
 
 
 
 
 
 
_______ Yes, I want to be in the study. 
 
______    No, I do not want to be in the study. 
 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
 
_____________________________________  
______________________ 
Signature of Physician or  
 
 
 
 
Date  
Responsible Investigator 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
141 
 
16.2 
Part B 
 
NANT 2017-01: A PHASE I STUDY OF 131I-MIBG WITH DINUTUXIMAB +/- VORINOSTAT FOR 
RELAPSED/REFRACTORY NEUROBLASTOMA 
 
FOR PATIENTS ON PART B 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol 
 
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1. Dr. _______________ is doing a research study about the treatment of neuroblastoma.  
 
2. You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. It 
may be that your cancer went away for a while but has come back. Or it may be that it has never 
gone away. We are asking you to take part in a research study because doctors want to learn more 
about treating neuroblastoma with three medicines called vorinostat, 131I-MIBG, and dinutuximab to 
see what effects (both good and bad) this medicine has on patients and their cancer. The doctors 
think that giving MIBG with dinutuximab and vorinostat may kill more neuroblastoma cancer cells.  
They also want to find out what the side effects are when MIBG is given together with dinutuximab 
and vorinostat. 
 
3. If you agree to be in this study this is what will happen: 
 
You can get up to two courses of this therapy as long as your tumor doesn’t get worse and you don’t 
have too bad of side effects. 
 
Vorinostat 
You will take vorinostat by mouth or by a tube inserted through the nose or stomach once a day for 
14 days. If you vomit within 15 minutes of taking the vorinostat you should retake the dose. If you 
vomit again with the second dose you should not try to take the dose again. If you vomit more than 15 
minutes after taking the vorinostat you should not try to retake the dose.       
 
131I-MIBG 
131I-MIBG is a radioactive medicine given into an IV over 2 hours on the first day. Because of this 
radiation treatment you will need to stay in your hospital room until you go home.   This is usually about 
5 days. Your parents cannot sleep in your room but they will be able to stay just outside your room and 
you will be able to see and talk to them anytime you want.  They can visit inside your room for a short 
time each day. 
 
Because not all hospitals can give the 131I-MIBG, you might have to go with your parents to another 
hospital to get the 131I-MIBG part. Your doctor will talk with you and your parents about the different 
hospitals that can give the 131I-MIBG, and which one will be the best for you. 
 
You may need to have a urinary catheter placed to help drain your urine while you are getting the 131I-
MIBG treatment. A soft tube will be put inside your urethra (the hole where urine comes out of our 
bodies), and up into your bladder (the place where urine waits inside our bodies until we go to the 
bathroom). Because the 131I-MIBG will be in your urine, and can cause damage to your bladder, the 
catheter is necessary to prevent this from happening by keeping your bladder completely empty all the 
time.    


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
142 
 
 
Dinutuximab 
You will get dinutuximab in your IV once a day for 4 straight days on Days 8-11 and Days 29-32. The 
dinutuximab is given over 10-20 hours.  You will be in the hospital when dinutuximab is given. 
 
Sargramostim/GM-CSF 
The GM-CSF helps the dinutuximab work better and also helps the blood cells grow back faster after 
treatment.  GM-CSF is given through your IV or as an injection (shot) from a very small needle into your 
leg that your parents will learn how to give you. It is given one time a day. You will get GM-CSF during 
the 4 days you are receiving dinutuximab and then for 6 days afterwards (total of 10 days with each 
dinutuximab; Days 8-17 and 29-38). You may also get GM-CSF if your blood cells are low after getting 
131I-MIBG, or your doctor may choose to give you a different medicine such as G-CSF or pegfilgrastim. If 
you are given GM-CSF because your blood cells are low it will be continued until your blood cells have 
started to grow back. We will know when the blood counts are high enough to stop the GM-CSF by doing 
a blood test. 
 
Stem Cells 
131I-MIBG is a medicine that can lower the numbers of your normal blood cells.  Stem cells make all the 
normal blood cells your body needs to be healthy. This includes white blood cells that fight infection, 
platelets that stop you from bleeding, and red blood cells that carry oxygen to your body.  When 131I-
MIBG is given at higher doses it can damage stem cells so they don’t make enough of the normal blood 
cells we need to live. Your stem cells which were collected from you from your initial visit will be given 
back to you like a blood transfusion after the 131I-MIBG and other treatments are finished.  This is called 
Stem Cell Infusion or Stem Cell Rescue.  Two weeks after getting 131I-MIBG, we will give the stem cells 
back through your central line either in the hospital or in the clinic. It is a lot like getting a platelet 
transfusion – the stem cells look like watery blood. 
 
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who are 
taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked so far. 
The doctors will want to do some special tests to find this information out. They will include; 
 
• 
Blood tests (we will do this twice each week to start with, and then less often) 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Tests for your heart and your kidneys 
• 
Check your urine 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having. 
• 
You may have to come to the clinic to have blood and platelet transfusions when the blood counts 
are low or stay in the hospital if you have a fever with low blood counts. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything is 
going well.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happen to kids in research studies that may make them feel bad.  These are called 
“risks”.  Some of the risks of this study are:  
• 
You may feel sick to your stomach and you may throw up.   
• 
You may feel tired. 
• 
You may have a bad appetite. 
• 
You may have pain or your body may hold onto too much fluid when you are getting the 
dinutuximab. 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
143 
 
• 
You might have a fever and maybe an infection where you will need to be in the hospital to get 
medicines to treat the infection.   
• 
You may feel tired and weak and need a blood transfusion or you may get bruises or have 
bleeding (most often a nosebleed) and need a platelet transfusion. 
• 
During 131I-MIBG, the urinary catheter may be uncomfortable, and some people feel 
embarrassed having it – but you will only need it for a few days.  It may also be hard to be in a 
room for a long time by yourself until the radiation levels are low enough that it is safe for your 
parents and everyone else to be around you all the time. 
• 
The treatments may not work, and your tumor may grow, or it might come back again after the 
treatment has finished. If this happens we will try other ways to stop the tumor from growing. 
• 
You could get a different kind of cancer, this doesn’t happen often, but can happen years later. 
• 
It is possible that you could die from the treatment or cancer. 
• 
Not all of these things may happen to you. Or things may happen that the doctors don’t know 
about yet. 
 
5. Things that happen to children in research studies that are good are called “benefits”.  Some of the good 
things for this research study could be: 
a. This treatment might make your neuroblastoma tumor stay the same size or get smaller for some 
time. 
b. We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
6. We will do everything possible to keep your information private and prevent people outside of the study 
from seeing information about you.  
 
7. Please talk this over with your parents before you decide whether or not to be in this study. We will also 
ask your parents to give their permission for you to take part in this study.  But even if your parents say 
“yes” you can still decide not to do this.   
 
8. Being in this study is up to you. You do not have to be in this study if you don’t want to. You may stop 
being in this study at any time but there are two times where you would be at more risk for being sick 
or having side effects or being dangerous to other people if you stopped being in the study.   
1)  If you got 131I-MIBG and left the special room before the doctors said it was ok to leave, then you 
would still be radioactive and this would be dangerous to everyone who was around you since 
you would give them radiation from your body.    
 
2)  If you decided to stop treatment after getting 131I-MIBG but before you were given your stem cells 
back, the high dose of 131I-MIBG could kill your blood cells so they would not grow back on their 
own without getting back your stem cells.  In this case you would not be able to make your own 
blood cells and could have bad infections or bleeding, and you could die from not having enough 
normal blood cells. 
 
9. You can ask any questions that you have about the study. If you have a question later that you didn’t 
think of now, you can call me or ask me next time you see me.   
• 
Study doctor’s phone number: __________________ 
 
10. Special Study Tests:  
You will have blood tests done to measure changes in the number and function of certain cells of your 
immune system, as well as to measure levels of certain proteins that cause inflammation in the body. 
You will also have blood tests done to look for antibodies that attach to the dinutuximab and make it so 
it can’t attack your neuroblastoma. These blood tests will be done 8 times over the first course of 
treatment. A central line can be used to draw these blood samples.  Otherwise you may need to have 
a needle poke or a small plastic tube placed in a vein of your hand or arm for these samples. 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
144 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study.   These extra tests are done for research only so the results won’t 
be told to your doctor or to you. 
 
 
#1:   
Check YES if it is ok for us to take 1/2 teaspoon of extra blood at different 8 times to learn 
more about how the body responds to this treatment. We will draw this blood at the same 
time blood is being drawn to take care of you.  
 
 
 
Check NO if it is not ok for us to take this extra blood. 
 
____________ 
YES,   you can draw the extra blood 
 
____________ 
NO,    I don’t want to have the extra blood drawn 
 
 
#2:  
Check YES if it is ok to use a little bit of blood (less than half a teaspoon) that was drawn to do 
another test on this study to look at the genes in charge of how your immune system responds 
to this treatment.  No extra blood draws are needed to do this test.  
 
____________ 
YES,   you can do this test. 
____________ 
NO,    I don’t want this test done. 
 
#3  
Check YES if it is OK to let us look at some leftover tumor collected from a surgery you had 
before as part of your treatment to learn more about the immune cells that are inside your tumor 
and outside surrounding it, and the genes that are in charge of your body’s immune response.  
In order to do this test, researchers also need to collect a small about of blood (half teaspoon) 
that would be sent to the laboratory at the same time as the tumor sample. 
 
____________ 
YES,    you can use my tumor samples and draw the extra blood 
 
____________ 
NO,    I don’t want my tumor samples to be used or have extra 
blood drawn for this test. 
 
 
 
#4 
Check YES if you agree to let researchers have a tumor sample if you have tumor surgery 
sometime after you finish treatment with MIBG on this study. Researchers want to see if the 
MIBG had any effect on the immune cells that are around and invade your tumor.   
 
____________ 
YES,    you can use my tumor samples collected in the future 
 
____________ 
NO,    I don’t want my tumor samples to be used 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
145 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
Name of Patient: _________________________ 
 
 
 
 
 
 
 
 
 
 
_______ Yes, I want to be in the study. 
 
______    No, I do not want to be in the study. 
 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
 
_____________________________________  
______________________ 
Signature of Physician or  
 
 
 
 
Date  
Responsible Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
NANT 2017-01 Amendment 5 v02.21.2022 
 
146 
 
 
APPENDIX I: 
PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to 
carry on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, 
no evidence of disease 
100 
Fully active, normal. 
 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in 
physically strenuous 
activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light 
or sedentary nature, 
e.g., light housework, 
office work. 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
80 
Active, but tires more 
quickly 
 
70 
Cares for self, unable to 
carry on normal activity or 
do active work. 
70 
Both greater restriction of 
and less time spent in 
play activity. 
2 
Ambulatory and capable 
of all self-care but 
unable to carry out any 
work activities. Up and 
about more than 50% of 
waking hours 
60 
Required occasional 
assistance, but is able to 
care for most of his/her 
needs. 
60 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities. 
 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies 
around much of the day; 
no active play, able to 
participate in all quiet play 
and activities. 
3 
Capable of only limited 
self-care, confined to bed 
or chair more than 50% 
of waking hours.  
40 
Disabled, requires 
special care and 
assistance. 
40 
Mostly in bed; participates 
in quiet activities. 
 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
30 
In bed; needs assistance 
even for quiet play. 
4 
Completely disabled. 
Cannot carry on any 
self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
20 
Often sleeping; play 
entirely limited to very 
passive activities. 
 
10 
Moribund, fatal 
processes progressing 
rapidly. 
10 
No play; does not get out 
of bed. 
 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.  
 


 
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APPENDIX II: SUMMARY FOR CORRELATIVE STUDIES 
 
Summary of Research Blood Samples: Blood volumes below are maximum values. For patients with a 
weight below the minimum required to tolerate all blood draws requested for correlative studies, please 
consult with study chair to determine prioritization of samples. The correlative studies are to be drawn 
only during the first course of therapy with exception of the N04-05 specimens. Please refer to the N04-05 
for complete collection requirements. 
 
When immune and cytokine profiling (section 8.2) and NB5 (TLDA assay) (N04-05) samples coincide, the 
priority is to collect the immune and cytokine profiling first and if maximum blood volume allowable for 
research purposes has not been surpassed then the NB5 (TLDA)   sample may be collected (refer to 
protocol section 8.3).  Patients can submit only bone marrow for NB5 (TLDA) if blood volumes for research 
do not allow for blood submission.   
 
This table is a summary overview of correlative studies.  Refer to specific protocol section for all details 
regarding specimen collection timing, processing, labeling and shipping. 
 
NOTE: There are separate tables for Part A and Part B. 
 
 
 


 
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Part A 
 
Phase of 
Therapy 
 
COURSE 1 
ONLY 
Required Study Specimens 
Optional Study Specimens 
Immune 
Profiling 
Section 8.1.2.1 
 
Cytokine 
Profiling 
Section 8.1.2.2 
(Refer to Appendix 
VI) 
and 
HACA/ADA 
levels 
Section 8.2 
NB5 assay 
by TLDA 
Refer to  
NANT 2004-05 
DNA for 
future gene 
expression 
(Section 8.6) 
RNA Gene 
Expression 
Section 8.5 
Tumor 
Microenvironment 
Section 8.8 
Fresh whole 
blood 
Frozen plasma 
Fresh whole 
blood and BM 
aspirate 
Fresh whole 
blood 
Frozen whole 
blood 
Soft tissue tumor and 
fresh whole blood 
Green top 
tube 
CPT tube 
Refer to  
NANT 2004-05 
Refer to 
immune 
profiling 
PAXgene tube 
3mL peripheral blood 
in purple top (EDTA) 
tube and FFPE block 
or 
tissue scrolls/slides 
Shipping 
Overnight 
(Section 8.3) 
Batch ship 
Course #1 
(Section 8.3) 
Batch ship 
Course #1 
(Section 8.3) 
Overnight any time 
course #1 
(Section 8.8) 
Screening 
 
 
X 
 
 
Submit tumor tissue 
if available at 
following time 
points: 
A.  Most recent biopsy 
performed before 
study registration and 
3mL fresh blood 
 
B.  Any biopsy done 
post completion of 
N17-01 therapy and 
subsequent to start of 
any other therapy. 
After study 
registration or 
Day 1#,* 
5 mL 
8 mL 
ALL COURSES 
X 
 
Day 1#,* 
 
 
 
2.5 mL  
Day 8^,* 
5 mL 
8 mL  
(Cytokine 
only) 
X 
2.5 mL 
Day 11$ 
 
8 mL 
(HACA/ADA 
only) 
 
2.5 mL 
Day 15*,& 
+/- 2 days 
5 mL 
8 mL 
(Cytokine 
only) 
X 
2.5 mL 
Day 29^,* 
5 mL 
8 mL 
X 
2.5 mL 
Day 32$  
 
8 mL 
(HACA/ADA 
only) 
 
2.5 mL 
Day 36 
 
 
 
2.5 mL 
End of Course* 
5 mL 
8 mL 
 X 
X 
2.5 mL 
 
# Specimen may be drawn earlier than day 1if study registration has been completed.  If performed on 
Day 1, please draw specimen prior to 131I-MIBG infusion. 
^To be drawn prior to dinutuximab infusion on day 8 and day 29; delay accordingly if start of dinutuximab 
is delayed. 
$ To be drawn prior to dinutuximab infusion on day 11 and day 32; delay accordingly if start of 
dinutuximab is delayed. 
* Specimens collected on these days will undergo PBMC freezing. 
& Must be drawn prior to stem cell infusion. 
 
 


 
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Part B 
 
Phase of 
Therapy 
 
COURSE 1 
ONLY 
Required Study Specimens 
Optional Study Specimens 
Immune 
Profiling 
Section 8.1.2.1 
 
Cytokine 
Profiling 
Section 8.1.2.2 
(Refer to Appendix 
VI) 
and 
HACA/ADA 
levels 
Section 8.2 
NB5 assay 
by TLDA 
Refer to  
NANT 2004-05 
DNA for 
future gene 
expression 
(Section 8.6) 
RNA Gene 
Expression 
Section 8.5 
Tumor 
Microenvironment 
Section 8.8 
Fresh whole 
blood 
Frozen plasma 
Fresh whole 
blood and BM 
aspirate 
Fresh whole 
blood 
Frozen whole 
blood 
Soft tissue tumor and 
fresh whole blood 
Green top 
tube 
CPT tube 
Refer to  
NANT 2004-05 
Refer to 
immune 
profiling 
PAXgene  RNA 
tube 
3mL peripheral blood 
in purple top (EDTA) 
tube and FFPE block 
or 
tissue scrolls/slides 
Shipping 
Overnight 
(Section 8.3) 
Batch ship 
Course #1 
(Section 8.3) 
Batch ship 
Course #1 
(Section 8.3) 
Overnight any time 
course #1 
(Section 8.8) 
Screening 
 
 
X 
 
 
Submit tumor tissue 
if available at 
following time 
points: 
A.  Most recent biopsy 
performed before 
study registration and 
3mL fresh blood 
 
B.  Any biopsy done 
post completion of 
N17-01 therapy and 
subsequent to start of 
any other therapy. 
After study 
registration or 
Day 0#,*  
5 mL 
8 mL 
ALL COURSES 
X 
2.5 mL 
Day 1@,* 
5 mL  
8 mL 
(Cytokine 
only) 
X 
2.5 mL  
Day 8^,* 
5 mL 
8 mL  
(Cytokine 
only) 
X 
2.5 mL 
Day 11$ 
 
8 mL 
(HACA/ADA 
only) 
 
2.5 mL 
Day 15*,& 
+/- 1 day 
5 mL 
8 mL 
(Cytokine 
only) 
X 
2.5 mL 
Day 29^,* 
5 mL 
8 mL 
X 
2.5 mL 
Day 32$  
 
8 mL 
(HACA/ADA 
only) 
 
2.5 mL 
Day 36 
 
 
 
2.5 mL 
End of Course* 
5 mL 
8 mL 
 X 
X 
2.5 mL 
 
# Specimen may be drawn earlier than day 0 if study registration has been completed.  If performed on 
Day 0, please draw specimen prior to first dose of vorinostat.  
^ To be drawn prior to dinutuximab infusion on day 8 and day 29; delay accordingly if start of dinutuximab 
is delayed. 
$ To be drawn prior to dinutuximab infusion on day 11 and day 32; delay accordingly if start of 
dinutuximab is delayed. 
* Specimens collected on these days will undergo PBMC freezing. 
& Must be drawn prior to stem cell infusion. 
@ Must be drawn prior to MIBG infusion. 


 
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APPENDIX III: ADJUSTED BODY WEIGHT CALCULATION FOR STEM CELL DOSING 
 
For patients whose actual body weight exceeds ideal body weight (IBW) by more than 20%, the dose of 
stem cells may be based on adjusted body weight (ABW) rather than actual body weight.  
 
IBW Formulas:  
1-17 years: height is in cm, weight is in kg  
IBW = (height2 x 1.65)/1000  
 
1-17 years and 5 feet or taller:  
IBW in kg (male) = 39 + (2.27 x height in inches over 5 feet)  
IBW in kg (female) = 45.5 + (2.27 x height in inches over 5 feet)  
 
18 years and older:  
IBW in kg (male) = 50 + (2.3 x height in inches over 5 feet)  
IBW in kg (female) = 45.5 + (2.3 x height in inches over 5 feet)  
 
ABW is determined:  
ABW=IBW + 0.4 x (actual BW-IBW)  
 
(Reference: Bone Marrow Transplant. 2007; 40(7):665-9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX IV: COMPOUNDS THAT INTERFERE WITH 131I-MIBG METABOLISM AND UPTAKE 
 
 
1. Drugs Known To Reduce Uptake of 131I-MIBG 
 
Drug  
Mechanism  
Sympathomimetics# 
     Phenylephrine  
     Phenylpropanolamine  
     Pseudoephedrine, ephedrine  
Depletion of storage vesicle contents.  
These drugs occur in numerous non-
prescription decongestants and diet aids. Their 
use should be excluded.  
Antihypertensive / cardiovascular  
     Labetalol  
     Reserpine  
Inhibition of catecholamine uptake. Depletion of 
storage vesicle contents.  
Depletion of storage vesicle contents. Inhibition 
of vesicle active transport.  
Calcium-channel blockers  
Amlodipine, diltiazem, felodipine, isradipine, nicardipine, 
nifedipine , nisoldipine, verapamil  
Uncertain (also enhances retention of 
previously stored norepinephrine and MIBG by 
blocking Ca++ mediated release from vesicles)  
Tricyclic antidepressants  
     Amitriptyline, amoxapine, desipramine , doxepin,  
imipramine, nortriptyline , protriptyline, trimipramine  
Inhibition of catecholamine uptake  
Cocaine  
Inhibition of catecholamine uptake  
#: Systemic use 
 
2. Drugs Expected To Reduce Uptake of 131I-MIBG 
 
Drug  
Mechanism  
Sympathomimetics  
     Amphetamine and related compounds  
 
Beta-sympathomimetics#  
     Dobutamine, Dopamine, Metaraminol  
Depletion of storage vesicle contents.  
Atypical antidepressants  
     Maprotiline  
     Trazodone  
Inhibition of catecholamine uptake.  
Antipsychotics (major tranquilizers)  
     Phenothiazines*  
     Thioxanthines  
     Butyrophenones  
Inhibition of catecholamine uptake.  
Antihypertensive / cardiovascular  
     Adrenergic neuron blockers  
Guanethidine, guanadrel, bethanidine, 
debrisoquine, bretylium, reserpine, metyrosine 
Depletion of storage vesicle contents. Competition 
for transport into vesicles.  
#: Systemic use. Effect unlikely with aerosol administration 
 *Occasionally used as an antiemetic/antipruritic agent 
 
 
 
 
 
 
 
 
 


 
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APPENDIX V: QUALITY CONTROL FOR FREE IODINE IN 131I-MIBG (DETECTION OF RADIOLYTIC 
DECOMPOSITION) 
 
NOTE: As of 10/20/21, radiochemical purity testing at clinical sites following receipt of 131I-MIBG 
from Jubilant Radiopharma is no longer required. Sites are still to check for discoloration and 
particulate matters prior to product administration to the patient. Additionally, if a “Temperature 
Alarm” is detected on the temperature monitor provided in the 131I-MIBG shipment, sites are NOT to 
use the product and should store the vial in the lead pot and call JRP Customer Service immediately 
for further instructions.  
 
Should clinical sites still wish to perform radiochemical purity testing, the below is a suggested 
technique:  
 
Radiopharmaceutical   
131I-MIBG from Jubilant Radiopharma 
 
Preparation  
 
 
Receipt of therapeutic 131I-MIBG from supplier 
 
Materials  
 
 
Waters Accell Plus CM Sep-Pac 
Ethanol 
Sterile water 
10 ml test tubes 
 
Instrumentation  
 
Capintec well counter 
Calculator 
 
Procedure 
1. Using a Waters Accell Plus CM Sep-Pac cartridge, wet the Sep-Pac with 5 ml ethanol. the long tip of 
the Sep-Pac must be connected to the flushes 
2. Rinse with 5 ml sterile water 
3. Add one drop to 1/20 ml mibg to Sep-Pac. Dilute to around 0.5 uCi 
4. Flush Sep-Pac with 5 ml sterile water into a 10 ml test tube (flush tube) 
5. Place cartridge into a second 10 ml test tube (A) 
6. Place the cartridge tube into a well counter and record (A), set counter on 131-I 
7. Count both tubes (A and flush) in the well counter, add counts together and record (B), set counter on 
131-I 
8. A/A+B x 100 = % tagged. Must be greater than 95% for Jubilant Radiopharma product- compare to 
TLC 
 
 
Comments  
Procedure must be performed within 24 hours of receipt of dose from supplier. 
Results of bound iodine should be greater than 95% for Jubilant Radiopharma product. 
Record results on worksheet. Contact physicians if there is an aberrant or low result. 
 
All centers administering 131I-MIBG therapy must perform an assay for radiolytic 
decomposition; the above is a suggested technique. Other techniques may be used 
provided they meet institutional radiopharmaceutical guidelines. 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX VI: Isolation and Storage of Plasma and Peripheral Blood Mononuclear Cells (PBMCs) 
 
Purpose 
To isolate Plasma and Peripheral Blood Mononuclear Cells (PBMCs) for long-term storage.  This protocol 
applies to blood samples that have been collected in Sodium Heparin Cell Preparation Tubes (CPT). 
 
Equipment and Material Required 
➢ Blood Samples in 8mL Sodium Heparin CPT tube 
➢ Centrifuge (capable of centrifugation at 3,000 x rcf) 
➢ Pipette and Pipette Tips 
➢ 1.0 mL and 1.8 mL cryovials (capable of being stored at -80˚C or -150˚C) 
➢ Extra collection tubes (to counterbalance during centrifugation) 
➢ PBS with 2% FBS (room temperature) 
➢ Freeze Media 1 and Freeze Media 2 (room temperature)  
 
Note 
• 
After collection, store tube upright at room temperature until centrifugation. 
• 
Blood samples should be centrifuged within 2 hours of blood collection. 
 
Procedure 
1. Gently invert tubes 5 times before placing in the centrifuge. 
2. Counter balance extra collection tubes for centrifugation. 
3. Centrifuge samples in a horizontal (swing bucket) rotor for 15 minutes at 1,600 rcf at room 
temperature. 
4. Remove blood collection tubes from centrifuge and ensure that tubes are kept in the upright position.   
5. Using a sterile serological pipette, draw off (transfer) the upper layer (plasma) into a new 15mL 
conical tube labeled “plasma”.  Leave the mononuclear layer undisturbed (see image above). 
6. Using a sterile pipette, transfer everything remaining above the polyester gel layer (plasma, 
mononuclear cells, platelets, and density solution) into a new 15 mL conical tube labeled “PBMCs.” 
7. Discard blood collection tubes in the appropriate biohazard waste container. 
Additional Plasma Processing (after step 5) 
8. Counter balance extra 15 mL conical tubes for centrifugation. 
9. Centrifuge plasma for 10 minutes at 3,000 rcf at room temperature. 
10. Aliquot platelet-free plasma into the provided cryovials as described in the table below.   


 
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11. Place all cryovials in the provided 81-place cryobox and store the box, upright, in a - 80˚C freezer. 
 
Tube Number 
Volume 
Label 
1 
0.2 mL 
Cytokine 
2 
0.2 mL 
Cytokine 
3 
0.2 mL 
HACA 
4 
0.2 mL 
HACA 
5 
0.2 mL 
Cytokine 
6 
0.2 mL 
Cytokine 
7 
0.5 mL (if available) 
Extra 
8 
0.5 mL (if available) 
Extra 
9 
0.5 mL (if available) 
Extra 
 
Additional Peripheral Blood Mononuclear Cell (PBMC) Processing (after step 6) 
12. Using a sterile serological pipette, bring the total volume in the 15mL conical tube (containing plasma, 
mononuclear cells and platelets, and density solution) to 15 mL using PBS with 2% FBS. 
13. Close the cap of the 15 mL centrifuge tube and mix the cells by gently inverting the tube 5 times. 
14. Centrifuge the sample at 300 rcf for 15 minutes at room temperature. 
15. Aspirate or decant (gradually pour off) as much supernatant as possible without disturbing the cell 
pellet.   
16. Resuspend the cells by gently vortexing or tapping the tube with your index finger. 
17. Using a sterile serological pipette, add 10 mL of PBS with 2% FBS to the 15 mL conical tube 
containing the cell pellet.  
18. Close the cap of the 15 mL centrifuge tube and mix the cells by gently inverting the tube 5 times. 
19. Centrifuge the sample at 300 rcf for 10 minutes at room temperature. 
20. Aspirate or decant (gradually pour off) as much supernatant as possible without disturbing the cell 
pellet.   
21. Resuspend the cells by gently vortexing or tapping the tube with your index finger. 
22. Using a pipette and sterile pipette tip, add 1 mL of Freeze Media 1 to the 15 mL conical tube 
containing the resuspended cell pellet.   
23. To ensure adequate resuspension of cells, pipette the freeze media/cell suspension up and down 8 
times.   


 
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24. Using a pipette and sterile pipette tip, add 1 mL of Freeze Media 2 dropwise to the 15 mL conical tube 
containing the resuspended cell pellet.   
25. To ensure adequate resuspension of cells, pipette the freeze media/cell suspension up and down 8 
times.   
26. Aliquot 1 mL of cells/freeze media into each of 2 x 1.8 mL cryovials. 
27. Transfer cryovials into a controlled cell freezing apparatus (Mr. Frosty) and place in -80˚C freezer for 
24 hours. 
28. Transfer cells to a liquid nitrogen freezer for storage.  
***NOTE: For ONLY sites that don’t have liquid nitrogen storage available: Store the day 1, 8, 
and 15 samples at -80 ˚C and then after the day 15 draw, ship these 3 samples overnight on dry ice 
to the CCTDC. Then, store the day 29 sample at -80 ˚C until after the end of course sample is drawn, 
and then ship these 2 samples, along with the tubes for cytokine analysis (sites without liquid 
nitrogen storage only), overnight on dry ice to the CCTDC.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX VII: MEDICATIONS ASSOCIATED WITH PROLONGED QTc 
 
The use of the following medications should be avoided during vorinostat therapy if reasonable 
alternatives exist. This is not an all-inclusive list. Because the lists of these agents are constantly 
changing, it is important to regularly consult frequently updated medical references. For the most current 
list of medications, please refer to the following reference: www.Crediblemeds.org.  
 
Drugs that are generally accepted as having a 
known risk of causing Torsades de pointes 
 
Prohibited within one week of vorinostat on 
Arm C 
Drugs that are generally accepted as having a 
possible risk of causing Torsades de pointes  
 
Use with caution in patients on Arm C 
Amiodarone (Cordarone®, Pacerone®) 
Aripiprazole (Abilify, Aripiprex) 
Anagrelide (Agrylin®, Xagrid®) 
Atomoxetine (Strattera)  
Arsenic trioxide (Trisenox®) 
Bedaquiline (Sirutro®) 
Azithromycin (Zithromax®, Zmax®) 
Bendamustine  
Bepridil (Vascor)  
Betrixaban (Bevyxxa) 
Chloroquine (Aralen®) 
Bortezomib (Velcade)  
Chlorpromazine (Thorazine®) 
Bosutinib (Bosulif)  
Cirpofloxacin (Cipro)  
Buprenorphine  
Citalopram (Celexa®, Cipramil®) 
Cabozantinib 
Clarithromycin (Biaxin®) 
Capecitabine 
Disopyramide (Norpace®) 
Certinibi 
Dofetilide (Tikosyn®) 
Clozapine (Clozaril® 
Donepezil (Aricept) 
Cobimetinib 
Dronedarone (Multaq®) 
Crizotinib 
Droperidol (Inapsine®) (not on US mkt) 
Dabrafenib 
Erythromycin (E.E.S.®) 
Dasatinib 
Escitalopram (Cipralex®, Lexapro®) 
Desipramine 
Flecainide (Tambocor®) 
Dexmedetomidine 
Fluconazole (Diflucan)  
Dolasetron (Anzemet®) 
Haloperidol (Haldol®) 
Encorafenib 
Hydroxychloroquine  (Plaquenil)  
Entrectinib (Rozlytrk) 
Ibutilide (Corvert®) 
Eribulin (Havalen®) 
Levofloxacin (Levaquin)  
Felbamate (Felbatol®) 
Methadone (Dolophine®) 
Fingolimod (Gilenya®) 
Moxifloxacin (Avelox®, Avalox®) 
Flurouracil (5FU) 
Oxaliplatin (Eloxatin) 
Gemifloxacin (Factive®) 
Pentamidine (NebuPent®, Pentam®) 
Gilteritinib (Xospata) 
Pimozide (Orap®) 
Glasdegib (Daurismo) 
Procainamide (Pronestyl®, Procan® ) 
Granisetron (Kytril®) 
Quinidine (Quinaglute®, Duraquin®) 
Iloperidone (Fanapt®) 
Sevoflurane (Ulane®) 
Imipramine (Tofranil)  
Sotalol (Betapace®) 
Inotuzumab ozogamicin (Besponda) 
Thioridazine (Mellaril®) 
Isradipine (Dynacirc®) 
Vandetanib (Caprelsa®) 
Ivosidenib (Tibsovo) 
 
Lapatinib (Tykerb®) 
 
Lefamulin (Xenleta) 
 
Lenvatinib (Lenvima)  
 
Leuprolide (Lupron)  
 
Levetiracetam (Keppra) 
 
Lithium (Eskalith®) 


 
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Midostaurin (Rydapt) 
 
Mirtazapine (Remeron®) 
 
Moxepril/HCTZ (Uniretic®) 
 
Nicardipine (Cardene®) 
 
Nioltinib (Tasigna®) 
Norfloxacin 
 
Nortriptyline (Pamelor)  
 
Ondansteron (Zofran) A 
 
Ofloxacin (Floxin®) 
 
Oxytocin (Pitocin®) 
 
Paliperidone (Invega®) 
 
Palonosetron (Aloxi)  
 
Panobinostat (Farydak) 
 
Pazopanib (Votient) 
 
Promethazine (Phenergan®) 
 
Proprofol (Diprivan) B 
 
Ribociclib (Kisqali)  
 
Romidepsin (Istodax) 
 
Rucaparib (Rubraca)  
 
Selpercatinib (Retevmo)  
 
Sorafenib (Nexavar) 
Sunitinib (Sutent®) 
 
Tacrolimus (Prograf®) 
 
Tamoxifen 
 
Tazmetostat (Tazverik)  
 
Televancin (Vibativ) 
 
Telithromycin (Ketik) 
 
Tizanidine (Zanaflex®) 
 
Tolterodine (Detrol®) 
Tramadol 
 
Vemurafenib (Zelvoraf)  
 
Venlafaxine (Effexor®) 
 
 A-Risk of QTc prolongation demonstrated in doses of 32mg.  Doses ≤ 8 mg demonstrated to NOT induce prolongation of QTc.  
www.Fda.gov  
Krammes SK, Jacobs T, Clark JM, Lutes RE. Effect of Intravenous Ondansetron on the QT Interval of Patients' Electrocardiograms. 
Pediatr Emerg Care. 2018;34(1):38-41 
 
B-QTc prolongation reported in those with a baseline QTc > 500 msec 
Safaeian R, Hassani V, Mohseni M, et al. Comparison of the Effects of Propofol and Sevoflurane on QT Interval in Pediatrics 
Undergoing Cochlear Implantation: A Randomized Clinical Trial Study. Anesth Pain Med. 2019;9(4):e88805. Published 2019 Aug 5. 


 
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APPENDIX VIII: VORINOSTAT DOSING NOMOGRAM 
For patients unable to swallow capsules, vorinostat will be given as a 50 mg/mL extemporaneous liquid 
preparation (see section 6.6.4 for compounding instructions) rounded to the nearest 10 mg according to 
the following dosing nomogram.  
 
Patients who are able to swallow capsules may receive vorinostat capsules instead of suspension if their 
calculated vorinostat dose is within +/- 10% of a 100 mg increment (e.g. 100 mg, 200 mg, 300 mg, or max 
dose 400 mg). Otherwise, they will need to receive vorinostat as suspension and dosed according to the 
following dosing nomogram. 
 
 
Body Surface Area (m2 ) 
Dose Level 4 
Vorinostat 180 mg/m2 
Dose Level 4a 
Vorinostat 150 mg/m2 
0.3-0.35 
60 
50 
0.36-0.39 
70 
60 
0.4-0.45 
80 
60 
0.46-0.49 
90 
70 
0.5-0.55 
90 
80 
0.56-0.59 
100 
90 
0.6-0.65 
110 
90 
0.66-0.69 
120 
100 
0.7-0.75 
130 
110 
0.76-0.79 
140 
120 
0.8-0.85 
150 
120 
0.86-0.89 
160 
130 
0.9-0.95 
170 
140 
0.96-0.99 
180 
150 
1.0-1.05 
180 
150 
1.06-1.09 
190 
160 
1.1-1.15 
200 
170 
1.16-1.19 
210 
180 
1.2-1.25 
220 
180 
1.26-1.29 
230 
190 
1.3-1.35 
240 
200 
1.36-1.39 
250 
210 
1.4-1.45 
260 
210 
1.46-1.49 
270 
220 
1.5-1.55 
270 
230 
1.56-1.59 
280 
240 
1.6-1.65 
290 
240 
1.66-1.69 
300 
250 
1.7-1.75 
310 
260 
1.76-1.79 
320 
270 
1.8-1.85 
330 
270 
1.86-1.89 
340 
280 
1.9-1.95 
350 
290 
1.96-1.99 
360 
300 
2.0-2.05 
360 
300 
2.06-2.09 
370 
310 
2.1-2.15 
380 
320 
2.16-2.19 
390 
330 
> 2.2 
400 
340