Clinical trial NCT02035137
Conditions: Neuroblastoma
Sponsor: New Approaches to Neuroblastoma Therapy Consortium
Start date: 2014-07-01; Completion date: 2021-02-26
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare three treatment regimens containing metaiodobenzylguanidine (MIBG) and compare their effects on tumor response and associated side effects, to determine if one therapy is better than the other for people diagnosed with relapsed or persistent neuroblastoma.

Detailed description:

Arms: arm 1: Single-agent 131I-MIBG (Arm A) 18 mCi/kg 131I-MIBG on Day 1 and autologous stem cell infusion on Day 15. arm 2: Vincristine / irinotecan / 131I-MIBG (Arm B): vincristine 2 mg/m2 (maximum dose 2 mg) intravenously on Day 0; irinotecan 50 mg/m2 (maximum dose 100 mg) intravenously on Days 0 to 4. Patients will also receive diarrhea prophylaxis with cefixime 8 mg/kg/day orally on Days -1 to +6. 131I-MIBG, 18 mCi/kg on Day 1 and autologous stem cell infusion on Day 15. arm 3: Vorinostat / 131I-MIBG (Arm C); vorinostat 180 mg/m2 (maximum dose 400 mg) orally once daily on Days -1 to +12 (14 total doses). 131I-MIBG, 18 mCi/kg on Day 1 and autologous stem cell infusion on Day 15.
Interventions: intervention 1: 131I-MIBG intervention 2: Vincristine intervention 3: Irinotecan intervention 4: Vorinostat
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
NANT 2011-01 Version Amendment #8  01-10-2018     1 
 
 
NEW APPROACHES TO NEUROBLASTOMA THERAPY (NANT) CONSORTIUM 
 
NANT 2011-01: RANDOMIZED PHASE II STUDY OF 131I-MIBG VS. 131I-MIBG WITH VINCRISTINE 
AND IRINOTECAN VS. 131I-MIBG WITH VORINOSTAT FOR RESISTANT/RELAPSED 
NEUROBLASTOMA. 
 
IND# 120414 
 
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 
Katherine K. Matthay, MD, Phone: 415-476-0603; Email: matthayk@peds.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 
 
Lucile Packard Children's Hospital, Stanford University, 1000 Welch Road, Suite 300 Palo Alto, CA 94304 
Sheri Spunt, MD, Phone: 650-723-5535; Email: sspunt@stanford.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, B1-208 Ann Arbor, MI 48109 
Gregory Yanik, MD, Phone: 734-746-3243; Email: gyanik@umich.edu 
 
Seattle Children’s Hospital, 4800 Sand Point Way Northeast, MB.8.560 Seattle, WA 98105 
Navin Pinto, MD, Phone: 206-987-5783; Email: navin.pinto@seattlchildrens.org  
 
Children’s Hospital Boston, Dana-Farber Cancer Institute, 450 Brookline Avenue, Suite 350 Boston, MA 02115                                   
Suzanne Shusterman, MD, Phone: 617-632-4901; Email: suzanne_shusterman@dfci.harvard.edu 
 
Hospital for Sick Children, 555 University Avenue, Toronto, Ontario Canada M5G1X8 
Meredith Irwin, MD, Phone: 416-813-7654 Email: meredith.irwin@sickkids.ca 
 
Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Rm 446 Atlanta, GA 30322 
Kelly Goldsmith, MD, Phone: 404- 727-2655; Email: kgoldsm@emory.edu 
University of Chicago, Comer Children’s Hospital, 5841 S. Maryland Ave. MC4060 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 
 
University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599 
Patrick Thompson, MD, Phone: 919-962-4991; Email: patom@email.unc.edu 
 
SEE www.nant.org FOR LIST OF MIBG CENTERS 
 
Protocol Chair 
Steven DuBois, MD 
Dana-Farber Cancer Institute 
Phone:  (617) 632-5460 
Email: steven_dubois@dfci.harvard.edu 
Protocol Vice-Chair 
Meaghan Granger, MD 
Cook Children’s Medical Center 
Phone: (682) 885-2580 
Email: mgranger@cookchildrens.org 
 
 
 
 
 
Activated: 12-17-2013 
 
Version Date: 
01-10-2018 


NANT 2011-01 Version Amendment #8  01-10-2018     2 
 
Table of Contents 
STATEMENT OF CONFIDENTIALITY 
4 
STUDY COMMITTEE 
5 
NANT CONSORTIUM INSTITUTIONS 
6 
IND SPONSOR AND MEDICAL MONITOR 
7 
ABSTRACT 
 
8 
TREATMENT SCHEMA 
9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
10 
2.0 
BACKGROUND 
11 
2.1 
Neuroblastoma 
11 
2.2  
131I-MIBG: Clinical Data in Neuroblastoma 
11 
2.3   
Rationale for Combination of 131I-MIBG with Irinotecan 
12 
2.4   
Rationale for Combination of Vorinostat with 131I-MIBG 
14 
2.5 
Summary and Rationale for Current Trial 
17 
2.6 
Correlative and Exploratory Studies 
18 
3.0 
PATIENT ELIGIBILITY CRITERIA AND REGISTRATION 
23 
3.1 
Patient Preparation for Study Entry and Registration 
23 
3.2 
Inclusion Criteria 
24 
3.3 
Exclusion Criteria 
27 
3.4 
Regulatory 
28 
4.0 
TREATMENT PROGRAM 
29 
4.1  
Treatment Overview 
29 
4.2  
Non-MIBG Drug Administration by Assigned Treatment Arm 
30 
4.3 
131I-MIBG Administration for All Treatment Arms 
32 
4.4 
Autologous Peripheral Stem Cell Infusion for All Treatment Arms 
34 
4.5 
Myeloid Growth Factor Support for All Patients 
34 
4.6 
Criteria to Receive a Second Course of Therapy 
35 
4.7 
Toxicity Assessment and Definition of Engraftment 
35 
4.8 
Dose Modification 
35 
4.9 
Concomitant Therapy 
36 
5.0 
SUPPORTIVE CARE 
38 
5.1 
Prophylaxis for Pneumocystis Pneumonia 
38 
5.2 
Use of Myeloid Growth Factors 
38 
5.3 
Hydration status 
38 
5.4 
Management of Irinotecan-Associated Diarrhea 
38 
6.0 
DRUG INFORMATION 
40 
6.1 
Vorinostat 
40 
6.2 
131I-METAIODOBENZYLGUANIDINE (Draximage ®  Therapeutic 131I-MIBG) 
43 
6.3 
131I-METAIODOBENZYLGUANIDINE (131I-MIBG) 
47 
6.4 
VINCRISTINE 
47 
6.5 
IRINOTECAN 
48 
6.6 
CEFIXIME 
49 
6.7 
CEFPODOXIME PROXETIL 
50 
6.8 
POTASSIUM IODIDE (KI, SSKI) 
50 
6.9 
GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) 
51 
6.10 
PEGFILGRASTIM (NEULASTA) 
52 
6.11  
LOPERAMIDE 
53 
6.12 
Drug Inventory Records 
53 
7.0    
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
54 
7.1 
Clinical and Laboratory Studies 
54 
7.2 
Recommended Follow-Up Observations 
55 
7.3 
Documentation of Tumor Response 
55 


NANT 2011-01 Version Amendment #8  01-10-2018     3 
 
8.0 
CORRELATIVE BIOLOGY STUDIES 
56 
8.1 
Evaluation of Minimal Residual Disease by TaqMan low density array (TLDA) 
56 
8.2 
Evaluation of Blood Markers of Radiation Exposure 
56 
8.3 
Evaluation of NET Protein Expression 
59 
8.4 
Evaluation of Automated MIBG Scoring System 
60 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
61 
9.1 
Criteria for Removal from Protocol Therapy 
61 
9.2 
Off Study Criteria 
61 
10.0 
STATISTICAL CONSIDERATIONS 
62 
10.1 
Pick-the-Winner Design 
62 
10.2 
Randomization 
63 
10.3 
Response Evaluation 
63 
10.4 
Toxicity Evaluation 
64 
10.5 
Sample Size and Study Duration 
64 
10.6 
Monitoring Plan for Toxicity 
65 
10.7  
Analysis of Correlative and Exploratory Studies 
66 
10.8      Inclusion of Women and Minorities 
69 
11.0 
NANT RESPONSE CRITERIA V 1.2 
70 
11.1 
Response Criteria for CT/MRI Lesions 
70 
11.2 
Response Criteria for Morphologic Bone Marrow Disease 
71 
11.3. 
Response Criteria for MIBG Avid Lesions 
72 
11.4  
Urine Catecholamines 
75 
11.5 
Definition of Overall Response for Each Patient 
75 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
77 
12.1 
Purpose 
77 
12.2 
Expedited Adverse Event Reporting to the FDA 
77 
12.3 
NANT Operations Center Role in Expedited Adverse Event Reporting to the FDA 77 
12.4 
NANT Site Investigator Role in Expedited Adverse Event Reporting 
78 
12.5  
Additional Adverse Event Reporting Requirements  
 
 
for  Merck & Co, Jubilant DraxImage and NDP 
78 
12.6 
Definitions of Adverse Event Terminology 
78 
12.7 
Reporting Secondary AML/MDS or Any Other Second Malignancy 
79 
13.0 
RECORDS AND REPORTING 
80 
14.0 
REFERENCES 
81 
15.0 
SAMPLE INFORMED CONSENT 
87 
16.0   
SAMPLE ASSENT FORM 
108 
APPENDIX I: 
PERFORMANCE STATUS SCALES/SCORES 
113 
APPENDIX II.  MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
114 
APPENDIX III.  VORINOSTAT DOSING NOMOGRAM 
115 
APPENDIX IV: QUALITY CONTROL FOR FREE IODINE IN 131I-MIBG (DETECTION OF RADIOLYTIC 
DECOMPOSITION) 
116 
APPENDIX V: COMPOUNDS THAT INTERFERE WITH MIBG METABOLISM AND UPTAKE 
117 
APPENDIX VI:  ADJUSTED BODY WEIGHT CALCULATION 
118 
APPENDIX VII.  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
119 
APPENDIX VIII.  INTERIM ANALYSES USING BAYESIAN RULES 
120 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     4 
 
STATEMENT OF CONFIDENTIALITY 
 
This protocol is protected by the Certificate of Confidentiality granted by the National Cancer Institute to the 
NANT Operations Center 
 
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 2011-01 Version Amendment #8  01-10-2018     5 
 
STUDY COMMITTEE 
 
STUDY CHAIR  
Steven 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 
 
STUDY VICE CHAIR 
Meaghan Granger, MD 
Cook 
Children’s 
Medical 
Center 
901 Seventh Avenue 
Fort Worth, TX 76104 
Office: (682) 885-2580 
Fax: (682) 885-1712 
Email: 
mgranger@cookchildrens.org 
STUDY STATISTICIAN 
Susan Groshen, PhD 
USC School of Medicine 
Dept of Preventive Medicine 
1441 Eastlake Avenue, MS-
44 
Los Angeles, CA 90089 
Phone:  323-865-0375 
Fax: 323-865-0133 
Email: groshen@usc.edu 
 
 
COMMITTEE MEMBER 
Katherine Matthay, MD 
UCSF School of Medicine 
550 16th Street, 4th Floor 
San Francisco, CA 94158 
Phone: 415-476-0603 
Fax:  415-476-5356 
Email: matthayK@peds.ucsf.edu 
 
COMMITTEE MEMBER 
Araz Marachelian, MD 
Hematology/Oncology  
Children’s Hospital Los 
Angeles 
4650 Sunset Blvd, MS-54 
Los Angeles, CA 90027 
Phone: (323) 361-8573 
Fax: (323) 361-1803 
Email: 
AMarachelian@chla.usc.edu 
COMMITTEE MEMBER 
Samuel Volchenboum, MD, 
PhD 
University of Chicago  
Department of Pediatrics, 
KCBD 5th Floor 
900 East 57th Street, KCBD 
5130 
Chicago, IL 60637 
Phone:  773-702-3709 
Fax:  773-326-3670 
Email:  slv@uchicago.edu 
 
COMMITTEE MEMBER 
Robert Seeger, MD 
Childrens Hospital of Los Angeles 
Division of Hematology/Oncology 
4650 Sunset Boulevard, MS # 57 
Los Angeles, CA 90027 
Office:  (323) 361-5618 
Fax:  (323) 361-3889 
Email:  rseeger@chla.usc.edu 
 
PROTOCOL NURSE 
Fabienne Hollinger, FNP 
UCSF School of Medicine 
550 16th Street, 4th Floor 
San Francisco, CA 94158 
Phone:  415-514-0238 
Fax:  415-476-5356 
Email:  
hollingerf@peds.ucsf.edu 
 
PROTOCOL 
COORDINATOR 
Suzy Ghazarian, MPA 
NANT Operations Center 
Children’s Hospital Los 
Angeles 
4650 Sunset Blvd, MS-54 
Los Angeles, CA  90027 
Phone:  323-361-5631 
Fax: 323-361-1803 
Email: 
sghazarian@chla.usc.edu 
 
STUDY PHARMACIST 
Sarah Scarpace Lucas, Pharm D 
UCSF Benioff Children’s Hospital 
1975 4th Street 
San Francisco, CA 94158 
Office:  415-353-1531 
Email: 
Sarah.Scarpace.Lucas@ucsfmedctr.org 
 
RESEARCH COORDINATOR 
NANT Operations Center 
Children’s Hospital Los 
Angeles 
4650 Sunset Blvd., MS-54 
Los Angeles, CA 90027 
Office : 323-361-5687 
Fax : 323-361-1803 
Email: nantcrf@chla.usc.edu 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     6 
 
NANT CONSORTIUM INSTITUTIONS 
 
 
Katherine Matthay, MD 
UCSF School of Medicine 
Department of Pediatrics 
550 16th Street, 4th Floor 
San Francisco, CA 94158 
Office: 415- 476-0603 
Fax: 415-467-5356 
Email: matthayk@peds.ucsf.edu 
 
Araz Marachelian, MD 
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 
 
 
Sheri Spunt, MD 
Lucile Packard Children’s Hospital, 
Stanford University 
1000 Welch Road, Suite 300 
Palo Alto, CA 94304 
Office: 650-723-5535 
Fax: 650-723-5231 
Email: sspunt@stanford.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 
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: gyanik@umich.edu 
 
Navin Pinto, MD 
Seattle Children’s Hospital 
4800 Sand Point Way NE MB.8.560 
Seattle, WA 98105 
Office: 206-987-5783 
Fax:206-987-3946 
Email:navin.pinto@seattlechildrens.org 
 
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.harvard.edu 
Meredith Irwin, MD 
Hematology-Oncology 
Hospital for Sick Children  
555 University Avenue,  
Toronto, Ontario Canada M5G1X8  
Phone: 416-813-7654 
Fax: 416-813-5327 
Email: meredith.irwin@sickkids.ca 
 
 
 
 
 
Kelly Goldsmith, MD 
Children’s Healthcare of Atlanta.   
2015 Uppergate Drive, Rm 446  
Atlanta, GA 30322 
Office: 404-727-2655 
Fax: 404-727-4859 
Email:  kgoldsm@emory.edu 
Ami Desai, MD 
University of Chicago 
Comer Children’s Hospital 
5841 S. Maryland Avenue MC4060 
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 
 
Margaret Macy, MD 
Children’s Hospital Colorado 
13123 East 16th Ave. B-115 
Aurora, CO 80045 
Phone : 720-777-8866 
Fax : 720-777-7289 
Email: 
Margaret.macy@childrenscolorado.org 
Patrick Thompson, MD 
The University of North Carolina at Chapel Hill 
101 Manning Drive 
Chapel Hill, North Carolina 
Office: 919-962-4991 
Fax: 919-966-7629 
Email:patom@email.unc.edu 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     7 
 
 
 
IND SPONSOR AND MEDICAL MONITOR 
 
Steven 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 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     8 
 
ABSTRACT 
 
131I-Metaiodobenzylguanidine (131I-MIBG) is one of the most active agents for patients with relapsed or 
refractory neuroblastoma.  A large multicenter phase 2 study yielded an estimated overall response rate in 
this population of 36% using single-agent 131I-MIBG.  Recent NANT clinical trials have demonstrated the 
feasibility of combining 131I-MIBG with systemic radiation sensitizers, with the aim of enhancing the 
antitumor activity of 131I-MIBG.   
 
NANT 04-06 was a phase 1 dose escalation study of 131I-MIBG together with vincristine and protracted 
irinotecan (20 mg/m2/day IV x 5 days x 2 weeks) as a radiation sensitizer.  This combination was tolerable 
using 131I-MIBG doses up to 18 mCi/kg.  However, more patients than anticipated from either drug alone 
developed protocol-associated diarrhea, a known toxicity of protracted irinotecan exposures.  Furthermore, 
the new national standard shown to be effective in other tumor types has been a 5-day higher dose 
irinotecan schedule.  Therefore, a pilot study at UCSF evaluated 131I-MIBG together with vincristine and 
irinotecan given at higher doses for a shorter exposure (50 mg/m2/day IV x 5 days x 1 week).  This study 
confirmed that vincristine and irinotecan could be safely combined with 131I-MIBG up to doses of 18 mCi/kg, 
with lower rates of diarrhea compared to NANT 04-06.  Promising antitumor activity was seen in both 
studies of this combination.   
 
NANT07-03 was a phase 1 dose escalation study of 131I-MIBG together with vorinostat, an oral histone 
deacetylase (HDAC) inhibitor.  The rationale for this study included three main points.  First, vorinostat has 
modest activity against neuroblastoma in preclinical models.  Second, vorinostat has been shown to 
sensitize tumor cells, including neuroblastoma, to the effects of radiation therapy.  Third, vorinostat 
upregulates the expression of the norepinephrine transporter on neuroblastoma cell lines.  This phase 1 
study demonstrated that 14 days of vorinostat could safely be combined with 131I-MIBG up to doses of 18 
mCi/kg. 
 
While these combination trials have demonstrated promising antitumor activity, these small phase 1 studies 
have not clarified whether combination therapy results in increased response rates compared with single- 
agent 131I-MIBG.  The current randomized phase 2 pick the winner study is therefore designed to select the 
131I-MIBG treatment regimen associated with the highest objective response rate.  Patients with relapsed or 
refractory neuroblastoma and MIBG-avid disease will be randomized at study entry to one of three treatment 
arms:  single-agent 131I-MIBG; 131I-MIBG with vincristine and irinotecan; and 131I-MIBG with vorinostat.  All 
patients will receive 18 mCi/kg 131I-MIBG with prophylactic autologous stem cell support two weeks following 
131I-MIBG infusion.  Patients enrolling prior to Amendment 7A may receive up to two courses of therapy.  
Patients enrolling with Amendment 7A and after may receive only one course of therapy.  The primary 
endpoint is objective response following the first course of therapy, using standard NANT response criteria.  
Secondary and other endpoints will include toxicity, site specific response, best response for patients 
treated with two courses of therapy (if applicable), overall survival, and correlative biology endpoints related 
to radiation exposure.  Up to a total of 105 eligible and evaluable patients will be randomized to one of the 
three arms. 
 
 
Hypothesis: 
 
We hypothesize that: 
• 131I-MIBG, combined with either vorinostat or irinotecan, will be associated with a higher objective 
response rate compared with single-agent 131I-MIBG; 
• 131I-MIBG, combined with either vorinostat or irinotecan, will be tolerable but associated with an 
increase in protocol-associated toxicity compared with single-agent 131I-MIBG; 
• 131I-MIBG, combined with either vorinostat or irinotecan, will be associated with increased measures 
of radiation exposure as assessed by peripheral blood markers. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     9 
 
TREATMENT SCHEMA 
 
Patients will be randomized at study entry to one of three treatment arms. 
 
 
 
 
Patients assigned to single-agent 131I-MIBG (Arm A) will receive 18 mCi/kg 131I-MIBG on Day 1 and 
autologous stem cell infusion on Day 15. 
 
Patients randomized to receive vincristine / irinotecan / 131I-MIBG (Arm B) will receive vincristine 2 mg/m2 
(maximum dose 2 mg; see 4.2.2.1 for dosing if < 3 years old) intravenously on Day 0.  They will receive 
irinotecan 50 mg/m2 (maximum dose 100 mg) intravenously on Days 0 to 4.  Patients will also receive 
diarrhea prophylaxis with cefixime 8 mg/kg/day orally on Days -1 to +6.  Patients will receive 18 mCi/kg 
131I-MIBG on Day 1 and autologous stem cell infusion on Day 15. 
 
Patients randomized to receive vorinostat / 131I-MIBG (Arm C) will receive vorinostat orally once daily on 
Days -1 to +12 (14 total doses) at a dose of 180 mg/m2 (maximum dose 400 mg).  Patients will receive 18 
mCi/kg 131I-MIBG on Day 1 and autologous stem cell infusion on Day 15.   
 
All patients will undergo disease restaging between Day 43 and 50, 6-7 weeks after 131I-MIBG infusion.  
Patients enrolling prior to Amendment 7A with at least stable disease after the first cycle can receive a 
second cycle of therapy, provided they meet specified protocol criteria.   
   
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     10 
 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aim: 
 
1.1 
To identify the 131I-MIBG treatment regimen associated with the highest overall response rate after one 
course of treatment on the following three arms:  single-agent 131I-MIBG; vincristine / irinotecan / 131I-
MIBG; or vorinostat / 131I-MIBG 
 
Secondary Aim:  
 
1.2 
To compare the toxicity profiles associated with each of the following three 131I-MIBG treatment regimens: 
single-agent 131I-MIBG; vincristine / irinotecan / 131I-MIBG; or vorinostat / 131I-MIBG 
 
Exploratory Aims: 
 
1.3 
To describe best overall response for patients treated with two courses of therapy, site-specific response of 
bone marrow, soft tissue, and MIBG-avid lesions as well as overall survival and progression-free survival 
following each of three 131I-MIBG treatment regimens 
 
1.4 
To assess peripheral blood and bone marrow minimal residual disease at study entry and following each of 
three 131I-MIBG treatment regimens quantified using a neuroblastoma-specific NB 5-gene detection assay 
(NB5 assay) by TaqMan® low density array (TLDA) 
 
1.5 
To compare whole body radiation exposure in patients with neuroblastoma treated with each of three 131I-
MIBG treatment regimens 
 
1.6 
To evaluate peripheral blood lymphocyte γ-H2AX foci levels, expression of a panel of DNA damage 
response genes in peripheral blood mononuclear cells, plasma Flt-3 ligand, serum amylase, and 
circulating tumor DNA as markers of radiation exposure, response, and toxicity in patients with 
neuroblastoma treated with each of three 131I-MIBG treatment regimens 
 
1.7 
To evaluate the performance of a computerized MIBG scan scoring system in patients with relapsed or 
refractory neuroblastoma treated with 131I-MIBG therapy 
 
1.8 
To evaluate the association between tumor norepinephrine transporter (NET) protein expression and 
response to protocol therapy.   
 
1.9 
To describe the concordance rate between institutional Curie score and centrally reviewed Curie score in 
patients with relapsed or refractory neuroblastoma.   
 
1.10 
To describe the incidence and severity of sinusoidal obstruction syndrome (SOS) in patients with 
neuroblastoma who receive 131I-MIBG therapy on this protocol and subsequently receive high-dose 
chemotherapy with stem cell rescue as part of their clinical care. 


NANT 2011-01 Version Amendment #8  01-10-2018     11 
 
2.0 
BACKGROUND 
 
2.1 
Neuroblastoma 
 
Neuroblastoma is the most common extracranial solid cancer of childhood.1  Most patients are initially 
diagnosed prior to 10 years of age.  Approximately 50% of patients present with initially metastatic 
disease.  Many of these patients are either refractory to initial therapy or develop recurrent disease after 
receiving multimodal therapy.  The outcome for patients with recurrent or refractory disease remains poor. 
Novel approaches to treating these patients are required to improve their outcome. 
 
2.2 131I-MIBG: Clinical Data in Neuroblastoma 
 
131I-metaiodobenzylguanidine (MIBG) is a guanethidine analog with specific uptake in sympathetic 
nervous system tissues. The norepinephrine transporter mediates uptake of 131I-MIBG into the cells of 
these tissues.2  As a tumor derived from the sympathetic nervous system, neuroblastoma cells avidly 
accumulate 131I-MIBG.3-5  Low doses of both 131I-MIBG and 123I-MIBG are widely used as nuclear 
medicine imaging agents in the diagnostic evaluation of patients with neuroblastoma.   
 
Given that neuroblastoma is radiosensitive, high-dose 131I-MIBG has been evaluated as a targeted 
radiopharmaceutical in the treatment of patients with neuroblastoma for the past 25 years.  Unlike 
standard external beam radiotherapy, 131I-MIBG is administered intravenously and then distributes 
throughout the body.6  The biological or effective half-life of the administered radiation in the blood of 
patients with neuroblastoma ranges from 9-130 hours, reflecting clearance mainly in the urine.6-8  
Radiation that is not cleared in the urine or stool remains in the body and decays with a half-life of 
approximately 8 days, the physical half-life of 131I.9  Since 131I-MIBG taken up by neuroblastoma cells is 
not cleared in the urine or stool, these cells are exposed to radiation with a half-life that more closely 
follows the physical half-life of 131I.  Therefore, three weeks following therapeutic 131I-MIBG administration, 
tumor cells may still be exposed to small amounts of radiation.   
 
The whole body radiation dose received is approximately linear with 131I-MIBG dose administered.  After a 
dose of 12 mCi/kg, patients receive a calculated whole-body radiation dose of approximately 2 Gy.10  As a 
targeted radiopharmaceutical, the dose delivered to the tumor is much higher.10   
 
Aside from transient nausea and xerostomia, the main early toxicity of 
131I-MIBG therapy is 
myelosuppression.  With higher doses (> 12 mCi/kg 131I-MIBG), hematologic toxicity becomes dose-
limiting and hematopoietic stem cell infusion has been used to promote hematologic recovery.11  
Thrombocytopenia occurs more often and is more prolonged than neutropenia, particularly for those 
patients with bone marrow disease prior to 131I-MIBG treatment.12  In one study using 18 mCi/kg 131I-
MIBG, the median time to platelet nadir was 24 days and patients who did not receive hematopoietic stem 
cell support required platelet transfusions for a median of 5 weeks.12  Nonhematologic toxicity has been 
minimal, even at higher doses.  In a phase I dose escalation study of 131I-MIBG, no grade 3 or 4 
nonhematologic toxicities were observed following a single course of therapy.11  In a phase II study in 
which patients received 18 mCi/kg 131I-MIBG, 22% of patients had a grade 3 non-hematologic toxicity and 
9% of patients had a grade 4 non-hematologic toxicity.13  The majority of these toxicities consisted of 
febrile neutropenia and other infectious complications.  Patients on these studies have been able to 
receive multiple courses of therapy without unanticipated toxicity.13-15  In one series, 28 patients received 
at least two courses of therapy with a median 131I-MIBG dose of 18 mCi/kg given at a median interval of 
98 days between treatments.15 Of the 24 patients who received two courses of 131I-MIBG, only 8 patients 
received stem cell reinfusion to support hematologic recovery.  Non-hematologic toxicity was as expected 
based upon patients treated with only one course of 131I-MIBG.  Potential late toxicities include 
hypothyroidism, secondary malignancy, and reduced fertility.16-18      
 
Early studies evaluated 131I-MIBG as monotherapy for patients with recurrent or refractory disease.  The 
objective response rate in these studies ranged from 30% to 37%.11, 13, 14, 19  The response rate with 
monotherapy may be even higher in patients with newly diagnosed disease.20, 21  A recent large phase II 
trial demonstrated that 131I-MIBG is one of the most active agents in patients with progressive, relapsed, 
or refractory neuroblastoma.13  Of 164 patients, of whom 148 were treated with 18 mCi/kg, 36% had an 
objective response.  Patients > 12 years of age and those with disease limited to either bone/bone 
marrow or soft tissue, but not both, were more likely to achieve response following 131I-MIBG as single-
agent therapy.  A more recent study has confirmed that older patients appear to have a higher response 
rate to 131I-MIBG.22  
 


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The use of multiple 131I-MIBG treatments to higher cumulative doses has also been assessed.  Multiple 
treatments of 131I-MIBG at 56 day intervals have been shown to be tolerable.23  NANT protocol 2000-01 
evaluated double infusion of 131I-MIBG given two weeks apart to cumulative doses of up to 42 mCi/kg, 
supported by PBSC infusion.24  Doses of 18 mCi/kg x 2 doses (36 mCi/kg) were well-tolerated.  
Cumulative lifetime doses of 54 mCi/kg have also been used, mainly on compassionate access protocols.  
There have not been any late liver, renal, or cardiac toxicity in patients with multiple infusions.  Recent 
studies from the Children’s Hospital of Philadelphia have shown that 131I-MIBG can be given at 42 day 
intervals without increased toxicity.25  
     
Based on these encouraging results, the NANT consortium has conducted phase 1 trials evaluating 131I-
MIBG in combination with radiation sensitizers (see below).  In addition, the Children’s Oncology Group 
has opened a pilot study incorporating 131I-MIBG therapy into the upfront treatment of children with high-
risk neuroblastoma. 
 
2.3   
Rationale for Combination of 131I-MIBG with Irinotecan  
 
2.3.1 
Clinical Use of Irinotecan and Irinotecan / Vincristine in Neuroblastoma 
 
Irinotecan has been shown to be active against pediatric solid tumors in several clinical trials.  A COG 
phase II trial treated 171 children with solid tumors with irinotecan at a dose of 50 mg/m2/dose IV x 5 
days.26  This regimen was found to be tolerable and 1/18 patients with neuroblastoma had an objective 
partial response.  Subsequent trials evaluated irinotecan in combination with other chemotherapy agents.  
A COG rhabdomyosarcoma trial established that the combination of irinotecan (20 mg/m2/dose IV for 5 
days/week x 2 weeks) with vincristine was associated with greater activity compared to irinotecan alone.27  
 
Several studies have evaluated the combination of irinotecan and temozolomide specifically in patients 
with neuroblastoma.  A Children’s Oncology Group phase II study was conducted in 59 patients with 
recurrent or refractory disease using temozolomide 100 mg/m2/day orally x 5 days and irinotecan 10 
mg/m2/day IV once daily for 5 days  each week for two weeks.28  The objective response rate was 16%.  
Stable disease was documented as best response to therapy in an additional 47% of patients.  A NANT 
phase I study in patients with neuroblastoma evaluated oral irinotecan together with temozolomide.29  
This combination resulted in 1 patient out of 14 total patients with a complete response as well as 
stabilization of disease in an additional 6 patients.  A report of a single institution study describes 49 
patients with neuroblastoma treated with temozolomide 150 mg/m2/day orally x 5 days and irinotecan 50 
mg/m2/day IV once daily for 5 days for one week.30  One third of patients (12/36) treated in this series 
showed tumor regression, although only 3 of the 36 evaluable patients had a complete or partial 
response. 
   
The incidence of thrombocytopenia or neutropenia > grade 3 associated with this combination appears to 
be relatively low.  In the COG phase II study in neuroblastoma, 9% and 25% of patients experienced > 
grade 3 thrombocytopenia or neutropenia, respectively.28  In one case series in patients with Ewing 
sarcoma, 11% and 12% of cycles were associated with > grade 3 thrombocytopenia or neutropenia, 
respectively.31  These results suggest that an additional myelosuppressive agent could be added to 
irinotecan-based therapy.  Moreover, the incidence of grade 3 or 4 diarrhea was < 5% with this regimen, 
suggesting that non-hematologic toxicity is also manageable with irinotecan at this dose and schedule.28, 
31   
 
This protocol utilizes irinotecan administered once daily for 5 days for one week.  This schedule has been 
selected for several reasons.  First, irinotecan administered with temozolomide on this schedule has 
activity in patients with neuroblastoma.30  Second, experience in patients with rhabdomyosarcoma on 
COG protocol ARST0121 has shown that the antitumor activity of this combination is not compromised by 
the use of a one week schedule.  Third, the one week schedule is advantageous in terms of cost and 
patient convenience.  Fourth, the risk of diarrhea is anticipated to be lower with this schedule.      
 
2.3.2 
Camptothecins as Radiation Sensitizers 
 
The combination of a topoisomerase I inhibitor with radiotherapy has an attractive rationale. The 
presumed mechanism is potentiation of radiation-induced double stranded DNA breaks (in G2M-phase) 
through inhibition of DNA repair by removal of topoisomerase-I activity (in the subsequent S-phase).32 


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Studies have shown that radiation-induced cytotoxicity in non-actively dividing cells requires an intact 
stereo-specific interaction between camptothecin and topoisomerase-I.33 The process is initiated by 
topoisomerase-I complex with DNA. Sub-lethal DNA damage occurs when this complex prevents re-
sealing of the topoisomerase-I mediated single strand breaks. Collision of the replication fork and drug-
stabilized single strand DNA or the addition of radiation greatly enhances tumoricidal activity. 
 
Pre-clinical studies have evaluated the timing of drug incubation with irinotecan-radiosensitized breast 
cancer and melanoma cells. Drug given before or during radiation demonstrated an enhanced effect over 
radiation alone.33  Radiosensitization experiments using 9-aminocamptothecin (9-AC) used a low dose 
with radiation.34 With a constant total dose, dosing on multiple days weekly was more effective than a 
single dose given weekly.  
 
Given the preclinical data for radiosensitization, a large number of studies have evaluated irinotecan in 
combination with external beam radiotherapy in adults with a range of carcinoma diagnoses.  These 
studies have specifically evaluated patients with:  esophageal35; head/neck squamous cell36; non-small 
cell lung37-39; pancreatic40; rectal41-47; and small cell lung48-50 cancers.  Irinotecan has typically been given 
on a weekly schedule in these studies, in several cases with additional chemotherapy agents.  The 
overall conclusion from most of these studies is that there are no toxicities linked specifically to the 
combination of irinotecan with external beam radiation.   
 
One study evaluated the combination of irinotecan and cisplatin together with external beam radiotherapy 
in patients with small cell lung cancer.51  Irinotecan was given once every three weeks and this regimen 
resulted in excessive non-hematologic toxicity (diarrhea, dehydration, and esophagitis).  In contrast, daily 
irinotecan was tolerable up to 18 mg/m2 for 5 weeks concurrent with radiotherapy in patients with 
pancreatic cancer.40   
 
One study evaluated the combination of irinotecan and temozolomide together with external beam 
radiotherapy in patients with glioblastoma and anaplastic astrocytoma.52  This combination resulted in 
excessive hematologic and infectious toxicity and has not been developed further.   
 
In pediatrics, the combination of vincristine and irinotecan has been used concurrently with external beam 
radiotherapy in patients with high-risk rhabdomyosarcoma.  This combination has been shown to be 
tolerable in this setting.53  Importantly, this experience has been with identical vincristine and irinotecan 
dosing as is used in the current protocol.   
 
Irinotecan has also been safely combined with yttrium-90 microspheres for the treatment of patients with 
liver metastases from colorectal cancer, indicating that it is feasible to combine irinotecan with other forms 
of radiotherapy aside from external beam radiotherapy.54   
 
2.3.3 
Camptothecins with 131I-MIBG 
 
Two cell lines expressing the norepinephrine transporter were used to evaluate three treatment schedules 
with topotecan and 131I-MIBG with the goal of determining the efficacy of the combination.55 Topotecan 
administration given before, during, or after 131I-MIBG therapy was evaluated in in vitro and in vivo model 
systems. Supra-additive cytotoxicity was achieved when the topotecan was administered before, during, 
but not after the 131I-MIBG therapy. The mean times required for a 10-fold increase in tumor volume were 
18.6 days (untreated), 31.9 days (131I-MIBG alone), 25.3 days (topotecan alone), 37.1 days (topotecan 
before 131I-MIBG), and 49.7 days (topotecan after 131I-MIBG).  100% of tumors were cured with no 
myelotoxicity when topotecan was given simultaneously with 131I-MIBG. 
 
A pilot study performed in children with advanced neuroblastoma used 12 mCi/kg of 131I-MIBG given on 
days 1 and 15 along with 5 days of topotecan starting on days 1 and 15, followed by stem cell rescue.56  
Eight patients were treated without significant toxicity and all had marrow reconstitution. Efficacy was not 
reported. 
 
Based on these data, the NANT consortium initiated protocol 04-06 evaluating vincristine, irinotecan, and 
131I-MIBG.  In this phase I trial, escalating doses of 131I-MIBG were given on Day 1 together with fixed 
doses of vincristine (1.5 mg/m2 on days 0 and 7) and irinotecan (20 mg/m2 on days 0-4 and 7-11).  All 
patients treated with 131I-MIBG doses > 12 mCi/kg received autologous hematopoietic stem cell support 


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on day 13.  The dose escalation portion of this study (NANT04-06) demonstrated that this combination 
was tolerable at a maximum 131I-MIBG dose of 18 mCi/kg.  Dose-limiting toxicities 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.  The objective response rate 
among patients treated at dose levels 8-18 mCi/kg was 25%.57 
 
Closer evaluation of NANT 04-06 has suggested that the incidence of diarrhea was higher than would 
have been anticipated based on prior experience using irinotecan at that dose and schedule, particularly 
since all patients received cefixime or cefpodoxime for diarrhea prophylaxis.57, 58  The overall incidence of 
grade 3 diarrhea was 6 / 18 patients, or 33%.  In contrast, the incidence of grade 3 or 4 diarrhea was < 
5% when irinotecan was given at a similar dose and schedule together with temozolomide in 79 patients 
with either neuroblastoma or Ewing sarcoma.28, 31   
 
Since 131I-MIBG uptake is often seen in the bowel, it is possible that the combination of irinotecan with 
131I-MIBG directly increased the risk of diarrhea.  The schedule-dependence of irinotecan toxicity is well-
documented, with more myelosuppression observed with shorter higher-dose therapy and more diarrhea 
observed with protracted lower-dose therapy.59  Therefore, investigators at UCSF conducted a pilot study 
of the combination of 131I-MIBG together with vincristine and irinotecan on a 5 day x 1 week schedule 
(irinotecan given as 50 mg/m2/day).  Two dose levels of 131I-MIBG were evaluated, 15 and 18 mCi/kg.  
This irinotecan schedule was tolerable with 131I-MIBG doses of 18 mCi/kg.  Preliminary assessment of the 
first 12 patients treated revealed that only 6% of patients had grade 3 or 4 diarrhea, which compares 
favorably with the results obtained on NANT 04-06.60  The objective response rate in the first 12 patients 
was 25%, suggesting that the anti-neuroblastoma activity of this combination is not compromised by this 
irinotecan dose and schedule.    
 
2.4   
Rationale for Combination of Vorinostat with 131I-MIBG 
 
2.4.1 
Vorinostat 
 
Vorinostat is a potent inhibitor of HDAC activity, binding directly to the catalytic pocket of HDAC enzymes 
and ultimately blocking enzymatic deacetylation. Active at low nanomolar concentrations, vorinostat has 
been found to inhibit the enzymatic activity of several HDACs including HDAC1, HDAC2, HDAC3 (Class I 
variants) and HDAC6 (Class II variant).61, 62  All 4 core nucleosomal histones (H2A, H2B, H3 and H4) 
become hyperacetylated following culture of normal and malignant cells with vorinostat.62 Vorinostat 
inhibition of HDAC activity and subsequent accumulation of acetylated histones, leads to enhanced 
transcription of genes that promote differentiation and apoptosis as well as inhibition of tumor growth.61, 62 
Vorinostat induces apoptosis in human myelomonocytic cells and acute T cell leukemia. It also inhibits 
the proliferation of cultured transformed human cells derived from leukemias, non-small cell lung 
carcinoma, colon carcinoma, central nervous system tumors, melanomas, ovarian carcinomas, renal cell 
carcinomas, prostate and breast cancer.63  Vorinostat has also been shown to have significant antitumor 
activity in xenograft models of human prostate carcinoma, breast carcinoma and colon carcinoma. Activity 
has also been demonstrated in a transgenic murine model of APL. In all models, activity occurred in the 
absence of significant toxicity.63  
 
2.4.2 
Pre-clinical Studies of Histone Deacetylase (HDAC) Inhibitors in Neuroblastoma 
 
Several groups have evaluated HDAC inhibitors other than vorinostat in neuroblastoma cell lines.  A 
variety of HDAC inhibitors (including trichostatin A, CBHA, butyrate, valproic acid, MS-27-275, and 
BL1521) promote apoptosis and differentiation in a range of neuroblastoma cell lines.64-70  Treatment of 
neuroblastoma cells in culture with HDACI sensitizes these cells to TRAIL-mediated apoptosis.71  HDAC 
inhibition increases the activity of pro-apoptotic Bax and increases cell-cycle regulator p21 in 
neuroblastoma cells.64, 67, 68, 70  Use of the HDAC inhibitor depsipeptide was shown to sensitize 
chemotherapy-resistant neuroblastoma cells to chemotherapy.72 
 
Other groups have also evaluated HDAC inhibitors in neuroblastoma xenografts.  Treatment of 
neuroblastoma mouse xenografts with the HDAC inhibitor CBHA suppressed tumor growth compared 
with vehicle-treated tumors.  Some tumors regressed with this treatment and this group observed a 
synergistic effect with addition of all-trans retinoic acid.73  Mouse neuroblastoma xenografts treated with 
HDAC inhibitor MS-27-275 showed decreases in tumor growth, decreases in tumor vascularity, and 
decreases in tumor p21 and MYCN oncoprotein expression.66 


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Additional preclinical studies have focused specifically on vorinostat and have demonstrated modest 
single-agent activity against neuroblastoma cell lines.  One group treated SH-SY5Y neuroblastoma cells 
in culture with vorinostat (0.5-2 micromolar) and documented consistent increases in histone H3 
acetylation.74  This treatment increased expression of the cyclin dependent kinase inhibitor p21.  After 48 
hours of incubation with 1-2 micromolar vorinostat, these cells showed decreased cell viability.  The 
addition of all-trans retinoic acid appeared to potentiate this effect.74  Studies performed at UCSF by Dr. 
Haas-Kogan have established that the IC50 of vorinostat in the MYCN amplified neuroblastoma cell line 
NB1691 is approximately 2 micromolar.75 
 
The NIH-sponsored Pediatric Preclinical Testing Program has also evaluated vorinostat in mouse 
xenografts established from six different neuroblastoma cell lines.  Xenografts derived from four of these 
lines showed statistically significant prolongation in event-free survival compared to control-treated 
mice.76 
 
Additional studies conducted at UCSF have demonstrated that neuroblastoma cell lines exposed to 
vorinostat at clinically attainable concentrations results in an increase in norepinephrine transporter 
mRNA and protein expression.77  Vorinostat treated neuroblastoma cells also showed an increase in 
norepinephrine and 123I-MIBG uptake compared with control treated cells.  This effect was seen in three 
neuroblastoma cell lines exposed to clinically relevant concentrations of vorinostat.  These results 
suggest that vorinostat will increase the uptake of 131I-MIBG by neuroblastoma cells. 
 
2.4.3 
Preclinical Studies of HDAC Inhibitors as Radiation Sensitizers 
 
A large body of preclinical data indicates that HDAC inhibitors other than vorinostat potentiate the effects 
of radiation on tumor cells across a range of human cancers.78  The mechanism by which HDAC inhibitors 
enhance the effect of radiation appears to involve three distinct processes. Firstly, HDAC inhibitors lead 
to an open chromatin conformation allowing more significant DNA damage through double and single 
strand breaks. Secondly, HDAC inhibitors alter the production of cellular reactive oxygen species 
generating increased free radicals in addition to modulating the cell redox potential. Thirdly, HDAC 
inhibitors down-regulate the expression of DNA repair proteins.  These studies have indicated that 
treatment with the HDAC inhibitor prior to radiation therapy provides the optimal level of synergy, though 
treatment following radiation exposure may also be important. 
 
Vorinostat has been evaluated as a radiosensitizing agent in preclinical models of melanoma, glioma, 
prostate cancer, and colon cancer.79-81  Pretreatment with vorinostat increases apoptosis in response to 
radiation in these tumor types.  As with other HDAC inhibitors, the ability of vorinostat to enhance the 
radiation effect appears to result from impairment of DNA repair mechanisms.  Specifically, vorinostat has 
been shown to decrease DNA repair proteins (including Ku70, Ku86, and Rad50) and prolong expression 
of γ-H2AX. 
 
Dr. Haas-Kogan’s laboratory at UCSF has demonstrated enhanced efficacy of vorinostat when combined 
with low-dose radiotherapy in neuroblastoma.75  Her group treated NB1691 neuroblastoma cell lines with 
vorinostat across a range of concentrations.  After 24 hours of exposure to vorinostat, cells were treated 
with 1 Gy radiation and remained exposed to vorinostat.  The effect of this treatment on cell viability was 
then determined at hour 72.  Control cells treated with radiation alone had 100% relative viability.  
Pretreatment with vorinostat at 1 micromolar reduced cell viability to approximately 20%, such that the 
IC50 for this combination was < 1 micromolar.  This result compares favorably with IC50 of 2 micromolar for 
vorinostat alone. When this experiment was repeated using 2 Gy radiation, cells treated with 1 
micromolar had less than 20% viability and no viable cells were observed at vorinostat concentrations of 
2.5 micromolar and higher.   
 
Dr. Haas-Kogan’s laboratory also evaluated the combination of vorinostat and external beam radiation in 
a mouse neuroblastoma xenograft model.  In this metastatic model of neuroblastoma, NB1691 cells are 
injected into nude mice and metastatic deposits reliably develop.  Mice were then treated with vorinostat 
150 mg/kg by intraperitoneal injection, whole body radiation 1 Gy, or vorinostat 150 mg/kg by 
intraperitoneal injection plus whole body radiation 1 Gy.  Treatment was started 17 days after tumor cell 
injection and treatments were administered every other day for total of 3 treatments. Tumor volumes were 
measured and the average tumor volume per treatment group (5 mice in control group; 10 mice in 
treatment groups) was determined.   Mice treated with the combination of vorinostat and radiation had 
significantly smaller tumors compared to the other treatment groups (p < 0.05).75    


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2.4.4 
Clinical Experience with Vorinostat 
 
Vorinostat has been used extensively in adults and has been granted US FDA approval for the treatment 
of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, 
persistent, or recurrent disease on or following two systemic therapies (Vorinostat Package Insert).82  The 
approved adult dose is 400 mg orally once daily.  This dose was approved based on a series of phase I 
and II studies.   
 
The first human experience with vorinostat was in an adult phase I study of an IV formulation.83  A total of 
37 patients were treated.  Patients with solid tumors were evaluable for hematologic toxicity.  In these 
patients, appreciable thrombocytopenia only occurred with multiple cycles of therapy.  Platelets typically 
recovered within 7 days off drug.  Other toxicities observed included mild gastrointestinal symptoms, 
fatigue, tumor pain during drug infusion, and mild renal insufficiency that resolved off drug. 
 
This study was followed by an adult phase I study of oral vorinostat.84  A total of 73 patients were treated.  
The maximum tolerated dose and schedule were 400 mg orally once daily or 200 mg orally twice daily or 
300 mg orally twice daily for 3 days each week. x 3 days.  Dose-limiting toxicities included anorexia, 
dehydration, diarrhea, elevated AST/ALT, and fatigue.  The most common toxicities were fatigue, 
gastrointestinal symptoms, hyperglycemia, hypocalcemia, anemia, and thrombocytopenia.  This study 
noted more thrombocytopenia with the twice daily continuous dosing schedule.  Approximately 34% of 
patients reported dyspnea without consistent chest radiograph or electrocardiogram findings.  A mild 
increase in creatinine was reported in 64% of patients.  One patient developed a grade 3/4 increase in 
creatinine.  The pharmacokinetic evaluations on this study indicated that vorinostat was 43% bioavailable.  
The exposure was linear across the range of 200-600 mg tested.  The half-life was approximately 100 
minutes.  The mean concentration obtained after a 400 mg dose was approximately 1 micromolar 
(Investigator Brochure).  An increase in histone H3 acetylation was noted at all dose levels within 2 hours 
of dose.  The duration of this effect was dose dependent and extended up to 10 hours for the highest 
doses studied.   
 
Another study sought to evaluate the effect of food on the pharmacokinetics of oral vorinostat.85  Twenty-
three adult patients were treated with vorinostat 400 mg orally once daily.  A high-fat meal increased drug 
exposure by 38% and slowed the rate of absorption of the drug.  After 22 days of therapy, the 24 hour 
exposure was similar to the initial exposure, suggesting that the drug does not accumulate and that the 
metabolism does not change over time.  Most patients did not have drug detectable 24 hours after a 
dose.  The most common toxicities on this study were gastrointestinal symptoms, anorexia, and fatigue.  
Approximately 13% of patients had grade 3 anemia and grade 3 thrombocytopenia. 
 
An initial phase II study evaluated the activity of vorinostat in patients with refractory cutaneous T-cell 
lymphoma.86  Thirty-three patients enrolled and were treated in one of three dosing arms:  400 mg orally 
once daily; 300 mg orally twice daily for 3 days each week for 4 weeks then 300 mg twice daily for 5 days 
each week; or 300 mg orally twice daily for 14 days then 200 mg orally twice daily.  Eight patients had a 
partial response.  The most common toxicities were fatigue, diarrhea, nausea, thrombocytopenia, taste 
changes, and dry mouth.  Thrombocytopenia and dehydration were the most common grade 3 or 4 
toxicities.  Thrombocytopenia was most common in patients treated with 300 mg twice daily for 14 days.  
There appeared to be a lower response rate in patients who received discontinuous dosing. 
 
A follow-up phase II study enrolled 74 patients with cutaneous T-cell lymphoma.87  Patients received 
vorinostat 400 mg orally once daily.  The study reported a 29.7% overall objective response rate and an 
additional 48% of patients were noted to have a clinical benefit from drug.  The most common toxicities 
were diarrhea, fatigue, nausea, anorexia, taste disturbance, and thrombocytopenia.  Grade 3 or 4 
thrombocytopenia was noted in 5.4% of patients.  There were three cases of QTc prolongation. 
 
One clinical trial utilizing vorinostat as a radiation sensitizer has been completed.88  In that trial, 16 adult 
patients with pelvic gastrointestinal carcinoma were treated with the combination of vorinostat and 
external beam radiotherapy.  The maximum tolerated dose of vorinostat was 300 mg once daily prior to 
daily radiation fractions for 2 weeks, with dose limiting fatigue and anorexia noted in one of six patients 
treated at that dose level.  Other trials evaluating vorinostat in combination with external beam radiation 
are ongoing.   
 
 
 


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2.4.5 
Clinical Experience with Vorinostat in Pediatric Patients 
 
The clinical experience with vorinostat in children is limited.  The Children’s Oncology Group has 
completed an initial phase I study of vorinostat administered orally once daily.89  The maximum tolerated 
dose was 230 mg/m2/day.  This dose corresponds closely to the adult dose of 400 mg/day, assuming an 
average adult body surface area of 1.8 m2.  The dose limiting toxicities included deep vein thrombosis, 
hypokalemia, neutropenia, and thrombocytopenia.  Patients also experienced manageable hepatoxicity, 
including ALT, AST, and bilirubin elevations.  This study was extended to also study the combination of 
vorinostat and cis-retinoic acid and to study a pediatric liquid formulation of vorinostat.  Twelve patients 
were treated with the oral suspension at a dose of 230 mg/m2/day.  Four patients developed protocol-
defined dose limiting toxicities in the first cycle of therapy (grade 4 thrombocytopenia in two patients; 
grade 3 ALT; grade 3 hyponatremia).      
 
Following the first day’s dose of vorinostat, patients reached a median peak concentration of 1.3 μM 
(range 0.37-2.2 μM), 0.66 μM (range 0.33-2.2 μM), and 1.2 μM (range 0.05-2.2 μM) after doses of 180 
mg/m2, 230 mg/m2, and 300 mg/m2, respectively.  Most patients reached peak concentration within 2 
hours of the oral dose.  Peak drug concentrations were higher after 28 days of dosing, with mean values 
of 2.5 μM, 1.7 μM, and 1.7 μM at these same dose levels.  These results indicate that a target peak 
plasma concentration of 1 μM is attainable in pediatric patients.  
 
Follow-up pediatric studies have evaluated or are evaluating vorinostat combination regimens.  These 
trials include NANT protocol N08-02 (vorinostat plus cis-retinoic acid), COG protocols ADVL0819 
(vorinostat plus temozolomide), ADVL0916 (vorinostat plus bortezomib), and ACNS0822 (vorinostat plus 
external beam radiotherapy for pediatric high-grade glioma).    
 
2.4.6 
Clinical Experience with Vorinostat and 131I-MIBG 
 
The NANT consortium initiated protocol N07-03 based on three main pieces of evidence.  First, vorinostat 
has modest activity against neuroblastoma in preclinical models.  Second, vorinostat has been shown to 
sensitize tumor cells, including neuroblastoma, to the effects of radiation therapy.  Third, vorinostat also 
appears to upregulate the expression of the norepinephrine transporter on neuroblastoma cell lines.   
 
N07-03 was a phase 1 dose escalation study of 131I-MIBG (Day 3) together with once daily vorinostat 
(Days 1-14).  All patients received autologous stem cell rescue on Day 17.  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 
dose-limiting toxicity.  The 6th patient at this dose level is without DLT mid-cycle 1 and will not impact final 
dose selection.  Dose limiting toxicities included grade 4 hypokalemia in one patient treated with 131I-
MIBG 15 mCi/kg and vorinostat 230 mg/m2/day, grade 3 bleeding in one patient treated with 131I-MIBG 18 
mCi/kg and vorinostat 230 mg/m2/day, and grade 3 QTc prolongation and grade 5 CNS bleeding in one 
patient treated with 131I-MIBG 18 mCi/kg and vorinostat 230 mg/m2/day.  Central review of response has 
not yet been completed.       
 
2.5 
Summary and Rationale for Current Trial 
 
131I-MIBG is a targeted radionuclide with one of the highest reported single-agent response rates in 
patients with relapsed or refractory neuroblastoma.  More recent studies have attempted to combine 131I-
MIBG with systemic radiation sensitizers in an attempt to improve upon this single-agent activity.  Since 
131I-MIBG will be incorporated into planned clinical trials for patients with newly diagnosed high-risk 
neuroblastoma, it is imperative to select the most active 131I-MIBG treatment regimen for further 
evaluation. 
 
Phase I studies of 131I-MIBG with either irinotecan or vorinostat have demonstrated that these 
combinations are tolerable and active.  Small sample sizes, patient heterogeneity, and escalating 131I-
MIBG doses do not allow the activity of these regimens to be fully assessed or compared with single- 
agent 131I-MIBG.  While we hypothesize that combination regimens will be superior to single-agent 131I-
MIBG, these regimens will likely be associated with increased toxicity.  Therefore, the current study is a 3-
arm randomized phase 2 trial designed to identify the optimal 131I-MIBG treatment regimen for further 
study.  The three treatment arms are single-agent 131I-MIBG, 131I-MIBG with vincristine/irinotecan, and 
131I-MIBG with vorinostat.  Objective response rate following a single course of therapy will be the primary 
endpoint driving selection of the regimen to move forward into future studies.   
 


NANT 2011-01 Version Amendment #8  01-10-2018     18 
 
2.6 
Correlative and Exploratory Studies 
 
2.6.1 
Whole Body Radiation Exposure Following 131I-MIBG Therapy 
 
Previous studies of therapeutic 131I-MIBG have derived estimates of whole body radiation exposure 
typically by using serial measurements of radiation exposure rate with an ionization chamber set at a 
fixed distance and geometry from the patient.10  Patients treated with doses > 10 mCi/kg typically have 
estimated whole body radiation doses of > 200 cGy.10, 90  In a group of 53 patients treated with 18 mCi/kg 
131I-MIBG, the median estimated whole body radiation dose was 292 cGy, with a broad range of 173 – 
418 cGy.12  Higher whole body radiation dose appears to correlate with increased hematologic toxicity10, 
12, 90, though the impact of whole body radiation dose on response  to 131I-MIBG  therapy remains 
unclear.10  Moreover, it is not clear whether the addition of irinotecan or vorinostat might impact whole 
body radiation dose.  Two potential mechanisms by which these agents might impact whole body 
radiation dose include increasing tumor uptake and/or retention of 131I-MIBG or by delaying physiologic 
clearance of 131I-MIBG. 
 
In the current study, all patients will have whole body radiation doses calculated based on serial 
measurements of radiation exposure rate with an ionization chamber set at a fixed distance and 
geometry.  The primary analyses will compare whole body radiation dose between randomized treatment 
groups and also between responders vs. non-responders.  Secondary analyses will compare whole body 
radiation dose between patients with and without grade 4 neutropenia, grade 4 thrombocytopenia, and 
grade > 3 non-hematologic toxicity.  
 
2.6.2 
Five Gene (NB5) TLDA Assay for Neuroblastoma Tumor Cell Detection 
 
Dr. Robert Seeger’s laboratory developed a five gene (NB5) TLDA assay 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. 
 
TLDA 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 NB5 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 TLDA.  These data further confirm that the NB5assay is more sensitive than 
immunocytology for detecting tumor cells.  Moreover, detection of occult bone marrow tumor cells by 
TLDA 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 NB5 assay. 
 
The current study includes a secondary aim to evaluate neuroblastoma cell detection in blood and bone 
marrow by NB5 assay.  These samples will be obtained as part of the companion NANT biology study 
(N04-05), such that only patients who have co-enrolled on that study will contribute samples for this 
secondary aim.     
 


NANT 2011-01 Version Amendment #8  01-10-2018     19 
 
 
2.6.3 
γ-H2AX as a Marker of Radiation Exposure 
 
Ionizing radiation introduces double strand DNA breaks.  In response to double strand DNA breaks, 
histone H2AX near these DNA breaks becomes phosphorylated to γ-H2AX, which facilitates DNA repair.91  
Recently, multiple groups have evaluated γ-H2AX levels in peripheral blood cells as a marker of double 
strand DNA breaks and, therefore, as a marker of radiation exposure.  In one of the earliest studies of this 
approach, peripheral blood lymphocytes from patients undergoing diagnostic CT scans were evaluated 
using immunofluorescence for γ-H2AX.92  As early as 30 minutes following CT scan, an increase in the 
number of γ-H2AX foci could be detected, with levels returning to baseline by 24 hours post-radiation 
exposure.  This marker has also been utilized to estimate radiation exposure in children undergoing 
cardiac catheterization.93   
 
Quantification of γ-H2AX has also been used as a biomarker of radiation exposure in patients with cancer.  
In one study, patients receiving external beam radiotherapy to a range of tumor sites had lymphocyte γ-
H2AX levels quantified.94  γ-H2AX showed a linear correlation with estimated whole body radiation 
exposure.  The slope of the correlation varied both with tumor site and with time from start of 
radiotherapy, with later time points showing a less steep slope.  
 
Another study evaluated γ-H2AX foci in patients receiving cisplatin and external beam radiotherapy.95  
Cisplatin reduced the formation of γ-H2AX foci in response to radiation, suggesting that cisplatin may 
compromise DNA repair following radiation-induced double strand DNA breaks.  These findings have 
direct relevance for the current study evaluating two putative radiation sensitizers (vorinostat and 
irinotecan) in combination with 131I-MIBG. 
 
One study has evaluated γ-H2AX foci by immunofluorescence in patients with thyroid carcinoma receiving 
therapeutic 131I (mean dose 92 mCi).96  They noted that γ-H2AX levels peaked by 2 hours post-infusion, 
but remained elevated above baseline even by 120 hours post-infusion.  These findings have direct 
relevance to the current study utilizing another 131I radionuclide, 131I-MIBG.     
 
Preliminary studies from UCSF demonstrate that γ-H2AX foci increase after 131I-MIBG, with a peak at 
hour 72-96 before decreasing at hour 120.  In the current study, we will evaluate γ-H2AX levels as a 
biomarker of radiation exposure and as a pharmacodynamic tool to assess whether the addition of either 
irinotecan or vorinostat to 131I-MIBG impairs DNA repair pathways.  Patients who consent to this optional 
correlative biology study will have peripheral blood obtained at study entry for baseline quantification of γ-
H2AX foci by flow cytometry. Due to radiation safety concerns about handling peripheral blood within the 
first 72 hours following 131I-MIBG infusion, follow-up peripheral blood samples will be obtained at hours 72 
and 96 after 131I-MIBG infusion.   
 
2.6.4 
Expression of DNA Damage Response Genes 
 
Therapeutic radiation exerts its antitumor effect by inducing DNA damage.  Specific cellular pathways are 
initiated in response to this DNA damage.  Expression of genes involved in these pathways can be 
quantified using quantitative RT-PCR.97, 98   
 
The Coleman Laboratory at Lawrence Livermore National Laboratory has developed a panel of 16 genes 
whose peripheral blood expression changes in response to external beam radiotherapy, with extent of 
change correlated to radiation exposure.  Preliminary data from 11 patients treated with 131I-MIBG at 
UCSF demonstrate 5 transcripts (CDKN1A, FDXR, GADD45A, BCLXI, and XPC) with significant changes 
in gene expression detectable in peripheral blood mononuclear cells between 0 to 72 hours (p<0.05) and 
7 transcripts (CDKN1A, FDXR, GADD45A, STAT5B, BCLXI, XPC, and BIM) with significant changes in 
gene expression between 0 to 96 hours (p<0.05). Only 2 transcripts (CDKN1A and FDXR) had significant 
differential gene expression across all time points (p<0.05). Using multiple regression analysis, 7 
transcripts (CDKN1A, FDXR, GADD45A, STAT5B, BCLXI, XPC, and BIM) showed elevated responses 
that were dependent on time.  Two transcripts (GADD45A and BCLXI) showed elevated responses that 
were dependent on chemotherapeutic treatment (131I-MIBG combination protocol vs. single-agent 131I-
MIBG). 
 


NANT 2011-01 Version Amendment #8  01-10-2018     20 
 
The current study will include an optional correlative biology study in which mRNA from peripheral blood 
mononuclear cells will be collected at baseline and at hours 72 and 96 following 131I-MIBG infusion.  
Quantitative RT-PCR will be used to quantify each gene of interest and the change in expression will be 
determined for each patient.  We will compare change in gene expression between randomized treatment 
groups.  We will also compare changes in these markers based on groups defined by treatment response 
and treatment-associated toxicity.     
 
2.6.5 
Plasma Flt3 Ligand and Serum Amylase as Biomarkers of Radiation Exposure 
 
Hematologic toxicity is the main dose-limiting toxicity of 131I-MIBG.12  Recent evidence suggests that 
plasma levels of Flt3 ligand may predict hematologic toxicity of other forms of radiotherapy.  In one study 
of non-human primates, plasma Flt3 ligand levels increased in response to radiation, with the level 
correlated 
to 
radiation 
dose.99 
 
Another 
study 
demonstrated 
that 
patients 
treated 
with 
radioimmunotherapy who had elevated plasma Flt3 ligand levels at baseline were more likely to develop 
grade > 3 thrombocytopenia.100  Another group evaluated serial plasma Flt3 ligand levels in patients 
receiving fractionated external beam radiotherapy.101  Measures of plasma Flt3 ligand during radiotherapy 
correlated with the proportion of bone marrow radiated.    
 
Evaluation of serum amylase levels 24 hours after total body radiation have indicated a correlation 
between amylase level and whole body radiation dose.102  A previous group evaluated changes in serum 
amylase in 8 patients treated with 131I-MIBG therapy.  All 8 patients demonstrated peak increases in 
serum amylase at a median of 24 hours after 131I-MIBG infusion, likely due to known salivary gland uptake 
by 131I-MIBG.103    
 
Preliminary data from 26 patients treated at UCSF demonstrate robust modulation of plasma Flt3 ligand 
by 72 hours after 131I-MIBG infusion (median fold increase from baseline 3.6; p=0.0005), with levels 
continuing to increase in some patients by hour 96.  Patients receiving 131I-MIBG as part of a combination 
protocol (with either vorinostat or irinotecan) showed greater degree of Flt3 modulation at hour 72.  
Serum amylase was also significantly modulated by 72 hours after 131I-MIBG infusion (median fold 
increase from baseline 3.1; p <0.0001), with levels decreasing by hour 96.    
 
Given our limited ability to predict toxicity and response following 131I-MIBG therapy, the current study will 
include an optional correlative study in which patients will have plasma Flt3 ligand and serum amylase 
measured at study entry and again at hours 72 and 96 following 131I-MIBG infusion.  We will compare 
changes in these markers between randomized treatment groups.  We will also compare changes in 
these markers based on groups defined by treatment response and treatment-associated toxicity.     
 
2.6.6 
Assistive MIBG Scan Scoring System 
123I-MIBG scans are typically interpreted qualitatively or semi-quantitatively by radiologists, often with poor 
inter-reader reliability. The Center for Research Informatics and the Human Imaging Research Office at 
the University of Chicago have developed a computerized method for assistive scoring of MIBG scans to 
overcome this inter-reader variability and to improve longitudinal comparisons.  In a pilot study, 25 scans 
from 11 patients treated at the University of Chicago were evaluated. Planar images were scored by two 
experienced radiologists, according to the currently accepted standard of assigning each of 9 skeletal 
segments and one segment for any soft tissue disease with an uptake score of 0-3 per region.  A semi-
automated, computerized segmentation algorithm was developed to divide the scan image into 9 
segments and assign an extension score by relative MIBG signal intensity when compared to physiologic 
MIBG uptake in the liver. Of the 25 scans, there was complete agreement between computer and the 
radiologists for 13 (52%). The two radiologists agreed on 21 scans (84%). There were six false positives 
(24%) and no false negatives, illustrating the high sensitivity of this method. 
 
Recently, the group has extended the efficiency of the segmentation algorithm. The current scoring 
system is an assistive platform, designed to provide a consistent and standardized method for recording 
and tallying MIBG-avid lesions. The University of Chicago group is currently piloting this scoring platform 
by evaluating fifty scans obtained both from the University of Chicago and the Quality Assurance Review 
Center (QARC).  
 
The current trial will include a correlative radiology study to prospectively evaluate this technique in a 
group of patients with relapsed MIBG-avid neuroblastoma treated with 131I-MIBG therapy. 


NANT 2011-01 Version Amendment #8  01-10-2018     21 
 
 
2.6.7 
NET Protein Expression and MIBG Avidity 
The norepinephrine transporter (NET) appears to be the main mediator of active MIBG uptake by 
neuroblastoma cells.  In cell lines, extent of MIBG correlates with norepinephrine transporter mRNA 
expression.5   Uptake of MIBG by neuroblastoma cells in vitro can be blocked using desipramine, a 
norepinephrine transporter inhibitor.104  In archival neuroblastoma tumor samples, norepinephrine 
transporter mRNA and protein expression correlate with MIBG avidity on diagnostic scans.3, 105  However, 
the correlation between NET protein expression and response to 131I-MIBG therapy remains unknown.   
 
In the current trial, archival tumor material will be used to quantify NET protein expression by 
immunohistochemistry and results correlated with response to 131I-MIBG therapy.   
 
2.6.8 
Institutional Assignment of Curie Score 
The Curie score is a semi-quantitative scoring system to describe the burden of 123I-MIBG-avid disease in 
patients with metastatic neuroblastoma.106  Curie scoring has largely been used as part of research 
studies and as part of response assessment in clinical trials, including centrally-reviewed assignment of 
Curie score in NANT trials.  Recently, data have emerged that response as assessed by Curie score is 
prognostic in patients with newly-diagnosed high-risk metastatic neuroblastoma.107, 108  Based on these 
results, clinical assignment of Curie score has become more critical.  However, it is not known to what 
extent institutional assignment of Curie score will correlate with assignment of Curie score by experienced 
central review radiologists.  Efforts are underway to study this issue in patients with newly-diagnosed 
metastatic neuroblastoma (in Children’s Oncology Group protocol ANBL12P1).  In the current study, we 
will assess this issue in patients with relapsed or refractory neuroblastoma.   
 
2.6.9 
Sinusoidal Obstruction Syndrome (SOS) after 131I-MIBG therapy 
The risk of SOS in patients who receive myeloablative chemotherapy following 131I-MIBG therapy is not 
well understood.  A previous NANT trial (NANT01-02) evaluated a block of 131I-MIBG therapy two weeks 
prior to conditioning with carboplatin, etoposide, and melphalan and determined that this regimen was 
tolerable, though the dose of 131I-MIBG was 12 mCi/kg.  More recent efforts have focused on increasing 
the dose of 131I-MIBG and allowing a longer period of recovery between 131I-MIBG and the start of 
conditioning.  Anecdotal cases of SOS have been reported, though the exact risk is not known.109  
Moreover, the impact of a radiation sensitizer given together with 131I-MIBG on the risk of subsequent 
SOS is not known. 
 
It is anticipated that only a minority of patients will receive subsequent myeloablative therapy after 
completing therapy on the current protocol.  Nevertheless, these patients provide an opportunity to track 
and describe the incidence of SOS in these patients after subsequent myeloablative therapy.  
 
2.6.10 Circulating Tumor DNA 
Recently, new technology has emerged that enables detection of tumor-specific genetic aberrations in 
cell free DNA collected from the plasma. This technology enables detection of a range of potential 
mutations, amplifications, copy number alterations, and translocations of interest.  For example, Dr. Brian 
Crompton has used this approach on baseline plasma from five children with newly diagnosed high-risk 
neuroblastoma and was able to quantify circulating tumor DNA (ctDNA) burden from all five patients 
based upon copy number alterations and MYCN amplification (personal communication).  This testing will 
be explored on a research basis to describe baseline levels of ctDNA and changes in ctDNA levels in 
response to therapy.   
 
2.7 
Rationale for Amendments 
 
2.7.1 
Amendment 4 
Amendment 4 includes three main changes.  First, the platelet criterion for proceeding to course 2 of 
therapy has been lowered from > 50,000/µl (no transfusions for one week) to > 25,000/µl (no transfusions 
for one week).  This change is made as patients may have stable, low level thrombocytopenia after 131I-
MIBG therapy and stem cell rescue without clinical consequence.  As stem cell support is mandated after 
the second course of therapy, proceeding to a second course without having to wait for full platelet 
recovery is expected to be in the best interest of patients enrolling to study.  This approach has been 
shown to be safe.25  Second, patients who might otherwise have enrolled on study have declined 
participation as they would have had to travel to return to a NANT center to receive stem cell support.  
Since stem cells are considered supportive care and not anticancer therapy, Amendment 4 explicitly 


NANT 2011-01 Version Amendment #8  01-10-2018     22 
 
allows receipt of stem cells at a non-NANT COG designated transplant center.  This change also reduces 
expense of shipping stem cells and potential risk of damage to stem cell product during shipment.  Third, 
selected patients previously treated with 131I-MIBG will now be eligible to participate.  This change is 
based upon experience from a prior NANT trial (NANT07-01) and a trial of 131I-MIBG with vincristine and 
irinotecan.  Both trials allowed prior 131I-MIBG therapy on other protocols and the toxicity profile of both 
trials was acceptable.  Compassionate access 131I-MIBG protocols typically allow up to a cumulative 
lifetime exposure of 54 mCi/kg (three infusions of 18 mCi/kg).  To account for potential disparate 
response rates between patients previously treated with and without 131I-MIBG, randomization will now 
also be stratified based upon this prior therapy.   
 
2.7.2 Amendment 5 
This amendment reflects the change of institution for Steven DuBois, MD, Study Chairperson and IND 
holder, from University of California, San Francisco to Dana-Farber Cancer Institute.   An additional 
update to NANT participating sites includes a change in Principal Investigator for Hospital for Sick 
Children, Toronto from Sylvain Baruchel, MD to Meredith Irwin, MD.  The shipping address for correlative 
study specimens was revised. There are also minor editorial and informed consent changes associated 
with the change in shipping addresses.  
 
2.7.3 Amendment 6 
This amendment adds a late blood draw (protocol Day 15 at time of stem cell infusion) to extend the 
correlative radiobiology studies.  Since it is possible that the markers under investigation as part of Aim 
1.6 remain elevated at the 72 and 96 hour time point, it is of interest to determine whether these markers 
return to baseline by Day 15 and whether failure to return to baseline by Day 15 correlates with increased 
risk of toxicity.  Changes were made to Sections 10.1 and 10.3.1.  Section 10.1 clarifies how protocol 
enrollment will be handled during performance of scheduled interim analyses and a change to Section 
10.3.1 clarifies the definition of evaluable for response in a secondary per-protocol analysis.  Clarifying 
language has been added to Section 6.3 to accommodate local needs at one MIBG treating center.  
Additional updates include changes in the site investigator at Stanford, change in protocol coordinator, 
updated address for shipment of correlative radiobiology samples, and minor editorial changes.    
 
2.7.4  Amendment 7A 
This amendment changes the preferred 131I-MIBG supplier from Jubilant Draximage to NDP, adds 
evaluation of circulating tumor DNA as a correlative biomarker to existing Aim 1.6, and modifies the 
statistical plan to add a rule for stopping the trial early if a winner can be identified at the time of planned 
interim analysis.  Moreover, for patients enrolled with Amendment 7A and later, only a single course of 
therapy will be allowed due to financial limitations.  Additional updates include changes in the site 
investigator at Stanford and minor editorial changes. Required observations for anatomical imaging were 
clarified and the response criteria v1.2 was revised to clarify intent of these criteria for morphologic bone 
marrow disease and overall response. Editorial revisions were made to update the TLDA assay to NB5 
TLDA assay within the protocol and the informed consent document. 
 
2.7.5 Amendment 8 
This amendment includes the change in NANT Site Principal Investigator for University of Chicago, 
Comer Children’s Hospital from Susan Cohn, MD to Ami Desai, MD as well as the change in NANT Site 
Principal Investigator for Seattle Children’s Hospital from Julie Park, MD to Navin Pinto, MD.  It also 
includes the removal of Memorial Sloan Kettering Cancer Center as a site and the addition of University 
of North Carolina, Chapel Hill as a new site. 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     23 
 
3.0 
PATIENT ELIGIBILITY CRITERIA AND REGISTRATION 
 
3.1 
Patient Preparation for Study Entry and Registration 
 
The NANT Operations Center will accept reservations for this study from MIBG and non-MIBG institutions 
via email to nantrsvp@chla.usc.edu.  Reservations for a treatment slot made by a non-MIBG institution 
must be confirmed by a NANT MIBG institution within 7 calendar days of reservation.   
 
Notification of MIBG Treatment Center and Submission of MIBG Scans for Review: 
The referring physician is expected to contact the MIBG treating institution to discuss the patient. The 
most recent MIBG scan and report must be sent to the MIBG treatment center as part of this review. The 
MIBG institution will confirm they have accepted the patient as a possible candidate for this study with the 
NANT Operations Center. 
  
Co-Enrollment on NANT04-05 
Co-enrollment on NANT04-05, the NANT 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 11-01.   
 
Confirmation of an Adequate Stem Cell Product for Study Entry: 
Written documentation of a stem cell product that meets eligibility criteria (section 3.2.6) must be received 
and reviewed in the NANT Operations Center to confirm stem cell eligibility. This documentation must 
be sent to the Operations Center once consent is obtained and well in advance of patient 
registration in order to allow time to confirm this aspect of study eligibility. 
 
Documentation of Bone Marrow Disease Status for Study Entry: 
On study bone marrow aspirate and biopsy report is required prior to randomization on this study.  Bone 
marrow status at entry will be used for stratification. 
 
Timing of Registration and Treatment Initiation: 
It is recommended that patients be registered no later than the Friday prior to therapy initiation.  Initiation 
of protocol therapy is required within 7 days of registration on study. 
 
Patient Registration On Study: 
NANT trials have two components for data entry workflow: 1. Paper collection and data entry at the NANT 
Operations Center through CAFÉ database; 2. Remote data entry via Medidata Rave clinical data 
management system. 
 
Sites will initiate the enrollment process by completing the subject screening form in Medidata Rave web-
based application.  The subject screen form alerts the NANT Operations Center to all prospective 
enrollments and timing.  Sites will continue to send patient demographic information, signed informed 
consent and all documentation confirming eligibility to NANT Operations Center at Childrens Hospital Los 
Angeles by FAX at (323) 361-1803 or emailed to nantcrf@chla.usc.edu Monday through Friday, 8:30am – 
5:00 pm Pacific Time at (323) 361-5687 except holidays. 
 
Receipt of the signed consent form from only the referral center is acceptable documentation for eligibility 
confirmation purposes.  However, consent from the MIBG center must be received prior to any protocol 
therapy administration at the MIBG institution.   
 
Once all necessary 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 
validate eligibility and assign a unique NANT registration and study subject number in Medidata RAVE. 
The treatment arm will be assigned by randomization by the NANT Operations Center at the time of study 
registration. Once eligibility is verified, the NANT Operations center will send an email confirming 
registration and randomized treatment arm.  This 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 the Table below. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     24 
 
Table:  Summary of Registration Steps 
# 
 
Comment 
1 
Complete subject screening form in Medidata RAVE 
 
2 
Send patient demographic information forms, signed informed 
consent and all documentation confirming eligibility to NANT 
Operations Center (available on the web site (www.NANT.org)) 
FAX at (323) 361-1803 or 
emailed to nantcrf@chla.usc.edu 
3 
Complete eligibility form in Medidata RAVE 
 
4 
NANT Operations Office verifies eligibility and assigns unique 
NANT registration and study subject number in Medidata 
RAVE 
 
Treatment arm will be assigned by randomization by the NANT 
Operations Center 
5 
NANT Operations Center will send an email confirming 
registration and assigning NANT registration/study number and 
randomized treatment arm.   
Confirmation sent to the treating 
facilities, Study Chair, Study 
Vice-Chair, and relevant 
committee members. 
6 
Patient can begin treatment 
Receipt of signed consent from 
MIBG treatment site in the NANT 
Ops Center is required before 
starting treatment 
 
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.  
 
 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 
 
 
 
 
  
To allow non-English speaking patients to participate in this study, bilingual health services will be 
provided in the appropriate language when feasible. 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived. 
 
3.2 
Inclusion Criteria 
 
 
3.2.1 
Age 
Patients must be > 12 months and < 30 years of age when registered on study.  
 
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 Stage/Risk Group 
Patients must have a history of high-risk neuroblastoma according to COG risk classification at the time of 
study enrollment.  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 
Patients must have at least ONE of the following: 
 
a. Recurrent/progressive disease at any time prior to enrollment (regardless of overall response 
to frontline therapy)  
 


NANT 2011-01 Version Amendment #8  01-10-2018     25 
 
b. Refractory disease: persistent sites of disease after achieving a best overall response of stable 
disease  to frontline therapy after a minimum of 4 cycles of induction therapy AND patient has 
never had recurrent/progressive disease 
 
c. Persistent disease:  persistent sites of disease after achieving a best overall response of partial 
response to frontline therapy after a minimum of 4 cycles of induction therapy AND patient has 
never had recurrent/progressive disease. 
 
1)  If patient has 3 or more MIBG avid sites OR a Curie Score of > 3, then no biopsy is 
required for eligibility. 
 
2)  If patient has only 1 or 2 MIBG avid sites AND Curie Score of 1-2, then a biopsy 
confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one site (bone 
marrow, bone, or soft tissue) is required to be obtained at least 2 weeks after last day of 
prior radiotherapy to that site or at least 2 weeks after last day of prior 
chemotherapy/biotherapy.  
 
3.2.5  Sites of Disease:  MIBG Uptake  
Patients must have evidence of MIBG uptake into tumor at ≥ one site (bone or soft tissue) within 3 weeks 
prior to entry on study and subsequent to any intervening therapy. 
 
3.2.6 Autologous peripheral blood hematopoietic stem cells 
 
The minimum dose for peripheral blood stem cells is 1.5 x 106 CD34+ cells/kg.   
 
Patients planning to receive a stem cell dose of 1.5 - 1.9 x 106 CD34+/kg must have a back-up aliquot of 
1.5 - 1.9 x 106 CD34+/kg available until a minimum of 6 patients have been rescued with stem cell dose 
of 1.5 - 1.9 x 106 CD34+/kg without delayed engraftment.  If the first 6 patients receiving this reduced 
stem cell dose do not have delayed engraftment, then future patients may enroll with only a minimum of 
1.5 x 106 CD34+ cells/kg and no back-up aliquot.  If any of the first 6 patients have delayed engraftment, 
then the required stem cell dose will be changed to 2.0 x 106 CD34+ cells/kg.  Participating centers will be 
notified of this change by a study-specific memo.     
 
Patients planning to receive a stem cells dose of > 2.0 x 106 CD34+/kg are not required to have a back-up 
aliquot at any time during the study.   
 
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 calculation of PBSC dose (Reference: Bone Marrow Transplant. 40(7):665-9; 
Appendix VI). 
 
3.2.7 
Performance status  
Patients must have a Lansky (< 10 years) or Karnofsky (> 10 years) score of at least 50 (Appendix I). 
 
3.2.8 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, 
or radiotherapy prior to entering this study.  
 
Myelosuppressive chemotherapy: Last dose of any myelosuppressive chemotherapy was given at least 2 
weeks before study enrollment.  
 
Prior therapy with irinotecan or vincristine is allowed as long as neither were given in combination with 
131I-MIBG.  
 
Biologic (anti-neoplastic agent; includes retinoids): must have received last dose at least 7 days prior to 
study enrollment. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     26 
 
Prior therapy with vorinostat is allowed as long as it was not given in combination with 131I-MIBG.  
 
Monoclonal antibodies: must have received last dose at least 7 days or 3 half-lives, whichever is longer, 
prior to study enrollment.  Please refer to table posted at www.nant.org for definition of half lives for 
specific monoclonal antibodies. 
 
Radiation: Patients must not have received radiation for a minimum of two weeks prior to study 
enrollment.  Patients whose only site(s) of disease have been radiated are eligible as long patient has 
MIBG avidity 2 weeks after completion of radiation.   
 
A minimum of 12 weeks prior to study enrollment is required following prior large field radiation therapy 
(i.e. craniospinal, whole abdominal, total lung, > 50% marrow space).   
 
Patients are excluded if they have received total body irradiation (TBI). 
 
Prior 131I-MIBG:  With Amendment 4, patients previously treated with 131I-MIBG are now also eligible if 
they meet other entry requirements as well as ALL of the following requirements: 
 
a. At least 6 months from the date of last 131I-MIBG; 
 
b. Response other than progressive disease on first restaging after 131I-MIBG; 
 
c. 131I-MIBG given as monotherapy and not in combination with systemic anticancer agents; 
d. Cumulative lifetime dose of 131I-MIBG at enrollment does not exceed 18 mCi/kg (based upon 
assigned dose during that prior therapy; to account for unavoidable dose rounding, maximum 
delivered dose must not exceed 19 mCi/kg). 
 
Stem Cell Transplant (SCT): Patients are eligible 6 weeks after myeloablative therapy with autologous 
stem cell transplant (timed from study enrollment).  Patients status post-allogeneic stem cell transplant 
are excluded.  Patients must meet adequate bone marrow function definition (see organ function 
requirements, below) post-myeloablative therapy.  Patients who received stem cell reinfusion following 
non-myeloablative therapy are eligible once they meet peripheral blood count criteria in 3.2.10.1. 
 
Growth factor(s): See section 3.2.10.1 for restrictions on hematopoietic growth factors.  
 
3.2.9 
Concomitant Therapy Restrictions  
a.  Patients must not be receiving any other anti-cancer agents or radiotherapy at the time of study 
entry or while on study. 
b. Since valproic acid has HDAC inhibitory activity, patients must not have received valproic acid 
within 30 days of study entry. 
c. Since vorinostat may prolong the QT interval, patients must not be receiving other medications 
known to prolong the QT interval at the time of study entry (see first column of table in Appendix 
II).  Pentamidine must not have been received within 1 week of study enrollment.   
d. Due to drug-drug interaction with irinotecan, patients must not be receiving enzyme-inducing 
anticonvulsants (phenobarbital, phenytoin, or carbamazepine) at the time of study entry.   
e. No medications that interfere with 131I-MIBG uptake should be given within 7 days of planned start 
date for 131I-MIBG (see Appendix V).  These same medications are prohibited within 7 days after 
131I-MIBG infusion.   
 
3.2.10 Organ Function Requirements 
 
3.2.10.1 Hematologic Function:   
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) 
b.  
Platelet count: > 50,000/µl, transfusion independent (no platelet transfusions within 7 days of 
blood draw documenting eligibility)  
c.  
These criteria must be met by all patients, regardless of bone marrow involvement with tumor. 
d. 
There is not an eligibility criterion for hemoglobin.   
Patients must have hemoglobin ≥ 10 g/dL on the day of or prior to each 131I-MIBG infusion. 
 
3.2.10.2 Renal Function:  


NANT 2011-01 Version Amendment #8  01-10-2018     27 
 
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 normal for age, and  
b.  
SGPT (ALT) < 3 x upper limit of normal (note that for ALT, the upper limit of normal for all NANT 
sites is defined as 45 U/L). 
 
3.2.10.4 Cardiac Function: 
a.  
Normal ejection fraction (≥ 55%) documented by either echocardiogram or radionuclide MUGA 
evaluation OR normal fractional shortening (≥ 27%) documented by echocardiogram, and 
b.      
Corrected QT (QTc) interval < 450 msec.  
 
3.2.10.5 Lung Function:  
Normal lung function with no dyspnea at rest or oxygen requirement. 
 
3.2.10.6 Coagulation Function:   
a. 
International Normalized Ratio (INR) < 1.5 
b. 
Partial thromboplastin time (PTT) < 1.5 times upper limit of normal.  
 
For patients having labs drawn via heparinized catheters, it is important to request heparin-adsorbed values.   
 
3.2.10.7  Reproductive Function: 
All post-menarchal females must have a negative beta-HCG.  Males and females of reproductive age and 
function must use effective contraception for the duration of their participation or for 3 months after last dose 
of protocol therapy, whichever is longer.   
 
3.2.11 Coexisting Medical Conditions   
Patients with other ongoing serious medical issues must be approved by the study chair prior to registration. 
 
3.3 
Exclusion Criteria 
 
3.3.1 
Pregnancy, breast feeding, or unwillingness to use effective contraception during the study. 
 
3.3.2 
Patients status post-allogeneic stem cell transplant are not eligible. 
 
3.3.3 
Patients who, in the opinion of the investigator, may not be able to comply with the safety 
 
monitoring requirements of the study. 
 
3.3.4 
Obese patients whose calculated dose of 131I-MIBG exceeds 1200 mCi must receive a treatment 
dose of at least 85% of protocol maximum dose of 1200 mCi to be evaluable for the primary 
endpoint of the study.  If such a dose cannot be administered at the planned treating center and the 
patient is not able to travel to another MIBG center that can accommodate a higher dose, then the 
patient will be ineligible.   
 
3.3.5 
Patients with disease of any major organ system that would compromise their ability to 
 
withstand therapy. 
 
3.3.6 
Patients who are on hemodialysis. 
 
3.3.7 
Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still 
eligible if they are culture negative, afebrile, and meet other organ function criteria.  


NANT 2011-01 Version Amendment #8  01-10-2018     28 
 
 
3.3.8 
Patients and/or families who are physically and psychologically unable to cooperate with the
 
radiation safety isolation. 
 
3.3.9 
Patients with a history of deep venous thrombosis that was not associated with the presence of a 
central venous catheter. 
 
3.3.10 Patients must not have active diarrhea (defined as > Grade 2 per CTCAE v4 [Grade 2 = increase of 
4-6 stools/day over baseline]) 
 
3.3.11 Known active infection with HIV, hepatitis B, or hepatitis C (testing of patients not known to be 
infected with these viruses is not required prior to study entry). 
 
3.3.12 Patients who are receiving Coumadin.  
 
3.3.13 Patient declines participation in NANT04-05.   
 
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 2011-01 Version Amendment #8  01-10-2018     29 
 
4.0 
TREATMENT PROGRAM 
 
4.1  
Treatment Overview 
 
Patients will be randomized at study entry to one of three treatment arms. 
 
 
 
 
All patients will undergo disease restaging between Day +43 and +50, 6-7 weeks after 131I-MIBG infusion.  
Patients enrolling prior to Amendment 7A with at least stable disease to the first cycle can receive a 
second cycle of therapy, provided they meet stem cell and organ function criteria to proceed to a second 
cycle (Section 4.6).  Patients enrolling with Amendment 7A and later may receive a single cycle.   
 
4.1.1  Single-Agent 131I-MIBG (Arm A) 
Patients assigned to single-agent 131I-MIBG will receive 18 mCi/kg 131I-MIBG on Day 1 (Section 4.3) and 
autologous stem cell infusion on Day 15 (Section 4.4). 
 
Days 
 
 
    
 1 
 
 15 
         43-50 
 
Therapy 
                          M 
 
HSC 
           Eval 
 
 
131I-MIBG 
 
M 
Day 1 
Stem Cell Infusion  
HSC 
Day 15 
Evaluation 
Eval 
Day 43-50 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     30 
 
 
4.1.2  131I-MIBG with Vincristine and Irinotecan (Arm B) 
Patients randomized to receive vincristine / irinotecan / 131I-MIBG will receive vincristine 2 mg/m2 
(maximum dose 2 mg; see section 4.2.2.1 for dosing if <3 years old) intravenously on Day 0.  They will 
receive irinotecan 50 mg/m2 (maximum dose 100 mg) intravenously on Days 0 to 4.  Patients will also 
receive diarrhea prophylaxis with cefixime 8 mg/kg/day orally on Days -1 to +6.  Patients will receive 18 
mCi/kg 131I-MIBG on Day 1 (Section 4.3) and autologous stem cell infusion on Day 15 (Section 4.4). 
Cefixime 
C 
Days -1 through Day 6 
131I-MIBG 
M 
Day 1 
Irinotecan  
I 
Days 0 through 4 
Vincristine 
VCR 
Day  0 
Stem Cell Infusion  
HSC 
Day 15 
Evaluation  
Eval 
Day 43-50 
 
4.1.3 131I-MIBG with Vorinostat (Arm C) 
Patients randomized to receive vorinostat / 131I-MIBG will receive vorinostat orally once daily on Days -1 
to +12 (14 total days) at a dose of 180 mg/m2/dose (maximum dose 400 mg).  Patients will receive 18 
mCi/kg 131I-MIBG on Day 1 (Section 4.3) and autologous stem cell infusion on Day 15 (Section 4.4).  
 
 
Vorinostat 
V 
Days -1 through +12 (14 total days) 
131I-MIBG 
M 
Day 1 
Stem Cells 
HSC 
Day 15 
Evaluation 
Eval 
Day 43-50 
 
4.2  
Non-MIBG Drug Administration by Assigned Treatment Arm    
 
4.2.1 
Single-Agent 131I-MIBG Arm 
 
Patients randomized to receive single-agent 131I-MIBG will receive only 131I-MIBG on protocol Day 
1 per Section 4.3.  They will receive stem cell infusion on protocol Day 15 per Section 4.4.  No 
other systemic anticancer agents will be administered.   
 
4.2.2 
Vincristine / Irinotecan / 131I-MIBG Arm 
 
Patients randomized to receive vincristine / irinotecan / 131I-MIBG will receive 131I-MIBG on 
protocol Day 1 per Section 4.3.  They will receive stem cell infusion on protocol Day 15 per 
Section 4.4.  In addition, they will receive: 
 
4.2.2.1 Vincristine   
 
Vincristine will be dosed according to the age and size of the patient at the time of scheduled 
treatment according to the following table. Vincristine should be administered according to 
institutional guidelines (by IV push or via mini-bag over 15 minutes) prior to irinotecan on day 0 of 
each course.  
Days 
-1 
0 
1 
2 
3 
4 
5 
6 
    15 
   43-50 
Therapy  
C 
C 
C 
C 
C 
C 
C 
C 
HSC 
Eval 
 
 
VCR 
 
 
 
 
 
 
 
 
 
 
I 
I 
I 
I 
I 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
Days 
-1 
0 
1 
2 
3 
4 
        5-12 
15 
43-50 
Therapy  
V 
V 
V 
V 
V 
V 
V 
HSC 
EVAL 
 
 
 
M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     31 
 
  
 
Age at time of treatment: 
Vincristine dose on Day 0 before irinotecan.  
≥ 3 years 
2.0 mg/m² IV Push (max dose 2.0 mg) 
≥1 year and < 3 years 
0.067 mg/kg IV Push (max dose 2.0 mg) 
 
 
4.2.2.2 Irinotecan 
 
Patients will receive irinotecan 50 mg/m2 (max dose 100 mg), given by IV infusion over 60-90 
minutes on days 0 to + 4.   
 
On the day of 131I-MIBG administration (protocol Day 1), irinotecan is administered 6 hours (+/- 3 
hours) after the completion of the 131I-MIBG infusion. 
 
If there is a delay in 131I-MIBG administration due to production or logistical reasons and the 
patient has already started Day 0 irinotecan, the remaining irinotecan doses should be held and 
re-dated to resume on the day of 131I-MIBG administration.  This strategy is intended to maximize 
the degree of overlap between the radiation exposure and remaining doses of irinotecan.  In this 
situation, cefixime or cefpodoxime should be extended to continue for two days after the last dose 
of irinotecan. 
 
 
See section 5.4 for supportive care guidelines for irinotecan-associated diarrhea. 
 
4.2.2.3 Cefixime or Cefpodoxime Diarrhea Prophylaxis 
 
Cefixime will be given at a dose of 8 mg/kg/day (maximum daily dose 400 mg) given once daily 
by mouth on days -1 to +6.   
 
If cefixime is unavailable in suitable oral form for adequate dosing, cefpodoxime may be 
substituted at 10 mg/kg/day (maximum dose 800 mg) divided twice daily on days -1 to +6. 
 
If patients have a documented allergy to third generation cephalosporins, cefixime or 
cefpodoxime may be omitted.  If desired, another broad-spectrum oral antibiotic not listed as a 
prohibited concomitant medication may be substituted.      
 
4.2.3 
Vorinostat / 131I-MIBG Arm 
 
Patients randomized to receive vorinostat / 131I-MIBG will receive 131I-MIBG on protocol Day 1 per 
Section 4.3.  They will receive stem cell infusion on protocol Day 15 per Section 4.4.  In addition, 
they will receive: 
 
4.2.3.1 Vorinostat 
 
Patients will receive vorinostat 180 mg/m2/dose (maximum dose 400 mg) once daily by mouth, 
NG, or G-tube on days -1 to +12 (14 total doses).  
 
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.  
 
For patients unable to swallow capsules, vorinostat will be given as a 50 mg/mL extemporaneous 
liquid suspension (see section 6.1 for preparation instructions) with dosing according to the 
nomogram in Appendix III.  The maximum absolute vorinostat dose is 400 mg.     
 
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 (eg. 100 mg, 200 mg, 
300 mg, or 400 mg).  Otherwise, they will need to receive vorinostat as suspension and dosed 
according to the nomogram in Appendix III.  The maximum absolute vorinostat dose is 400 mg.   


NANT 2011-01 Version Amendment #8  01-10-2018     32 
 
      
Vorinostat should be taken with food or within 30 minutes after a meal.  The dose should be taken 
in the morning whenever possible. 
 
On day 1 of therapy, vorinostat should be taken 1 hour prior to the start of the 131I-MIBG infusion.  
Note that patients on this arm of the trial are to have a BUN and Cr obtained on day 1 prior to the 
131I-MIBG infusion to confirm that Cr still meets eligibility criteria in 3.2.10.2.  See 4.8.1.5 for 
guidelines.   
 
4.3 
131I-MIBG Administration for All Treatment Arms 
 
The primary 131I-MIBG supplier for this study is Nuclear Diagnostics Products NDP.  If a supply of 
131I-MIBG is not available from NDP for a specified date, Jubilant DraxImage, Canada is a 
secondary 131I-MIBG supplier for this study.   
 
4.3.1 
131I-MIBG Dose and Administration 
 
131I-MIBG 18 mCi/kg is given on day 1 of therapy to all patients regardless of randomized 
treatment arm.   
 
The maximum absolute dose of 131I-MIBG on this protocol is 1200 mCi, though individual MIBG 
treating centers may have lower maximum allowed doses due to radiation safety considerations.     
The dose administered should be within 15% of the prescribed dose (see section 10.3.1 for 
definition of evaluable for response based upon administered 131I-MIBG dose).  There will be no 
adjustment for obesity except to cap the absolute dose at 1200 mCi.     
 
131I-MIBG is provided by both suppliers with a specific activity not less than 30 mCi/mg MIBG at 
the calibration date.   
 
Radiopurity is checked by both suppliers prior to shipment.  Free radioiodine content is to be re-
checked at the treating center prior to infusion according to the methods in Appendix IV and 
should be < 5% for 131I-MIBG from DraxImage and < 7% for 131I-MIBG from NDP.   
 
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 and 
bladder protection with a Foley catheter.  
 
The patient will remain in a radiation protected isolation room until radiation emissions meet 
institutional/state guidelines. This usually takes 3-5 days and then the patient can be discharged.  
 
Patients should be transfused as needed to achieve a documented hemoglobin on the day of or 
one day prior to 131I-MIBG administration of > 10 g/dL.   
 
4.3.2 
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 radiation dose rate 
is < 7 mrem/hr at 1 meter.  Once < 7 mrem/hr, IV hydration is at the discretion of the treating 
institution.     
 
For patients assigned to the vorinostat / 131I-MIBG arm, the total IV plus oral fluid intake must be a 
minimum of maintenance rate until the patient has completed vorinostat therapy. 
 
4.3.3 
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 hospital 
admission.  Catheters, if placed, should remain in place for at least 48 hours.  For continent 


NANT 2011-01 Version Amendment #8  01-10-2018     33 
 
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.   
 
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 72 hours following the infusion. 
 
 
4.3.4 
Thyroid protection   
 
Potassium iodide (KI) solution will be given in a 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 to 43.  
 
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 start the subsequent KI doses on schedule 
as though the 131I-MIBG infusion had been completed on schedule.   
 
4.3.5 
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.  
 
4.3.6 
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. 
 
4.3.7 
Whole body dosimetry   
 
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 assumes a 2-hour infusion.  
 
The minimum whole body measurements will be taken as follows, and the exact dates and times 
marked on the recording data form. All times are measured from the beginning of the MIBG 
infusion.   
 
Infusion 
  
 
 
Hour 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. 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     34 
 
4.4 
Autologous Peripheral Stem Cell Infusion for All Treatment Arms   
  
4.4.1 
Stem Cell Timing/Dosage 
 
Peripheral blood stem cells will be infused on Day 15 of each course for all patients.  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 if indicated (i.e. due to an infectious or bleeding 
complication) after consultation with the Study Chair, Study Vice Chair, or designee. 
 
Stem cell infusion is planned for 2 weeks after 131I-MIBG infusion (Day 15). However, stem cells 
may be infused in the window +/- 2 days from planned date to avoid weekend or holiday stem cell 
infusions.  If the 131I-MIBG infusion is delayed due to production or logistical reasons, the date of 
stem cell reinfusion should be re-dated for 14 days after 131I-MIBG infusion.   
 
The minimum dose for peripheral blood stem cells is 1.5 x 106 viable CD34+ cells/kg.  Patients 
planning to receive a stem cell dose of 1.5 - 1.9 x 106 CD34+/kg must have a back-up aliquot of 
1.5 - 1.9 x 106 CD34+/kg available until a minimum of 6 patients have been rescued with stem 
cell dose of 1.5 - 1.9 x 106 CD34+/kg without delayed engraftment (section 4.7).  If the first 6 
patients receiving this reduced stem cell dose do not have delayed engraftment, then future 
patients may enroll with only a minimum of 1.5 x 106 CD34+ cells/kg and no back-up aliquot.  If 
any of the first 6 patients have delayed engraftment, then the required stem cell dose will be 
changed to 2.0 x 106 CD34+ cells/kg and sites alerted to this change via consortium memo.     
 
Patients planning to receive a stem cells dose of > 2.0 x 106 CD34+/kg are not required to have a 
back-up aliquot at any time during the study.   
 
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 VI). 
 
4.4.2 
Pre-medications/Stem Cell infusion 
Stem cells will be infused following institutional guidelines for prophylaxis of hypersensitivity 
reactions and monitoring. 
 
4.4.3 
Location of Stem Cell Infusion 
Stem cell infusion is considered a supportive care measure on this protocol.  Stem cells may be 
infused at a NANT institution or at a COG-designated transplant center (typically closer to a 
patient’s residence).  If stem cells are infused at a non-NANT institution, the treating NANT center 
is responsible for collecting and submitting documentation of stem cell infusion, including dose of 
infused stem cells, date of infusion, and any AE.  According to standard clinical practice, any non-
NANT institution infusing stem cells will obtain clinical consent for the stem cell infusion. 
 
4.5 
Myeloid Growth Factor Support for All Patients 
 
Patients may receive prophylactic myeloid growth factor support following stem cell infusion at the 
discretion of the treating investigator according to institutional practice.  Myeloid growth factor 
support is strongly recommended for any patient who develops neutropenia (ANC < 500/µL).  A 
suggested practice is to use filgrastim at a dose of 5 micrograms/kg subcutaneously once daily 
starting when ANC < 500/µL and continuing until ANC > 2000/µL.  A single dose of pegfilgrastim 
(100 micrograms/kg; maximum dose 6 mg) given subcutaneously may be substituted for 
filgrastim according to institutional standard practice following 131I-MIBG therapy.   
 
If the ANC falls below 500/µL before stem cell infusion, myeloid growth factor may be initiated 
prior to stem cell infusion as long as both of the following criteria are met: 
• 
Off vorinostat and/or irinotecan for a minimum of 24 hours prior to start of growth factor; 


NANT 2011-01 Version Amendment #8  01-10-2018     35 
 
• 
Measured or estimated radiation level of < 1 mrem/hr at 1 meter prior to start of growth 
factor.   
 
 
4.6 
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 assigned therapy:  
 
• 
Enrolled prior to Amendment 7A (patients enrolling with Amendment 7A and later may receive a 
single course only); 
• 
Adequate stem cells to support a second course per section 3.2.6; 
• 
Organ function meets criteria in section 3.2.10 except: 
o 
EKG only needs to repeated prior to course 2 for patients randomized to vorinostat arm; 
all arms require repeat echocardiogram); and 
o 
Platelets only need to recover to > 25,000/µl (no transfusions for one week prior to CBC 
documenting platelet recovery to this level); 
• 
No intervening anti-cancer therapy between first course and planned second course; 
• 
Day 1 of planned second course no earlier than Day 43 of first course (minimum 6 weeks 
between 131I-MIBG infusions); 
• 
No delayed engraftment (section 4.7) or need for dose modification (section 4.8) in first course of 
therapy; 
• 
Disease status at end of first course of stable disease or better (section 11) 
• 
Cumulative lifetime assigned dose of 131I-MIBG does not exceed 36 mCi/kg at time of planned 
second infusion on this protocol (based upon assigned dose during that prior therapy; to account 
for unavoidable dose rounding, maximum previously delivered dose must not exceed 38 mCi/kg). 
 
4.7 
Toxicity Assessment and Definition of Engraftment            
 
Toxicity will be graded using the CTCAE criteria, version 4. 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).    
 
Neutrophil engraftment will be defined as ANC ≥500/µL for a minimum of 3 days following neutrophil 
nadir, with or without myeloid 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. 
 
Delayed engraftment will be defined as failure to engraft neutrophils by Day 43 of protocol therapy (28 
days from stem cell infusion) and/or failure to engraft platelets by Day 71 of protocol therapy (56 days 
from stem cell infusion), in the absence of progressive bone marrow metastatic disease.  Any case of 
delayed engraftment should be reported to the study chair and to the NANT Operations Center.   
 
4.8 
Dose Modification  
 
Any dose modification should be reported to the study chair and to the NANT Operations Center 
 
4.8.1 
Vorinostat Dose Modifications 
 
4.8.1.1 Patients who develop grade 4 neutropenia on protocol days -1 to +5 (first 7 days) will have 
vorinostat discontinued.  Myeloid growth factor can be initiated early per Section 4.5, recognizing that 
patients must have been off vorinostat for at least 24 hours and the measured or estimated radiation level 
must be < 1 mrem/hr at 1 meter prior to start of growth factor.   
 


NANT 2011-01 Version Amendment #8  01-10-2018     36 
 
4.8.1.2 Patients who develop grade 4 neutropenia AND one of the following complications of neutropenia 
on protocol days 6 to 12 (second 7 days) will have vorinostat discontinued and myeloid growth 
factor started per section 4.5:  
o 
Documented bacteremia with an organism other than Staphylococcus epidermidis 
o 
Clinical culture-negative sepsis 
o 
Documented systemic fungal infection 
 
Patients who develop grade 4 neutropenia without one of these complications on protocol days 6 
to 12 will continue to receive vorinostat at the prescribed dose and schedule.  Myeloid growth 
factor may be initiated starting on protocol day 13 according to Section 4.5 and investigator 
preference.   
 
4.8.1.3 Patients who develop grade 4 thrombocytopenia on protocol days -1 to +5 (first 7 days) will have 
vorinostat discontinued. 
 
4.8.1.4 Patients who develop grade 4 thrombocytopenia who become platelet transfusion refractory on 
protocol days 6 to 12 (second 7 days) will have vorinostat discontinued. 
 
Patients who develop grade 4 thrombocytopenia on protocol days 6 to 12 who can safely be 
supported with platelet transfusions will continue to receive vorinostat at the prescribed dose and 
schedule.   
 
4.8.1.5 Patients on Arm C with vorinostat who have a required creatinine on day 1 that exceeds eligibility 
criteria in 3.2.10.2 should have vorinostat discontinued permanently, hydration increased, and 
131I-MIBG infusion postponed until creatinine again within eligibility criteria.  If creatinine not back 
to eligibility levels by the time the dose of 131I-MIBG expires, then the 131I-MIBG should not be 
administered and the patient will be off protocol therapy.  
 
4.8.2 
Irinotecan Dose Modifications 
For patients who develop grade 3 diarrhea persisting more than 72 hours with appropriate 
therapy or any grade 4 diarrhea during the five-day course of irinotecan, the remaining doses of 
irinotecan should be omitted for the course. 
 
4.9 
Concomitant Therapy 
 
4.9.1 
No other cancer chemotherapy, radiotherapy, biologic therapy, or immunomodulating agents will be 
used.   
 
4.9.2 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care 
are to be used as necessary (see also Section 5.0). 
 
4.9.3 
No medications that interfere with 131I-MIBG uptake should be given during the week prior or after 
131I-MIBG therapy (see Appendix V). 
 
4.9.4 
Patients randomized to receive vorinostat may not receive valproic acid until disease re-
evaluation following the last planned course of therapy has been completed. 
 
4.9.5 
Patients receiving vorinostat have rarely had QT prolongation.110 A formal QT study was 
performed in which patients with advanced cancer received a single supratherapeutic dose of 
vorinostat of 800 mg or placebo.110 No patients had QTc prolongation of more than 30 msec and 
no patients had QTc > 480 msec.  The effect of vorinostat with other drugs that prolong the QT 
interval is not clear, though no issues were noted on NANT07-03 with vorinostat, 131I-MIBG, and 
allowed use of ondansetron. Patients assigned to the vorinostat arm may not receive other 
medications known to prolong the QTc interval within 1 week prior to or 1 week following 
vorinostat (Appendix II; note that this list prohibits the use of pentamidine and cautions 
investigators with the use of ondansetron). 
 
4.9.6 
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 2011-01 Version Amendment #8  01-10-2018     37 
 
 
4.9.7 
The following agents that may interfere with irinotecan metabolism may not be administered to 
patients assigned to the irinotecan arm until Day 15 of the second course of protocol therapy: 
• 
High-dose dexamethasone (other systemic corticosteroids allowed only for management of 
asthma, allergy, premedication for blood transfusions, or management of CNS lesions); 
• 
Aprepitant (Emend); 
• 
Ketoconazole and St. John’s Wort; 
• 
Phenobarbital, carbamazepine, phenytoin. 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     38 
 
5.0 
SUPPORTIVE CARE 
 
5.1 
Prophylaxis for Pneumocystis Pneumonia 
   
All patients should receive PCP prophylaxis according to institutional guidelines.  Pentamidine is 
prohibited during the week prior to and week following vorinostat therapy due to QTc prolongation.  
 
5.2 
Use of Myeloid Growth Factors   
See sections 4.5 and 4.8.1.   
 
5.3 
Hydration status 
Dose limiting toxicities in previous studies of vorinostat included anorexia, dehydration, diarrhea, 
and fatigue.  The combination of irinotecan and 131I-MIBG is associated with an increased risk of 
diarrhea.  Patients should maintain adequate fluid intake while receiving these therapies.  
 
5.4 
Management of Irinotecan-Associated Diarrhea 
 
Diarrhea can be profuse and can occur either early (minutes to hours) or late (days) in the treatment 
schedule. Early diarrhea results from cholinergic stimulation, while late diarrhea relates to bacterial 
processing of irinotecan metabolites.  
 
Early diarrhea: Patients who have the onset of diarrhea during the irinotecan infusion or in the hours 
following the completion of an irinotecan infusion should receive atropine (suggested dose 0.01mg/kg IV, 
maximum dose 0.4 mg). Prolongation of the irinotecan infusion to 90 minutes may be beneficial.  Early 
onset diarrhea is usually accompanied by cholinergic manifestations (diaphoresis and abdominal 
cramping). Since irinotecan is being administered on a prolonged schedule (daily x 5) it may become 
difficult to distinguish early vs. late diarrhea. If a patient with presumed early diarrhea does not improve 
with administration of atropine, they should be instructed to begin treatment for late diarrhea.  
 
Late diarrhea (more than 24 hours after irinotecan administration): Patients will be given Loperamide for 
late diarrhea based on body weight (according to the chart below). If late diarrhea occurs at home after 
the last dose of irinotecan is given, each family will be instructed to have antidiarrheal medication 
available and begin treatment at the first episode of poorly formed or loose stools or the earliest onset of 
bowel movements more frequent than normally expected for the patient. Patients will also be instructed to 
contact their physician if any diarrhea occurs.  Patients and families will be given the instruction sheet in 
Appendix VII.   
 
Loperamide dosing recommendations for late diarrhea  
 
Loperamide  1 teaspoon = 1 mg; 1 caplet = 2 mg 
 
Maximum dose of loperamide per day: < 6 years: 4 mg/day; 6-11 years: 6 mg/day; >11 years: 16 mg/day, 
using the non silicone-containing product. 
Weight:  > 43 kg: 
4 teaspoons or 2 caplets (4 mg) after the first loose bowel movement, 
followed by 2 teaspoons or 1 caplet (2 mg) every 2 hours. During the night the 
patient may take, 2 caplets (4 mg) every 4 hours rather than1 caplet (2 mg) 
every 2 hours.  
Weight: 30kg – 43kg: 
2 teaspoons or 1 caplet (2 mg) after the first loose bowel movement followed 
by 1 teaspoon or one-half caplet (1 mg) every 2 hours. During the night the 
patient may take, 1 caplet (2 mg) every 4 hours rather than one-half caplet 
every 2 hours. 
Weight: 20kg – < 30kg: 
2 teaspoons or 1 caplet (2 mg) after the first loose bowel movement followed 
by 1 teaspoon or one-half caplet (1 mg) every 3 hours. During the night, the 
patient may take 1 caplet (2 mg) every 4 hours rather than one-half caplet 
every 3 hours. 
Weight: 13kg - < 20kg: 
1 teaspoon (1 mg) after the first loose bowel movement followed by 1 
teaspoon (1 mg) every 3 hours. During the night, the patient may take 1 
teaspoon (1 mg) every 4 hours rather than every 3 hours. 
Weight: < 13kg: 
Half teaspoon (0.5 mg) after the first loose bowel movement followed by half 
teaspoon every 3 hours. During the night, the patient may take half teaspoon  
(0.5mg) every 4 hours rather than every 3 hours. 


NANT 2011-01 Version Amendment #8  01-10-2018     39 
 
If there is failure of loperamide to control diarrhea after 24 hours of use, patients should receive 
octreotide (Sandostatin™) at the dose of 10 micrograms/kg/dose subcutaneously every 12 hours x 3 
days. 
 
Because patients will be receiving prolonged exposure to antibiotics (i.e., cefixime or cefpodoxime), 
patients having significant diarrhea should have stool samples evaluated for C difficile toxin, as this is a 
potentially treatable cause of diarrhea. If patients have fever with diarrhea, or bloody diarrhea, evaluation 
of stools for bacterial culture should also be performed.  
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     40 
 
6.0 
DRUG INFORMATION 
 
6.1 
Vorinostat 
 
Vorinostat (also known as Zolinza™) 
CAS Registry Number: 149647-78-9 
NSC# 701852 IND# 71976 
6.1.1 Structure and Molecular Weight 
The chemical names for vorinostat are N-hydroxy-N’-phenyl-octane-1,8-diotic acid diamide or N-hydroxyl-
N’-phenyl (9CI) octanediamide. The molecular formula is: C14H20N203.  The molecular weight is 264.32. 
 
6.1.2 Description 
Vorinostat is a histone deacetylase (HDAC) inhibitor. Histone deacetylases (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.  
 
6.1.3 How Supplied  
Vorinostat is supplied by Merck and Co., Inc.  The 100 mg dose of vorinostat is provided in white opaque 
gelatin capsules (size 3). The capsules are supplied in HDPE (high-density polyethylene) bottles. Each 
bottle contains 120 of the 100 mg capsules. 
 
The inactive ingredients contained in each capsule are microcrystalline cellulose, sodium croscarmellose, 
and magnesium stearate. 
 
6.1.4 
Additional Information on Storage and Disposal of Vorinostat  
 
6.1.4.1 Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Clinical supplies are to be dispensed only in accordance with the 
protocol. The investigator is responsible for keeping accurate records of the clinical supplies received 
from the manufacturer, the amount dispensed to and returned by the subjects/patients, and the amount 
remaining at the conclusion of the study.  
 
6.1.4.2 In accordance with Good Pharmacy Practices, gloves should always be worn by study personnel 
if directly handling tablets or capsules that are returned (i.e., when counting returns). The Clinical Monitor 
should be contacted with any questions concerning investigational products where special or protective 
handling is indicated.  
 
6.1.4.3 Vorinostat should be stored at 20-25°C (68-77°F), with excursions permitted between 15-30°C 
(59-86°F). Vorinostat capsules should be stored at room temperature (do not store above 30°C) in a dry, 
limited-access area.  Care will be taken to maintain acceptable storage temperature. The clinical supplies 
storage area at the site will be monitored by the site staff for temperature consistency with the acceptable 
storage temperature range specified in this protocol or in the product label attached to the protocol.  
Documentation of temperature monitoring will be maintained on site. 
6.1.4.4 Vorinostat capsules should not be opened or crushed by patients or caregivers.  Vorinostat 
capsules will be opened by pharmacists for preparation of the liquid suspension (see below). Spills of 
powder from vorinostat capsules due to damaged or broken capsules should be cleaned up carefully to 
minimize inhalation of vorinostat, and direct contact of the powder in vorinostat capsules with the skin or 
mucous membranes should be avoided.  If such contact occurs, wash thoroughly. The affected area must 
be washed at least 3 times with ethyl alcohol, followed by water.  
6.1.4.5 Due to biohazard concerns unused study drug will be destroyed locally. Drug will be destroyed 
according to standard operating procedures of the institutional pharmacy.  
6.1.4.6 Drug accountability  
The investigator/pharmacist must maintain accurate records of the disposition of all vorinostat received, 
issued to the subject, and any drug accidentally destroyed.  At the end of the study, information 
describing vorinostat supplies (e.g. lot numbers) and disposition of supplies for each subject must be 


NANT 2011-01 Version Amendment #8  01-10-2018     41 
 
provided, signed by the investigator, and stored by study personnel.  Vorinostat may not be used outside 
the scope of this protocol, nor can vorinostat be transferred or licensed to any party not participating in 
this clinical study. Opened bottles returned by patients should be documented in the patient-specific 
investigational Agent Accountability Record (i.e. logged in as “returned by patients” and logged out as “for 
destruction”) and destroyed on-site in accordance with institutional policy.  
 
6.1.5 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.  During the period of vorinostat 
administration, patients are recommended to consume adequate fluid daily to prevent dehydration.  
Patient may require electrolyte replacement.  Early use of anti-emetics is encouraged. If patients 
experience dysgeusia, popsicles or Gatorade may be successful in maintaining oral intake.  Missed 
doses will not be made up and 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 (eg. 100 mg, 200 mg, 300 
mg, or 400 mg).   
 
The COG phase I study of vorinostat and NANT07-03 both used the following formula for preparing a 
liquid suspension with a final vorinostat concentration of 50 mg/mL.  This suspension should be prepared 
by the institutional investigational pharmacy. 
 
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. 
 
The maximum daily dose of vorinostat on this protocol is 400 mg. 
 
6.1.6 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. 
 
6.1.7 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. 
 
6.1.8 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.  
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     42 
 
6.1.9 Toxicities 
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 
100 children) 
• 
Anemia 
• 
Thrombocytopenia 
• 
Fatigue 
• 
Anorexia 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
 
• 
Lymphopenia 
• 
Weight loss 
• 
Fever with and without 
neutropenia 
• 
Neutropenia 
• 
Increased creatinine 
• 
Leukopenia  
• 
Hyperglycemia 
• 
Rigors/Chills 
• 
Alopecia 
• 
Constipation 
• 
Dehydration 
• 
Dry Mouth 
• 
Dyspepsia 
• 
Dysgeusia 
• 
Infection 
• 
Hypoalbuminemia 
• 
Elevated liver function tests 
(AST, ALT, Alk. Phos and 
bilirubin)  
• 
Electrolyte abnormalities 
(hypocalcemia; 
hypophosphatemia; 
hypokalemia; hyponatremia) 
• 
Muscle spasm and/or 
weakness 
• 
Dizziness 
• 
Abdominal pain 
• 
Cough 
• 
Dyspnea 
• 
Thrombosis 
• 
Skin necrosis 
• 
Prolonged QTc 
(Low-grade prolonged QTc 
interval has rarely been 
reported 
in 
patients 
receiving vorinostat, though 
the relationship to vorinostat 
remains undetermined)  
 
 
 
Also reported on vorinostat trials but with the relationship to vorinostat undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Left ventricular systolic 
dysfunction; Myocardial infarction; Palpitations; Pericardial effusion; Sinus bradycardia; Sinus 
tachycardia; Ventricular fibrillation 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal hemorrhage; Bloating; Cheilitis; Colitis; 
Dysphagia; Esophageal hemorrhage; Esophagitis; Flatulence; Gastric hemorrhage; Gastritis; Gingival 
pain; Lower gastrointestinal hemorrhage; Mucositis oral; Oral hemorrhage; Small intestinal obstruction; 
Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema 
limbs; Gait disturbance; General disorders and administration site conditions - Other (angioedema); 
General disorders and administration site conditions - Other (failure to thrive); Malaise; Multi-organ failure; 
Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Herpes zoster) 


NANT 2011-01 Version Amendment #8  01-10-2018     43 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Vascular access complication; 
Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cardiac troponin I increased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased4; Investigations - 
Other (elevated LDH); Lipase increased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Acidosis; 
Hypercalcemia; 
Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypoglycemia; Hypomagnesemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Chest wall 
pain; Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysphasia; Encephalopathy; Facial muscle weakness; Facial nerve disorder; Headache; Intracranial 
hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous system disorders - Other 
(Guillain-Barre syndrome); Nervous system disorders - Other (head injury); Nervous system disorders - 
Other (polyneuropathy); Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Personality change; 
Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Urinary frequency; 
Urinary incontinence; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Uterine hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Epistaxis; Hypoxia; Nasal congestion; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; 
Pleuritic pain; Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Purpura; Rash maculo-papular 
 
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. 
 
6.1.10  Vorinostat availability and ordering 
Vorinostat will be supplied by Merck & Co.  Vorinostat will be shipped to treating institutions through the 
contract pharmacy Almac.  Instructions and forms for ordering vorinostat from Almac are posted to the 
NANT website.   
 
6.2 
131I-METAIODOBENZYLGUANIDINE (131I-MIBG)  
[Nuclear Diagnostics Products (NDP) IND # 32,147] 
 
NOTE:  The primary 131I-MIBG supplier for this study is NDP.  If a supply of 131I-MIBG is not 
available from NDP for a specified date or a site cannot receive 131I-MIBG from NDP, Jubilant 
Draximage is a secondary 131I-MIBG supplier for this study.  Before a secondary supplier is 
authorized for use for this study, approval from the protocol chair/NANT Operations Center is 
required. 
 
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 


NANT 2011-01 Version Amendment #8  01-10-2018     44 
 
Formulation:  
The MIBG sulfate is synthesized by Nuclear Diagnostic Products (Rockaway, 
NJ) using the following materials:  
• 
MIBG (Iodophenyl-methly-guanidine hemisulfate)  
• 
Cupric Sulfate Powder, USP 
• 
Ammonium Sulfate Powder, FCC 
• 
Ascorbic Acid Injection, USP 
• 
Sodium Hydroxide, NF 
• 
Sterile Water for Injection, USP 
• 
131I as Sodium Iodide Solution  
• 
AG 1-X2 Resin  
 
Specific activity: 
Not less than 30 mCi/mg (1110 MBq/mg) MIBG at the calibration date. 
 
Radiochemical purity:   Not less than 95% of the 131I must be as MIBG upon initial measurement at 
NDP.  Not less than 93% of the 131I must be as MIBG upon re-check at the 
treating center.   
 
 
For sites other than Memorial Sloan-Kettering (MSKCC), thin layer 
chromatography and/or high pressure liquid chromatography (HPLC), or other 
standardized institutional method must be performed after the product is thawed 
and prior to infusion (Appendix IV).  For MSKCC, NDP will perform same day 
quality control for free iodine.  NDP will send a copy of the quality control report 
to the MSKCC Nuclear Pharmacy who will perform a confirmatory quality control 
assay per Appendix IV prior to infusion.   
 
Radiolytic decay: 
131I decays by beta emission and associated gamma emission with a physical 
half-life of 8.04 days.   
 
How supplied:  
For sites other than MSKCC, 131I-MIBG from NDP is supplied as a clear, 
colorless liquid in a single-dose 30 mL sterile vial.  Product is shipped frozen.  
For MSKCC, NDP will prepare the dose in 60 mL syringes for patient use and will 
be ready for administration.    
 
Storage: 
131I-MIBG from NDP is to remain frozen until ready for use, then thawed at room 
temperature prior to administration.   
 
Stability: 
 Product is stable for up to 45 hours at -70 °C.  Once thawed, product must be 
infused within 4 hours.    
 
Distribution 
NDP 131I-MIBG will be provided by Nuclear Diagnostic Products, Rockaway, NJ.  Call 3 weeks prior to 
infusion to place an order: 
Phone: (973) 664-9696 
Web: www.ndprx.com 
 
**Sites will need to inform NDP that orders for this study will be billed directly to the NANT Operations 
Center. When ordering please refer to “NANT 11-01.” 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     45 
 
Toxicity 
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out 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 
 
6.3 
131I-METAIODOBENZYLGUANIDINE (Draximage ®  Therapeutic 131I-MIBG)  
(Jubilant Draximage IND # 76,227) 
 
NOTE:  Jubilant Draximage will serve as a secondary supplier for 131I-MIBG if the drug is not available 
from NDP for the desired treatment date or site.  Before a secondary supplier is authorized for use for 
this study, approval from the protocol chair/NANT Operations Center is required. 
 
Common name 
Iobenguane sulfate (m-Iodobenzylguanidine sulfate, MIBG) 
 
Active ingredient: 
3-[131I]-iodobenzylguanidine Sulfate 
 
Pharmacologic class: Radiopharmaceutical therapeutic agent 
 
Structural formulae: 
 
 
 
 
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 Draximage (Kirkland, Quebec, Canada), 
with the following formulation:  
 
 
3-Iodobenzylguanidine Sulfate < 0.83 mg 
NH3
*·½ 
SO4
-
2NH3
*·½ SO4
-2 
NH
NH 
N
N 
H
H 
I
I 


NANT 2011-01 Version Amendment #8  01-10-2018     46 
 
 
Niacinamide 
16 mg 
 
Sodium Chloride 
9 mg 
 
Benzyl Alcohol 
9 µL 
 
Sodium Acetate Trihydrate 
0.68 mg 
 
Cupric Nitrate (II) 
< 0.02 mg 
 
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:   Not less than 95% of the 131I must be as MIBG upon re-check at the treating 
center.   
 
 
Thin layer chromatography and /or high pressure liquid chromatography 
(HPLC), or other standardized institutional method must be performed after the 
product is thawed and prior to infusion (Appendix IV). 
 
Radiolytic decay: 
131I decays by beta emission and associated gamma emission with a physical 
half-life of 8.04 days.   
 
How supplied:  
131I-MIBG from DraxImage is supplied in a single-dose 10 mL or 30 mL glass vial. 
 
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 
Draximage Therapeutic 131I-MIBG will be provided by Draximage, Canada.  Call 3 weeks prior to 
infusion to Draximage Customer Service at Order Department and Customer Service 
Phone: 1-888-633-5343; 8am – 5pm Eastern Time 
Fax: 1-866-431-4288 
Fax: 1-514-694-3865 
Email: customerservice@draximage.com 
Web: www.draximage.com 
 
**Sites will need to inform Draximage Customer Service that orders for this study will be billed directly to 
the NANT Operations Center. When ordering please refer to “NANT 11-01.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     47 
 
Toxicity 
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out 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 
 
 
6.4 
VINCRISTINE 
Source and Pharmacology: Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds 
to tubulin, disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. 
The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, 
the range of the terminal half-life in humans is from 19 to 155 hours. The liver is the major excretory 
organ in humans and animals; about 80% of an injected dose of vincristine sulfate appears in the feces 
and 10% to 20% can be found in the urine. Within 15 to 30 minutes after injection, over 90% of the drug is 
distributed from the blood into tissue, where it remains tightly, but not irreversibly bound. It is excreted in 
the bile and feces. There is poor CSF penetration. 
 
Formulation and Stability: Vincristine is supplied in a glass vial each mL of which contains vincristine 
sulfate, 1 mg (1.08 µmol); mannitol, 100 mg; sterile water for injection; Acetic acid and sodium acetate are 
added for pH control. The pH of Vincristine Sulfate Injection, USP ranges from 3.5 to 5.5. This product is 
a sterile solution. Store refrigerated at 2-8°C or 36-46°F. Protect from light and retain in carton until time 
of use. Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration: See the Treatment section of protocol. Vincristine sulfate must be 
administered via an intact, free-flowing intravenous needle or catheter. Care should be taken to ensure 
that the needle or catheter is securely within the vein to avoid extravasation during administration. The 
solution may be injected either directly into a vein or into the tubing of a running intravenous infusion.  
 
When dispensed the container or syringe containing vincristine must be enclosed in an over-wrap bearing 
the statement “Do not remove covering until moment of injection. Fatal if given intrathecally.  For 
Intravenous use only.” 
 
Vincristine Toxicity: 
Likely 
(happens to 21-100 
children out of 100) 
Less Likely 
(happens to 5 -20 
children out of 100) 
Rare 
(happens to less than 5 children out of 100) 
• Hair loss 
• Constipation 
• Loss 
of 
deep 
tendon reflexes 
• Jaw pain 
• Headache 
• Muscle Weakness 
• Abdominal pain and 
bloating  
• Bone marrow 
suppression that is 
mild and brief 
(leukopenia, 
• 
Extravasation is rare but if it happens it will 
cause local ulceration 
• 
Shortness of breath and bronchospasm 
• 
Paralytic ileus 
• 
Ptosis, diplopia, night blindness 
• 
Hoarseness 
• 
Vocal cord paralysis 
• 
SIADH 


NANT 2011-01 Version Amendment #8  01-10-2018     48 
 
thrombycytopenia, 
anemia)  
• Peripheral 
paresthesias 
including numbness, 
tingling and pain, 
clumsiness, wrist 
drop, foot drop, 
abnormal gait 
• 
Seizures 
• 
Defective sweating 
• 
Difficulty walking or inability to walk 
• 
Sinusoidal obstruction syndrome (SOS, 
formerly VOD) (when used in combination 
with other agents);  
• 
Blindness 
• 
Optic atrophy 
• 
Urinary tract disorders (including bladder 
atony, dysuria, polyuria, nocturia, urinary 
retention) 
• 
Autonomic neuropathy with postural 
hypotension 
• 
8th cranial nerve damage with dizziness, 
nystagmus, vertigo and hearing loss 
Risk to unborn child of unknown frequency or timing:  Fetal toxicities and teratogenic effects of 
vincristine (either alone or in combination with other antineoplastic agents) have been noted in humans. 
The toxicities include: chromosome abnormalities, malformation, pancytopenia, and low birth weight. It is 
unknown whether the drug is excreted in breast milk. 
 
Supplier: Commercially available. See package insert for more detailed information. 
 
 
6.5 
IRINOTECAN 
Mechanism of Action: Irinotecan is a semisynthetic water-soluble analog of camptothecin that exerts its 
cytotoxic effect through inhibition of the nuclear enzyme topoisomerase I. Irinotecan is a prodrug that 
undergoes deesterification to a much more potent topoisomerase-I inhibitor, SN-38. The lactone forms of 
both irinotecan and SN-38, undergo pH dependent hydrolysis to a hydroxy acid (carboxylate) species. 
SN-38 is glucuronidated to SN-38G.  
 
Formulation & Stability: Irinotecan is supplied in amber, glass, single-dose vials containing 40mg and 
100 mg of irinotecan hydrochloride (on the basis of trihydrate salt) as a 20 mg/ml solution. The intact vials 
should be stored at room temperature and protected from light.  
Guidelines for Administration: Irinotecan must be diluted before infusion.  Irinotecan should be diluted in 
5% Dextrose Injection USP (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration 
range of 0.12 to 2.8mg/ml.  The solution is physically and chemically stable for up to 24 hours at room 
temperature (approx 25 ΟC) and in ambient fluorescent lighting.  Solutions diluted in 5% Dextrose Injection, 
USP, and stored at refrigerated temperatures (approximately 2 Ο to  8 ΟC), and protected from light are 
physically and chemically stable for 48 hours.  Refrigeration of admixtures using 0.9% Sodium Chloride 
Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. 
 
Irinotecan should be administered as an intravenous infusion over 60-90 minutes.  For patients with early 
diarrhea, prolonging the infusion to 90 minutes is allowed. See protocol for supportive care measures. 
 
Irinotecan Toxicity:  
Likely 
(happens to 21-100 children out 
of 100) 
Less Likely 
(happens to 5 -20 children 
out of 100) 
Rare 
(happens to less than 5 children out of 
100) 
• 
Diarrhea (can be 
immediate) 
• 
Cholinergic symptoms: 
rhinitis, increased 
salivation, miosis, 
lacrimation,diaphoresis, 
flushing. 
• 
Mucositis  
• 
Nausea and vomiting 
• 
Stomach pain 
• Mildly high liver and 
kidney function tests  
• Constipation  
• Delayed Diarrhea 
• Headaches 
• Blood-clots** 
• Anemia 
• Thrombocytopenia 
• Rash  
• Skin inflammation  
• Trembling  
• Blood in the urine  
• Mildly increased level of protein and 
glucose in the urine  
• Low amount of protein in the blood  
• Mouth sores  
• Headache  
• Dizziness and hypotensiion 


NANT 2011-01 Version Amendment #8  01-10-2018     49 
 
• 
Loss of appetite 
• 
Fever 
• 
Loss of body water 
• 
Loss of strength and 
energy 
• 
Decrease in the number of 
red and white blood cells 
and platelets made in the 
bone marrow 
• 
Eosinophila 
• 
Hair loss 
• 
Elevations in 
transaminases, alkaline 
phosphatase, bilirubin,  
 
• Stomatitis Dyspepsia  
• Sensation of warmth on face 
• Confusion and/or disoreintation 
• Inflammation of the large intestine 
• Illeus 
• Anaphylaxis 
• Dehydration 
• Bradycardia 
• Pain at infusion site 
• Pneumonitis  
• Inflammation of the lungs with 
cough and congestion 
**this toxicity is seen more commonly when irinotecan is given in combination with fluorouracil and 
leucovorin, it may rarely be a life threatening event.  
 
Supplier: Irinotecan is commercially available.  See package insert for further details.   
 
 
6.6 
CEFIXIME 
Source and Pharmacology: Cefixime is a third generation cephalosporin antibiotic for oral administration  
that inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins and 
interfering with the final transpeptidation step of peptidoglycan synthesis. Its spectrum of activity is similar 
to other third-generation agents, including Enterobacteriaceae, and β-lactamase producing H. influenzae 
and N. gonorrhea, and Staph. aureus. It is excreted primarily by the kidney. It has a serum half-life of 
approximately 3-4 hours. 
 
Formulation: Cefixime is available in a powder for oral suspension, which when reconstituted, provides 
100 mg/5ml. The powder for oral suspension is strawberry flavored and contains sodium benzoate, 
sucrose, and xanthan gum (available as 50 ml, 75 ml & 100 ml bottle with powder for reconstitution). 
 
Toxicity: 
Likely 
(happens to 21-100 children 
out of 100) 
Less Likely 
(happens to 5 -20 children out 
of 100) 
Rare 
(happens to less than 5 children 
out of 100) 
 
• Diarrhea  
• Abdominal pain  
• Nausea and vomiting, 
• Dyspepsia 
 
• Headache  
• Dizziness 
• Seizures  
• Anaphylaxis 
• Hypersensitivity reactions 
• Thrombocytopenia, 
• Leucopenia, 
• Neutropenia, 
• Eosinophilia, 
• Pseudomembranous colitis,  
• Increase in BUN/SCr and 
ALKP, 
• Hepatitis, jaundice 
• Stevens 
Johnson 
/ 
toxic 
epidermal necrolysis 
 
Supplier: Commercially available through Lupin, Inc. See package insert for further information.  
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     50 
 
6.7 
CEFPODOXIME PROXETIL 
 
Source and Pharmacology: Cefpodoxime proxetil is a third generation cephalosporin antibiotic for oral 
administration  that inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding 
proteins and interfering with the final transpeptidation step of peptidoglycan synthesis. Its spectrum of 
activity is similar to other third-generation agents, including Enterobacteriaceae, and β-lactamase 
producing H. influenzae and N. gonorrhea, and Staph. aureus. It is excreted primarily by the kidney. It has 
a serum half-life of approximately 2-4 hours. 
 
Formulation: Cefpodoxime proxetil is available as 100 mg & 200 mg oblong tablets &  powder for oral 
suspension, which when reconstituted, provides either 50 mg/5 ml OR 100 mg/5 ml. The powder for oral 
suspension is lemon crème flavored (available as 50 ml, 75 ml & 100 ml bottle with powder for 
reconstitution). 
 
Cefpodoxime Proxetil Toxicity: 
Likely 
(happens to 21-100 children 
out of 100) 
Less Likely 
(happens to 5 -20 children out 
of 100) 
Rare 
(happens to less than 5 children 
out of 100) 
 
• 
Diarrhea  
• 
Diaper Rash 
 
 
• 
Abdominal pain  
• 
Nausea and vomiting, 
• 
Headache  
• 
Seizures  
• 
Anaphylaxis 
• 
Chest pain 
• 
Hypersensitivity reactions 
• 
Thrombocytopenia, 
• 
Leucopenia, 
• 
Neutropenia, 
• 
Eosinophilia, 
• 
Pseudomembranous 
colitis,  
• 
Increase in BUN/SCr and 
ALKPhos 
• 
Prolonged PT / PTT 
• 
Chest pain 
• 
Vaginal candidiasis 
• 
Aplastic Anemia 
• 
Stevens Johnson, 
• 
Toxic Epidermal 
Necrolysis 
 
 
Supplier: Commercially available through a variety of manufacturers (generically available).  See 
package insert for further information.   
 
6.8 
POTASSIUM IODIDE (KI, SSKI) 
 
Formulation: Oral solution 1 gram / milliliter.  
 
Diagnostic MIBG Scan: Dose 1 –3 drops / dose, administered daily beginning 30 minutes prior to 
radionuclide injection, and continuing for 3 days post-injection for 123I-MIBG and for 7 days for 131I-MIBG.  
 
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 8-43. 
 
Storage:  Room temperature 


NANT 2011-01 Version Amendment #8  01-10-2018     51 
 
 
Toxicity: 
Likely  
(happens to 21-100 children 
out every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out 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 
 
 
6.9 
GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) (Filgrastim, Neupogen).  
 
Source and Pharmacology: 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant DNA 
technology.  Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 daltons 
manufactured by recombinant DNA technology utilizing E.coli bacteria into which has been inserted the 
human granulocyte colony stimulating factor gene.  It differs from the natural specific colony-stimulating 
factor which regulates the production of neutrophils within the bone marrow and affects neutrophil 
progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced 
phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody 
dependent killing, and the increased expression of some functions associated with cell surface antigens).  
The elimination half-life is similar for subcutaneous and intravenous administration, approximately 3.5 
hours.  The time to peak concentration when administered subcutaneously is 2 to 8 hours. 
 
Formulation and Stability:  
Supplied as a clear solution in 300 ug/ml (1 ± 0.6 x 108 U/mg) (1 ml or 1.6 ml) vials. Vials are preservative 
free and are intended to be single-use vials; do not reuse opened vials. Filgrastim must be stored 
between 2° and 8°C. Stability has been demonstrated for at least 24 months when stored under these 
conditions. Do not use if discolored or if there is particulate matter. For IV use, dilute in D5W to 
concentrations > 15 ug/ml; G-CSF is incompatible with normal saline. At dilutions from 5 ug/ml to 14 
ug/ml, add human serum albumin to a final albumin concentration of 2 mg/ml to protect against 
absorption of the GCSF to container walls (glass or plastic). Filgrastim, when diluted as described above, 
is compatible with a number of plastics commonly used in the manufacture of syringes, IV bags, infusion 
sets, and IV pump cassettes. These include polyvinyl chloride, polyolefin, and polypropylene. Diluted 
filgrastim should be stored at 2° to 8° C and used within 24 hours. Do not shake or freeze. 
 
Guidelines for Administration:  
Administer once daily, subcutaneously without dilution or if necessary dilute with 5% dextrose in water, 
preferably to concentrations of 15 ug/ml or greater for IV administration. Dilutions should be prepared as 
close to the time of administration as possible (up to 24 hours), since the product is preservative-free. 
When diluting Filgrastim to 5-14 ug/ml in D5W, it is necessary at all times to add human serum albumin, 
to reach a final albumin concentration of 2 mg/ml. 
  
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 
100 children) 


NANT 2011-01 Version Amendment #8  01-10-2018     52 
 
• Mild to moderate medullary 
bone pain 
 
• Local pain or irritation at 
injection site 
• Increased alkaline 
phosphatase, LDH and uric acid 
• Thrombocytopenia 
• Fever 
 
• Allergic reactions  
(more common with IV than 
subcutaneous administration) 
• Skin rash, urticaria and/or facial 
edema 
• Respiratory wheezing and/or 
dyspnea 
• Hypotension and/or tachycardia 
•  Low grade fever 
• Splenomegaly 
• Splenic rupture 
• Worsening of existing skin rashes 
• Sickle cell crises in patients with 
sickle cell disease 
• Excessive leukocytosis 
• Cutaneous vasculitis 
• Adult respiratory distress syndrome 
• MDS or AML (in patients with 
severe chronic neutropenia and 
long term administration 
Supplier: 
Commercially available. See package insert for further information. 
 
6.10 
PEGFILGRASTIM (NEULASTA) 
 
Source and Pharmacology: 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). Pegfilgrastim is 
produced by covalently binding a 20-kilodalton (kD) monomethoxypolyethylene glycol molecule to the N-
terminal methionyl residue of filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a 
lineage specific colony-stimulating factor which regulates the production of neutrophils within the bone 
marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional 
activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with 
respiratory burst, antibody dependent killing, and the increased expression of some functions associated 
with cell surface antigens).After subcutaneous injection the elimination half-life of pegfilgrastim ranges 
from 15 to 80 hours and the time to peak concentration ranges from 24 to 72 hours. Serum levels are 
sustained in most patients during the neutropenic period postchemotherapy, and begin to decline after 
the start of neutrophil recovery, consistent with neutrophil-dependent elimination. After subcutaneous 
administration at 100 mcg/kg in 37 pediatric patients with sarcoma, the terminal elimination half-life was 
30.1 (+/- 38.2) hours in patients 0 to 5 years-old, 20.2 (+/- 11.3) hours in patients 6 to 11 years-old, and 
21.2 (+/- 16) hours in children 12 to 21 years-old. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     53 
 
Pegfilgrastim Toxicity: 
 
Likely  
(happens 
to 
21-100 
children out every 100 
children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 100 
children) 
 
• Mild to moderate 
medullary bone pain 
 
 
• 
Local pain or irritation 
at injection site 
• 
Headache 
• 
Increased alkaline 
phosphaste, lactate 
dehydrogenase and 
uric acid. 
• 
Thrombocytopenia  
 
 
• 
Low grade fever 
• 
Allergic reactions (anaphylaxis, 
angioedema, or urticaria) 
• 
Generalized erythema and flushing 
• 
Splenomegaly 
• 
 Splenic rupture 
• 
Sickle cell crises in patients with 
sickle cell disease (SCD) 
• 
Excessive leukocytosis 
• 
Sweet's syndrome (acute febrile 
neutrophilic dermatosis) 
• 
Adult respiratory distress syndrome 
 
 
Unknown frequency and timing:  Fetal toxicities and teratogenic effects of pegfilgrastim in humans are 
unknown. Conflicting data exist in animal studies. It is unknown whether the drug is excreted in breast 
milk. 
 
Supplier:  Commercially available. See package insert for further information. 
 
Formulation and Stability: 
Supplied as a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim (10 mg/mL) in a 
single-dose syringe with 27 g, ½ inch needle with an UltraSafe® Needle Guard. The needle cover of the 
prefilled syringe contains drug natural rubber (a derivative of latex). Store refrigerated at   2º-8ºC (36º-
46ºF) and in the carton to protect from light. Prior to injection, pegfilgrastim may be allowed to reach room 
temperature protected from light for a maximum of 48 hours. Avoid freezing. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol 
 
6.11 LOPERAMIDE 
 
Formulation and Stability: Supplied as a clear, cherry flavored syrup (1 mg/5 mL) or as a scored green 
caplet (2 mg).  
 
Mechanism of Action: Loperamide HCl acts by slowing intestinal motility and by affecting water and 
electrolyte movement through the bowel 
 
Toxicities: Overdoses of loperamide HCl may result in CNS depression, constipation, and nausea. Children 
may be more sensitive to CNS effects than adults.  
 
Supplier: Commercially available. See package insert for further information. 
 
6.12 
Drug Inventory Records   
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
inventory and disposition of all drugs. 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     54 
 
7.0    
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
7.1 
Clinical and Laboratory Studies 
Blood and urine studies must be performed within 2 weeks of study enrollment. Tumor disease evaluation 
(including appropriate imaging studies, bilateral bone marrow aspirate and biopsy for standard histology 
and urine catecholamines) are required within 3 weeks of study entry and subsequent to any prior 
therapy. Echocardiogram and ECG are required within 4 weeks of study entry and subsequent to any 
prior therapy. Initiation of protocol therapy is required within 1 week of study enrollment. 
References to second course of therapy in the following table are only relevant to patients enrolling prior 
to Amendment 7A.    
OBTAIN OTHER STUDIES AS NEEDED FOR GOOD PATIENT CARE. 
 
Observation 
Before 
Entry 
Days 
-1 to +7 of Each 
Course1 
Days 
8 to 43 of 
each Course 
Day 43 to 50 of 
each Course 
Physical Exam5 
(Ht, Wt, BSA, VS) 
Performance status only at entry 
 
X 
Day 4 (+/- 1 day) 
Every other 
week 
 
X 
CBC, Diff, Platelets5 
X 
Day 4 (+/- 1 day) 
Twice weekly2 
X 
AST, ALT5, Total5 + Direct Bilirubin, 
Albumin 
X 
Day 4 (+/- 1 day) 
Weekly 
X 
BUN, Serum Creatinine5 
X 
Day 1 prior to 
MIBG infusion for 
Vorinostat Arm 
Only and Day 4 (+/- 
1 day) for All 
Patients 
Weekly 
X 
PT/INR and PTT5 
X 
Weekly on 
Vorinostat Arm 
Weekly on 
Vorinostat Arm 
X 
Electrolytes, Calcium, Magnesium, 
Phosphorus 
X 
Day 4 (+/- 1 day) 
Weekly 
X 
T4, TSH 
X 
 
 
X 
Serum β-HCG3,5 
X 
 
 
X 
MUGA or Echocardiogram5 
X 
 
 
X 
Electrocardiogram5 
X 
Vorinostat Arm 
Only:  Day 4 (+/- 2 
days) 
 
X (Vorinostat 
Arm Only) 
Urinalysis 
X 
 
 
X 
Urine catecholamines VMA/HVA 
X 
 
 
X 
Bilateral BM Aspirate + Biopsy for 
morphology4,  7 
X 
 
 
X 
Blood and Marrow for N04-05 
X 
 
 
X 
Anatomic imaging (CT or MRI scan) 
of chest/abdomen/pelvis plus any 
other known sites of measurable 
disease4 
X 
 
 
X 
MIBG diagnostic scan 
(REQUIRED)4, 5 
Use same isotope with each scan 
X 
 
 
X 
MIBG whole body scan 
 
On release from 
radiation isolation 
 
 
Whole body dosimetry 
 
Days 1 to 46 
 
 
Blood for biology studies (if consent) 
 
See Section 8 
See Section 8 
 
Archival slides for biology studies (if 
consent) 
 
See Section 8 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     55 
 
1. No other routine bloodwork/radiology studies are required while patient is hospitalized unless clinically indicated. Patients with prior 
electrolyte imbalance should be monitored during the hydration. 
2. Continue until ANC > =500 cells/µL and platelet count > = 20,000 cells/µL x 3 days without transfusion then weekly until Day +43. 
3. Obtain for females 10 years of age and older or post-pubertal. 
4. Tumor imaging = CT and/or MRI (Chest abdomen pelvis) plus CT/MRI imaging of any other sites with MIBG update, MIBG for 
optimum visualization of all areas of bulk tumor (primary & metastasis) as well as chest/abdomen/pelvis. CT or MRI of 
chest/abdomen/pelvis + any other known lesions of tumor (repeat of chest/abdomen/pelvis CT or MRI is required even if scans are 
negative for tumor at study entry).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.  For patients with epidural or hepatic tumor lesions, 
MRI is the recommended imaging technique. All disease status tests must be performed < 3 weeks prior to study entry and 
subsequent to any intervening therapy 
5. Required for verification of eligibility.  All results should be faxed to NANT Operations Center with study registration eligibility. An 
eligibility worksheet is available in the data forms packet on NANT website (www.nant.org). 
6. See section 4.3.7 for dosimetry guidelines.  
7. Bilateral bone marrow aspirates and biopsies to be performed at each disease evaluation, even if negative at study entry.   
 
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 for 3 
years or until progression, death or other therapy.  
 
Patients will be followed for life for any delayed toxicities related to protocol therapy and for the 
development of second malignancies.  
 
Data on patients who undergo subsequent myeloablative therapy within 6 months of completing protocol 
therapy will be collected to assess the incidence and severity of SOS in these patients (Aim 1.10).    
 
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).  In 
addition, those patients who undergo subsequent myeloablative therapy within 6 months of completing 
protocol therapy will be followed for the development of SOS within 21 days following the infusion of stem 
cells post-myeloablative treatment.  
 
7.3 Documentation of Tumor Response 
 
Patients will undergo complete disease re-staging between Day 43 and Day 50 of each course of therapy 
(only a single course of therapy allowed for patients enrolling with Amendment 7A and later).  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 entry. 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 11.2.1). 
 
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 
protocol therapy. 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     56 
 
8.0 
CORRELATIVE BIOLOGY STUDIES     
Collection of samples for correlative biology studies is optional and not required for study entry. 
Although these studies cannot be mandated, all institutions are strongly urged to submit specimens 
for all consenting patients.   
 
Aside from submission of archival tissue to quantify NET expression (section 8.3), these studies are 
to be performed during both courses of therapy for patients enrolling prior to Amendment 7A and 
during the single allowed course of therapy for patients enrolling with Amendment 7A and later.     
 
8.1 
Evaluation of Minimal Residual Disease by 5 Gene NB5 assay TaqMan low density array 
(TLDA) Assay 
 
All patients are required to co-enroll onto the NANT Biology Study, N04-05.  Patients should submit blood 
and/or bone marrow at study entry and at the time of day 43-50 restaging studies.  Submission of blood and 
bone marrow for NB5 TLDA assay will be according to the instructions in N04-05.  Patients can submit only 
bone marrow for NB5 TLDA assay if blood volumes for research do not allow for blood submission.  
 
8.2 
Evaluation of Blood Markers of Radiation Exposure 
 
8.2.1 
Sample requirements 
The following samples will be obtained at each time point (see section 8.2.2): 
• 
2.5 mL of peripheral blood in PAXgene RNA blood tube (provided by the study) 
• 
5 mL of peripheral blood in EDTA (usually purple top) tube 
• 
5 mL of peripheral blood in serum separator (usually red top) tube 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     57 
 
 
8.2.2 
Sampling scheduling 
Samples will be obtained according to the following schedule.  Note that the schedule differs 
slightly based upon randomized arm of the study to which a specific patient has been 
assigned. 
 
 
Sample Timepoint 
(Obtain in Each Course) 
 
 
Samples to be Obtained 
Baseline Draw #1 
• 
For 131I-MIBG only arm:  Anytime on the day prior 
to 131I-MIBG infusion (Protocol Day 0) 
• 
For 131I-MIBG/vorinostat arm:  Prior to first dose of 
vorinostat (Protocol Day -1) 
• 
For 131I-MIBG/irinotecan/vincristine arm:  Prior to 
first dose of vincristine/irinotecan (Protocol Day 0) 
 
2.5 mL in PAXgene RNA blood tube 
 
5 mL in EDTA (usually purple top) 
 
5 mL in serum separator (usually red top) 
tube 
Baseline Draw # 2 
 
Day of 131I-MIBG infusion, anytime prior to start of infusion 
(all patients) = Protocol Day 1 
2.5 mL in PAXgene RNA blood tube 
 
5 mL in EDTA (usually purple top) 
 
5 mL in serum separator (usually red top) 
tube 
 
72 hours (+/- 2 hours) from start of 131I-MIBG infusion (all 
patients) = Protocol Day 4 
 
2.5 mL in PAXgene RNA blood tube 
 
5 mL in EDTA (usually purple top) 
 
5 mL in serum separator (usually red top) 
tube 
 
96 hours (+/- 2 hours) from start of 131I-MIBG infusion if 
patient still admitted to hospital (all patients) = Protocol Day 
5 
 
2.5 mL in PAXgene RNA blood tube 
 
5 mL in EDTA (usually purple top) 
 
5 mL in serum separator (usually red top) 
tube 
Protocol Day 15 (or whenever patient receives stem cell 
infusion, if stem cell infusion does not occur on Day 15) 
2.5 mL in PAXgene RNA blood tube 
 
5 mL in EDTA (usually purple top) 
 
5 mL in serum separator (usually red top) 
tube 
 
 
8.2.3 
Sample processing 
• 
PAXgene tubes:  After collecting blood into a PAXgene tube, the tube should be gently 
inverted 8-10 times.  Keep the tube at room temperature for 2 - 72 hours and then freeze 
upright in a wire rack (not Styrofoam holder) for 24 hours at -20°C and then transfer to -
70 or -80°C freezer until batch shipment.    
 
• 
EDTA tubes:  Blood from EDTA tubes will be used to obtain fixed cells for γ-H2AX testing 
(using the SmartTube system) and plasma for flt3 ligand testing.  Once collected, EDTA 
tubes should be gently inverted 6-8 times and transferred to the treating center’s 
specimen processing lab immediately.  Upon arrival in the specimen processing lab, 
remove 1 mL of whole blood, place the 1 mL of whole blood into a SmartTube (provided 
by the study), cap tightly, and for process as described below.  Reserve the remaining 4 
mL of whole blood for plasma isolation as described below. 
 
o 
SmartTube Processing:  Once 1 mL of whole blood has been added to the 
SmartTube, activate the tube manually.  To activate a SmartTube manually, 


NANT 2011-01 Version Amendment #8  01-10-2018     58 
 
make sure the cap is screwed on securely and then bend the SmartTube in the 
middle until you feel the ampoule inside break, then invert the SmartTube 10 
times to ensure good mixing.  Incubate the activated SmartTubes at room 
temperature for 8 minutes. 
After the 8 minute incubation, immediately transfer the SmartTubes to a -80°C 
freezer or place in direct contact with dry ice.  The SmartTubes should be stored 
at -80°C until ready for batch shipment.  Samples frozen in SmartTubes should 
not be stored at temperatures warmer than -80°C.  Smart Tubes have not been 
validated for storage in liquid nitrogen.  Retain frozen until ready for batch 
shipment.    
o 
Plasma Isolation:  Centrifuge the samples in a refrigerated centrifuge (4°C) for 10 
minutes at 1500 g or greater.  Next, remove the plasma using a transfer pipette 
and transfer the plasma into at least two cryovials with a minimum of 0.5 mL 
plasma per cryovial.  Cap the vials securely and label as described below. 
Immediately freeze the plasma in an upright position in a -70oC to -80oC freezer.  
Retain frozen until ready for batch shipment.    
 
• 
Serum separator tubes:  Allow the blood to clot at 4°C (or in a bucket with ice) for at 
least 30 minutes but no longer than 2 hours. Centrifuge the blood at 1000g for 15 
minutes at 4ºC (preferred) or room temperature to separate the serum (top, straw-colored 
layer) from the red blood cells (bottom, red layer). Aliquot the serum into at least two 
cryovials with a minimum of 0.5 mL serum per cryovial. Cap the vials securely and label 
as described below. Immediately freeze the serum in an upright position in a -70oC to -
80oC freezer.  Retain frozen until ready for batch shipment.    
 
8.2.4 
Sample labeling 
PAXgene tubes, SmartTubes, plasma aliquot tubes, and serum aliquot tubes should be labeled 
with the patient’s NANT ID number, the protocol number N11-01, the date of blood draw, “Course 
1” or “Course 2”, and one of the following indicators of the sample timing: 
--Baseline draw 1 
--Baseline draw 2 
--Hour 72 
--Hour 96 
--Day 15 (label as “Day 15” even if drawn on a different day due to timing of stem cell infusion) 
 
No other identifiers should be included on the label. 
 
8.2.5 
Sample shipment 
Frozen plasma aliquots, serum aliquots, SmartTubes, and PAXgene tubes from all four draws 
should be batch shipped after all samples from that course have been obtained.  These samples 
should be shipped frozen on dry ice.  Ensure adequate dry ice to keep the samples frozen.   
 
Sample shipment must include a generic NANT specimen transmittal form and the study-specific 
specimen transmittal form included in the study-specific data forms packet.   
 
Samples should be shipped by Federal Express Priority Overnight to the following address: 
 
ATTN:  Myriam Armant, TransLab 
Boston Children’s Hospital 
61 Binney Street 
ENDERS Room 428 
Boston, MA 02115 
(617) 713-8085 
 
FedEx account number 361615042 should be used for all shipments and be sure to also provide 
reference number 9618307. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     59 
 
Samples should only be shipped on Mondays-Thursdays to allow for weekday delivery.  Email 
both myriam.armant@childrens.harvard.edu and Dr. DuBois at steven_dubois@dfci.harvard.edu 
with the tracking number at the time of sample shipment.   
 
8.2.6 
Laboratory Methodology 
PBMCs will be isolated from SmartTubes. γ-H2AX foci will be quantified in fixed PBMCs using 
flow cytometry.  This work will be completed by the Haas-Kogan Laboratory at Dana-Farber.      
 
Total mRNA will be isolated from PAXgene tubes, using the commercial PAXgene Blood RNA kit.  
RT-PCR will be used to quantify expression levels of the 9 genes previously shown to be 
modulated by radiation exposure: GADD45A; CDKN1A; PCNA; SGK; HSP132; DDB2; TNRFSF6; 
XPC; and SESN1.  This work will be completed by the Coleman Laboratory at Lawrence 
Livermore National Laboratory.   
 
Plasma flt3 ligand and serum amylase will be quantified using commercial kits.  This work will be 
completed by the TransLab at Dana-Farber/Boston Children’s. 
 
8.3 
Evaluation of NET Protein Expression 
 
8.3.1 
Sample requirements 
Five unstained slides will be submitted once.  Material obtained from biopsy to diagnose or treat 
recurrent disease will be submitted.  If not available, material from biopsy/resection to obtain 
initial diagnosis of neuroblastoma will be submitted.  If not available, material from resection of 
primary tumor during initial induction will be submitted. 
 
Materials obtained during bone marrow biopsy or fine needle aspirate procedure are not 
acceptable to support this evaluation.   
 
8.3.2 
Sampling scheduling 
Samples will be submitted once, after study enrollment.    
 
8.3.3 
Sample processing 
No additional processing is required at the treating institution.  
 
8.3.4 
Sample labeling 
Slides or slide box should be labeled with the patient’s NANT ID number, the protocol number 
N11-01, and the date of biopsy/resection.   
 
No other identifiers should be included on the label. 
 
8.3.5 
Sample shipment 
Slides should be shipped by Federal Express overnight to the following address: 
Steven DuBois, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue, Dana 3, Room 3-109 
Boston, MA 02215 
Phone: 617-632-5460 
 
FedEx account number 361615042 should be used for all shipments and be sure to also provide 
reference number 9618307. 
 
Samples should only be shipped on Mondays-Thursdays to allow for weekday delivery.  Email Dr. 
DuBois at steven_dubois@dfci.harvard.edu with the tracking number at the time of sample 
shipment.   
 
8.3.6 
Laboratory Methodology 
NET protein expression will be assessed by immunohistochemistry and scored semi-
quantitatively as previously described.105  If other promising proteins involved in MIBG transport 


NANT 2011-01 Version Amendment #8  01-10-2018     60 
 
emerge, such as vesicular monoamine transporters (VMATs), then these proteins will also be 
quantified.   
 
8.4 
Evaluation of Automated MIBG Scoring System 
 
 
123I-MIBG scans from study entry and following course 1 of therapy will be uploaded to the NANT PACS 
system for all patients as part of planned central review.  These images will also be forwarded to Dr. 
Volchenboum at the University of Chicago for evaluation of computer-assisted MIBG scoring. The 
imaging group at the University of Chicago will not have access to MIBG scan reports from treating 
institutions or results of central review of scans. Following the study, the scores obtained using the 
computer-assisted platform will be compared to those assigned by treating institutions and/or by central 
review. 
 
8.5 
Evaluation of Circulating Tumor DNA 
 
Patients who provided consent for optional evaluation of blood markers of radiation exposure and have 
remaining aliquots of plasma leftover after quantification of plasma flt3 ligand will be included in this 
evaluation of circulating tumor DNA.  Aliquots will be transferred to the Crompton laboratory at Dana-
Farber Cancer Institute, cell free DNA extracted using standard techniques, and then sequenced using 
next generation sequencing techniques.  As appropriate, droplet digital PCR (ddPCR) may also be used 
to obtain comparative pilot data for these two approaches.  No additional samples need to be collected 
from patients to support this work.   
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     61 
 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
 
9.1 
Criteria for Removal from Protocol Therapy 
 
a. Progressive disease 
b. Completion of planned therapy (maximum of two courses of therapy on this protocol for patients 
enrolling prior to Amendment 7A and a maximum of one course of therapy on this protocol for 
patients enrolling with Amendment 7A or later) 
c.    Patient/parent withdrawal from therapy 
d. Unacceptable adverse events by protocol criteria or physician judgment 
 
e. Entry onto another therapeutic study and/or another anti-cancer therapy. 
f. 
Pregnancy 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for off study.  
 
9.2 
Off Study Criteria 
 
a. Death 
b. Lost to follow-up 
c. Patient/Parent withdrawal of consent. 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     62 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Pick-the-Winner Design 
Up to a total of 105 eligible and evaluable patients will be randomly assigned to one of the 3 MIBG arms.  
At completion of the study, the regimen with the highest observed response rate (by central review of 
response) after one course of therapy will be selected as the “winner” – i.e. the regimen that will be 
recommended as the MIBG backbone for future studies – provided that toxicity, tolerability, and other 
considerations confirm the feasibility of the regimen.   
 
Two interim analyses for futility (to drop an inferior arm) will be undertaken:  after 60 patients 
(approximately 20/arm) and after 81 patients (approximately 27/arm) have been randomized and 
completed at least one course and deemed evaluable for response.  This analysis will be performed 
initially using site report of response.  The following rule will be applied:  if one of the arms is clearly 
inferior to the other two, then consideration will be given to dropping that single regimen.  Study accrual 
will not pause while awaiting the results of any interim analysis (see below for modification per 
Amendment 7A).  However, study accrual will be halted if needed to complete central review of response 
prior to dropping any regimen.  The criterion to be used is based on Bayesian posterior probabilities (see 
Appendix VIII).   
 
In addition, if one arm is dropped at the time of the 1st interim analysis, then after 35 patients have been 
randomized to each of the remaining arms and evaluated after the 1st course, we will compare these 2 
remaining arms based on site report of response.  If one arm is not clearly superior according to Bayesian 
posterior probabilities, accrual will continue until 42 evaluable patients per remaining arm have been 
randomized (yielding total sample of 104 patients in this scenario). 
 
If neither futility rule is met, accrual will continue until 35 patients/arm are eligible and evaluable, for a total 
of 105 patients.  With Amendment 7A, the design was modified to apply stochastic curtailment principles 
to permit early selection of a winner (see below).  In order to account for potentially ineligible or 
inevaluable patients, a maximum of 115 patients are anticipated to enroll to yield 105 eligible and 
evaluable patients.      
 
10.1.1 Amendment 7A – Dated 6-8-2017 
The results of the 1st interim analysis were submitted to the independent DSMB on March 15, 2017, with 
the recommendation not to drop any arm at that time and to continue as planned - with one modification 
to the study design (addition of rules to permit early selection of a winner).  This recommendation was 
accepted by the DSMB. 
 
The proposed modification to the design involves applying “stochastic curtailment” at the time of the next 
interim analysis (after 81 patients).   Specifically, after 81 patients have been evaluated, the Arm with the 
greatest observed response rate will be identified (designated here as Arm X).  Under a variety of 
scenarios, exact calculations will be done to determine the probability (conditional on the observed data 
of the 1st 81 patients) that the observed response rate for Arm X will still be greater than the observed 
response rates for other 2 Arms after 105 patients have been enrolled and evaluated.   If this probability 
(or more precisely, the probability across a variety of scenarios) is greater than 0.90, then accrual will be 
terminated with the conclusion that the true response rate for Arm X is higher than the true response 
rates for the other 2 Arms.   See the Table below for skeleton of the table that will be created.  
Table: Calculations* for the Probability that Arm X will Still have the Highest Observed Response Rate** at 
the End of the Trial with 35 Patients per Arm (given the Results of the 1st 81 Patients) 
pX = True 
Probability of 
Response on 
Arm X 
p=0.10=True 
Probability of 
Response on the 2 
Other Arms 
p=0.15=True 
Probability of 
Response on the 2 
Other Arms 
p=0.20=True 
Probability of 
Response on the 2 
Other Arms 
p=0.25=True 
Probability of 
Response on the 2 
Other Arms 
0.10 
 
 
 
 
0.15 
 
 
 
 
0.20 
 
 
 
 
0.25 
 
 
 
 
0.30 
 
 
 
 
0.35 
 
 
 
 
**i.e. that the Arm X observed response rate would be greater than the observed response rates of other 2 arms 
*Calculations are based on exact binomial probabilities  


NANT 2011-01 Version Amendment #8  01-10-2018     63 
 
 
If this conditional probability is less than 0.90 for any one of the scenarios in which all 3 arms have the 
same true response rate (highlighted in the Table above), then the study will continue as originally 
planned – with the possibility that one arm will be dropped because its response rate is inferior to the 
response rates of the other 2 arms.   
 
The table below summarizes the minimal impact of incorporating stochastic curtailment at this stage, on 
the overall probability of correct selection, for a variety of scenarios (in none of these scenarios is the 
probability of correct selection decreased). 
 
Table:  Probability* of Selecting the Correct Arm 
True 
Probability 
of Response 
for the 2 
Inferior 
Arms 
Without Stochastic Curtailment 
Difference in True Probability of Response 
between Best Arm and the Other 2 (least 
favorable configuration) 
With Stochastic Curtailment 
Difference in True Probability of Response 
between Best Arm and the Other 2 (least 
favorable configuration) 
+0.0 
+0.05 
+0.10 
+0.0 
+0.05 
+0.10 
0.10 
1.00 
0.676 
0.855 
1.00 
0.705 
0.875 
0.15 
1.00 
0.627 
0.818 
1.00 
0.658 
0.827 
0.20 
1.00 
0.599 
0.780 
1.00 
0.622 
0.814 
0.25 
1.00 
0.592 
0.770 
1.00 
0.608 
0.788 
0.30 
1.00 
0.583 
0.736 
1.00 
0.607 
0.777 
*Probabilities of correct selection estimated by simulation, using same methods a results in the Appendix 
 
 
Logistic Considerations for 2nd Interim Analysis:  Study accrual will pause while awaiting the results of 
the 2nd interim analysis, until it is clear that 81 patients are “evaluable for response”.  In addition, no final 
decision will be made to terminate accrual or drop an arm, until central review of response is completed.   
 
10.2 
Randomization 
Patients will be randomized at study entry.  In order to increase the likelihood of good balance between 
groups, 
patients 
will 
be 
stratified 
prior 
to 
randomization 
according 
to: 
 
disease 
status 
(relapsed/progressive vs. refractory disease vs. partial response during induction); bone marrow 
involvement by routine morphology (bone marrow involved at study entry vs. bone marrow free of disease 
at study entry); age (< 18 years and > 18 years); and receipt of prior 131I-MIBG (received or not received).  
The dynamic allocation method of Simon and Pocock will be used to assign patients to one of the 3 MIBG 
regimens, while balancing across the margins of each of the four stratification variables.111   
 
10.3 
Response Evaluation 
 
10.3.1 Definition of Evaluable for Response 
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): 
 
a. Complete response 
b. Complete response-Minimal Residual Disease (MRD) 
c. Partial response 
d. Stable disease 
e.  Minor response 
f. 
Progressive disease 
g.   Early death from malignant disease 
h     Early death from toxicity 
i.     Early death because of other cause 
j.     Inevaluable (not assessable, insufficient data, patients off therapy early due to toxicity) 
k.    Never received any of the study drugs:  131I-MIBG, vorinostat, vincristine, or irinotecan. 


NANT 2011-01 Version Amendment #8  01-10-2018     64 
 
 
All eligible, randomized patients will be included in the intent-to-treat analysis of response, according to the 
randomization outcome. Patients in groups a through c will be classified as responders; patients in groups d 
through k 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 in the next paragraph). 
 
In the secondary analysis (per protocol), patients will be considered evaluable for response if they receive 
131I-MIBG that is at least 85% of their prescribed dose (or at least 85% of 1200 mCi protocol maximum 
dose for patients whose calculated dose exceeds 1200 mCi) plus at least 80% of any prescribed systemic 
agents (at least 4 days of irinotecan or at least 11 days of vorinostat), or withdraw early due to tumor 
progression, clinical progression/deterioration, or toxicity. In addition, patients who do not withdraw early 
must meet the criteria to be adequately evaluated for each of the 3 disease parameters (if they had 
disease at baseline for that parameter) as described in Section 11, in order to be considered evaluable for 
response. For each patient not evaluable for response, an additional patient will be enrolled to meet the 
accrual goals in Section 10.5.   
 
Per Amendment 7A (for clarification):  The primary analysis will be a modified intent-to-treat analysis:  all 
eligible, randomized patients who receive any amount of 131I-MIBG will be included.  There will be 2 
secondary, additional analyses:  an intent-to-treat analysis (all eligible, randomized patients) and a “per 
protocol” analysis based on all patients who are “evaluable for response” (described above).  These will 
serve as “sensitivity” analyses. 
 
 
10.3.2 Primary Response Endpoint and Additional Assessments of Treatment Effect 
The primary endpoint and analysis will be objective tumor response after one course of therapy based on 
central review, for all eligible randomized patients who received any amount of 131I-MIBG (modified intent-
to-treat analysis). Two secondary analyses will (a) include all eligible randomized patients and (b) only 
patients evaluable for response as defined in the paragraph above in section 10.3.1.  Patients will 
undergo complete disease staging (123I-MIBG diagnostic scan, bilateral bone marrow aspirate and biopsy, 
anatomic imaging with CT or MRI scan, and urine catecholamines) at baseline and then approximately 6 
weeks following 131I-MIBG infusion.  Response will be assessed according to NANT response criteria 
v1.1.  These criteria are modified from the International Neuroblastoma Response Criteria112 in that they 
utilize RECIST 1.1 criteria for measurable tumors113 and Curie score for MIBG scan response.106  Patients 
with an institutional report of complete response, complete response-MRD, partial response, or stable 
disease will have their response centrally reviewed.  An exact logistic regression analysis will be used to 
compare the 3 arms in terms of response, while controlling for the stratification variables. 
 
For the subset of patients receiving a second course of therapy (enrolled prior to Amendment 7A), the 
response to the second course of therapy will be reported as well as the overall response to two courses 
of protocol therapy.  Response to the first course will nevertheless be the primary endpoint for study.     
 
Additional endpoints for response to treatment will include response at each site of disease:  bone 
marrow; soft-tissue sites; and 123I-MIBG using NANT response criteria.  Progression-free survival and 
overall survival (summarized with Kaplan-Meier plots) will be additional secondary endpoints.     
 
10.4 
Toxicity Evaluation 
Toxicity is the secondary endpoint of this trial.  All patients who begin treatment with vincristine, irinotecan, 
vorinostat, or 131I-MIBG will be evaluable for toxicity.  Toxicity will be graded using the CTCAE criteria, 
version 4.0 which can be downloaded from the CTEP home page (http://ctep.cancer.gov).   
 
Patients will undergo standard screening for toxicity used in previous NANT 131I-MIBG studies.  All 
patients who begin study therapy will be evaluable for toxicity.  All toxicities will be tabulated and reported 
according to received treatment arm.  Differences in the incidence of toxicities between treatment arms 
will be assessed using the Fisher’s exact test.   
    
10.5 
Sample Size and Study Duration 
While we expect that both the vincristine/irinotecan and the vorinostat arms will demonstrate higher 
response rates compared to the MIBG-alone arm – and that the selection therefore will only involve those 


NANT 2011-01 Version Amendment #8  01-10-2018     65 
 
two arms – we have included the MIBG-alone arm to calibrate the improvement and better understand 
the impact of these chemotherapy additions.  However, for purposes of determining the number of 
required patients, we will consider that all three arms are candidates of selection (i.e. could result in the 
highest observed response rate). The number of patients (35 per MIBG regimen, if no arms are dropped 
as inferior) was calculated to ensure an 80% chance that the regimen with the highest response rate is 
selected – if in fact that response rate is at least 15% better than the other two (using the methods 
described by Sobel and Huyett 114 and summarized by Bechhofer, Santner and Goldsman 115).  Because 
we have incorporated Bayesian criteria for dropping an inferior arm or stopping early, the power of correct 
selection and other design characteristics were determined by simulation (see Appendix VIII for more 
details).   
 
Table A in Appendix VIII summarizes the probability of correct selection, the probability of dropping one 
arm for futility, the probability of dropping the superior arm for futility, and the average number of patients 
in the inferior arm.  
 
Estimates of the number of available patients for this study are derived from previous 131I-MIBG studies at 
NANT 131I-MIBG institutions.  Specifically, NANT01-02 accrued 50 patients with refractory disease over 
approximately 40 months of active patient recruitment.  NANT04-06 accrued 26 patients with relapsed or 
refractory disease over the approximately 40 months during which that study was open.  This accrual rate 
underestimates the number of available patients given that NANT04-06 was a phase I study that utilized a 
3+3 dose escalation strategy and accrual was closed for a minimum of 6 weeks after the third patient at 
each dose level was treated.  CHOP, Cincinnati Children’s, UCSF, and the University of Michigan treat 
25, 12, 12, and 7 patients per year on their respective expanded access 131I-MIBG protocols.  Newer 
NANT MIBG centers now include Children’s Hospital Boston, Cook Children’s Hospital, Children’s 
Hospital of Colorado, Hospital for Sick Children, and Seattle Children’s Hospital.  These newer centers 
will increase access to MIBG treatment slots.       
 
We therefore conservatively estimate that 4 patients per month will be available for enrollment in the 
current study.  This accrual rate will allow completion of the study within 30 months, assuming all three 
regimens accrue a total of 35 patients/arm (i.e. interim futility analysis does not result in early closure of 
one of the arms).  In order to account for potentially ineligible or inevaluable patients, a maximum of 115 
patients are anticipated to enroll to yield 105 eligible and evaluable patients.      
 
10.6 
Monitoring Plan for Toxicity 
 
Although we expect all three regimens to be generally well tolerated, several steps and procedures are in 
place in this trial, to monitor toxicities and safety.  These are summarized briefly here and described more 
fully in the subsections below.  All toxicities observed will be reported and summarized in the final report.  
The steps described below were developed for ongoing monitoring. 
 
(1) Delayed engraftment after reduced stem cell dose.  Until the 1st 6 patients who receive a stem 
cell dose of only 1.5 - 1.9 x 106 CD34+/kg, demonstrate timely engraftment without problems  
(Section 10.6.1), all patients must have a stem cell dose of at least 2.0 x 106 CD34+/kg, or must 
have a back-up aliquot.   
(2) Monitoring delayed engraftment.    Throughout the conduct of the trial, the details of any patient 
who fails to achieve timely engraftment will be formally reviewed (Section 10.6.2). 
(3) Monitoring for toxic death.  Each death during treatment or within 2 months of stem cell infusion 
will be formally reviewed (Section 10.6.3). 
(4) Monitoring plan for other toxicities.  Summaries are created every 6 months for review by the 
study PI and by the NANT DSMB.  In addition, at the time of the 1st interim futility analysis, 
toxicities will be formally compared (Section 10.6.4). 
 
10.6.1 Monitoring plan for delayed engraftment after reduced stem cell dose 
Previous NANT 131I-MIBG trials (NANT N04-06 and N07-03) utilized a slightly higher minimum stem cell 
dose (2.0 x 106 CD34+ cells/kg) than planned for the current trial (1.5 x 106 CD34+ cells/kg).  In order to 
evaluate the safety of this lower stem cell dose within this context, patients planning to receive a stem cell 
dose of 1.5 - 1.9 x 106 CD34+/kg must have a back-up aliquot of 1.5 - 1.9 x 106 CD34+/kg available until 
a minimum of 6 patients have been rescued with a stem cell dose of 1.5 - 1.9 x 106 CD34+/kg without 
delayed engraftment.  If the first 6 patients receiving this reduced stem cell dose do not have delayed 


NANT 2011-01 Version Amendment #8  01-10-2018     66 
 
engraftment, then future patients may enroll with only a minimum of 1.5 x 106 CD34+ cells/kg and no 
back-up aliquot.  If any of the first 6 patients have delayed engraftment, then the required stem cell dose 
will be changed to 2.0 x 106 CD34+ cells/kg.   
 
Patients planning to receive a stem cells dose of 2.0 x 106 CD34+/kg are not required to have a back-up 
aliquot at any time during the study.   
 
10.6.2  Monitoring plan for delayed engraftment 
Any time a patient fails to engraft (as defined in Section 4.7), the status of the study will be examined.  
Information reviewed will include the specific details of the patient whose engraftment was delayed, as 
well as the engraftment patterns of the other patients to date.   A decision will be made by the NANT 
Study Management Committee, whether to report immediately to the DSMC or to include the information 
in the next DSMC report (within 6 months).   
 
 
10.6.3    Monitoring plan for toxic death 
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 either 131I-MIBG or vorinostat, whichever occurs last, regardless of cause will 
be reviewed and reported to the NANT DSMB and to the FDA according to standard procedure.  
 
10.6.4  Monitoring plan for other toxicities 
In addition to monitoring for delayed engraftments and toxic deaths, we will formally summarize the 
toxicities experienced at the time of the first interim futility analysis (20 patients per arm).  The 
vincristine/irinotecan and the vorinostat arms will each be compared to the single-agent MIBG 
arm.   Differences in the occurrence of Grade 3+ non-hematologic toxicities that are significant at the 0.10 
level (two-sided Fisher’s exact test) at the time of the first interim futility analysis will be flagged for further 
evaluation.  The results of the interim analyses will be reviewed by the NANT Study Management 
Committee, reported to NANT DSMB and a decision in consultation with NANT DSMB will be made to 
close the trial, modify the trial, or continue unchanged.    
 
Every 6 months, reports are prepared for DSMB review.  These reports will summarize toxicities 
experienced which will allow an assessment of the safety for the trial overall, as well as each of the 3 
arms individually.  We do not plan to calculate p-values for every single type of toxicity, but the data 
summaries will permit identification of unexpected patterns in terms of severity or frequency. 
  
10.7  
Analysis of Correlative and Exploratory Studies  
The correlative biology studies are considered descriptive.  Based on prior NANT studies, we anticipate 
that a minimum of 80% of patients will agree to participate in studies that require additional blood 
sampling.   
 
10.7.1 Whole Body Radiation Exposure 
In the current study, all patients will have whole body radiation doses calculated based on serial 
measurements of radiation exposure rate with an ionization chamber set at a fixed distance and 
geometry.  Our primary analyses will compare whole body radiation dose between randomized treatment 
groups and also between responders vs. non-responders using analysis of variance.  Secondary 
analyses will compare whole body radiation dose between patients with and without grade 4 neutropenia, 
grade 4 thrombocytopenia, and grade > 3 non-hematologic toxicity.  
 
10.7.2 Minimal Residual Disease by NB5 Assay 
We will use TLDA to determine the ability of each the three 131I-MIBG regimens to reduce peripheral 
blood and bone marrow disease burden.  Peripheral blood and bone marrow samples will be obtained at 
study entry and at the time of subsequent bone marrow evaluations.  For each patient, we will calculate 


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their change in TLDA DG score from baseline to end of course 1 of therapy.  The primary analysis will be 
an analysis of variance to compare this change in TLDA DG score in the bone marrow between 
randomized treatment groups.  Secondary analyses will include evaluations of change in peripheral blood 
TLDA DG score as well as baseline level of blood and bone marrow disease burden by TLDA as 
predictors of response to 131I-MIBG therapy. 
 
10.7.3 Evaluation of γ-H2AX Foci, Flt3 Ligand, Amylase, and DNA Damage Response Genes 
For each radiation biomarker of interest, we will focus on comparing changes in each biomarker across 
the three randomized treatment arms.  Each biomarker is a continuous variable, with values measured at 
5 time points (two pre-131I-MIBG and one each at hours 72, 96, and Day 15 after start of 131I-MIBG 
infusion).  We will determine the relative (percent) change of the post-131I-MIBG values from 2nd 
evaluation for each biomarker for each patient.  The changes from the 1st to the 2nd value in the 131I-MIBG 
only arm will be used to estimate the within patient variability, while changes from the 1st to 2nd value in 
the other two arms will reflect the impact of each radiation sensitizer alone on each marker.  Changes 
post 131I-MIBG will be presented in context with the estimated intrapatient variation.   
To determine the effect of radiation sensitizers on each biomarker, we will use an analysis of variance 
(comparing treatment arms) with repeated measures (change at 72 hours, at 96 hours, and at Day 15) to 
model the relative change of each biomarker as a function of randomized treatment arm and time.  We 
will introduce a linear contrast to assess the general impact of the presence or absence of a radiation 
sensitizer (combining the irinotecan and vorinostat arms).  Additional models will evaluate calculated 
whole body radiation exposure as a covariate in the model and separately as the outcome variable as a 
function of randomized treatment arm.  
    
A series of secondary analyses will evaluate associations between baseline biomarker values and 
changes in biomarker values with toxicity and response to therapy.  We will test for a univariate 
association between the baseline value or the degree of change in each biomarker and clinical response 
using two-sample t-tests, with patients separated into groups of responders (partial response or better 
after one course) and non-responders (less than partial response).  We will evaluate an association with 
toxicity in a similar way, separating patients based on the presence or absence of grade > 3 non-
hematologic toxicity and also based on the presence or absence of grade > 4 neutropenia or grade ≥ 4 
thrombocytopenia in that course.  Although testing will be two-sided, our expectation is that greater 
changes post 131I-MIBG in each of the biomarkers will be associated with higher response rates and 
greater toxicity.  For each outcome, there will be 24 tests of association (6 biomarkers and 4 times).  
Nominal p-values will be reported without correction for multiple testing.  Resampling will be used to 
assess robustness and internal validity of the univariate associations. 
    
 
We will next construct a series of logistic regression models with response and toxicity (separately) as the 
dependent variables.  Key covariates will include the relative change of the biomarker of interest, the 
baseline value, randomized treatment arm, the disease status (recurrent vs. primary refractory) and 
calculated whole body radiation exposure.  If multiple biomarkers show promise, additional models will 
include covariates for each of these covariates or a composite biomarker score obtained using principal 
component analysis.   
 
We will also evaluate whether patterns observed in the first course of therapy are seen during the second 
course of therapy, though the primary analyses will be based on data from the first course of therapy.   
 
The sample size for the radiation biomarker studies is based on an estimated 80% participation rate, 
yielding 84 patients, or 28 patients per randomized arm.  For the primary analyses, an analysis of 
variance with repeated measures will be used to establish an effect of either vorinostat or irinotecan on 
the amount of change in each biomarker.  To obtain a (conservative) estimate of the power of the test of 
the effect of treatment arm, we will consider a one-way analysis of variance comparing the 3 arms at a 
single time point   With 28 patients in each arm, using a 0.05-level F-test for comparing the 3 mean 
changes, there will be 91% power when the true mean change in the group with the greatest change 
exceeds the true mean change in the group with the smallest change, by at least one “sigma” in 
magnitude – where “sigma” is equal to the common between-patient standard deviation (i.e. patient-to-
patient variability).   
 
10.7.4 Evaluation of Assistive MIBG Scoring System 
The performance characteristics of the assistive MIBG scoring system will be described, using NANT 
nuclear medicine central review as the gold standard.  Scatterplots and a general measure of 


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concordance (the concordance correlation coefficient 116 or the weighted kappa statistic 117, depending on 
the distributions of the nuclear medicine central review scores, will be used to summarize the agreement 
of the two measures. Since the long-range goal would be to replace standard nuclear medicine Curie 
scoring with the assistive scoring, regression methods will also be used to evaluate how well the assistive 
score can “predict” the gold standard score. 
 
10.7.5 Evaluation of NET Expression and Clinical Response to 131I-MIBG 
NET immunohistochemistry results will be coded on a semi-quantitative intensity scale (0 – 3).  We will 
utilize Fisher’s exact test to compare categories of NET intensity between patients with and without 
response to the first course of therapy (according to 10.3.1). 
 
In a secondary analysis, we will also attempt to validate a previous report of lower NET expression 
among patients with MYCN amplified tumors.  We will perform Fisher exact test to compare categories of 
NET expression between patients with MYCN amplified vs. non-amplified tumors.    
 
10.7.6 Concordance of Institutional and Central Assignment of Curie Score 
Treating institutions and NANT MIBG scan central reviewers will each assign patients a Curie score at 
diagnosis, end of course 1, and end of course 2 (if applicable).  For the purposes of this exploratory aim 
(aim 1.9), the analytic cohort will include any of these scans assigned a Curie score by an institution that 
does not include a designated NANT MIBG scan central reviewer.  Descriptive statistics will be provided 
that include 1) concordance rate between institutional and central review as well as 2) the percent of 
patients for whom MIBG response category (per section 11.3) would change based upon differences in 
Curie score between institutional and central review.  Analysis of the Curie scores will be the same as 
described in 10.7.4, with the gold standard being the NANT MIBG scan central reviewer.  For the 
comparisons of overall response, data will be summarized with contingency tables and the weighted 
kappa statistic.    
 
10.7.7 Sinusoidal Obstruction Syndrome after 131I-MIBG Therapy 
For the purposes of assessing Aim 1.10, the number of patients treated with protocol therapy who go on 
to receive subsequent myeloablative therapy with stem cell rescue within 6 months of completing study 
therapy will be determined based upon data collected during protocol follow-up.  Of this population, the 
number and percent of patients who develop SOS of any grade within 21 days of stem cell rescue after 
myeloablative therapy will be reported based upon specific query on protocol follow-up forms.   
 
For the purposes of this protocol, the definition of SOS will mirror the definition used in NANT and COG 
trials that include myeloablative therapy:  serum total bilirubin > 2.0 mg/dL, with at least 2 of the following 
findings within 21 days of receipt of stem cell infusion after myeloablative therapy:  
• 
hepatomegaly with right upper quadrant pain; 
• 
ascites; or  
• 
weight gain >5% above baseline. 
 
Severe SOS is defined as an episode of SOS in addition to a specific organ failure:  
a. Hepatic encephalopathy (CTC Grade 4 hepatic failure), OR  
b. Pulmonary dysfunction: Continuous oxygen support (CTC Grade 3 hypoxia) for > 48 hours, 
ventilatory support not clearly attributable to another cause, OR 
c. Renal dysfunction: serum creatinine > 3 times the ULN (CTC Grade 3 creatinine), or the need 
for dialysis (CTC Grade 4 renal), not clearly attributable to another cause.  
 
All other cases of SOS not meeting the definition of severe SOS will be considered mild-moderate.   
 
Additional details, including time from last 131I-MIBG to start of myeloablative therapy, type of conditioning 
for myeloablative therapy, severity of SOS, need for defibrotide therapy, and outcome of SOS will be 
collected and reported descriptively.  The number of patients undergoing myeloablative therapy and the 
number of those patients developing SOS will be reported according to randomized arm assignment.      
 
10.7.8 Circulating Tumor DNA (ctDNA) 
Evaluation of ctDNA in the context of this trial is considered a pilot investigation.  Descriptive data on 
percent of patients with detectable ctDNA at each time point will be reported for the entire cohort and then 
separately for responders and non-responders (as defined in section 10.3).  Data using next generation 


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sequencing method and ddPCR method obtained from the same time point will be presented using 
descriptive statistics, with no formal statistical testing planned.      
 
10.8     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. Although we will summarize the response rate by gender and race/ethnicity, the relatively small 
number of patients entered into this trial will not permit formal comparisons. 
 
 
 


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11.0 
NANT RESPONSE CRITERIA v 1.2 
Below are the NANT Response Criteria. Since patients on this study must have MIBG avid tumors, any 
reference to MIBG non-avid tumors is not applicable.   
 
Overall response will incorporate all three parameters: CT/MRI, MIBG (FDG-PET is substituted for MIBG 
non-avid tumors), 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 
Response Criteria for CT/MRI Lesions 
 
For lesions evaluated by CT/MRI, this study will use 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). 
 
11.1.1 Definition of soft tissue TARGET LESIONS on CT/MRI:   
 
Soft tissue target lesions that will be followed for response must meet criteria in a. and b. below:   
a.  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 >10 mm, or for lymph nodes >15 
mm in short axis.  (The short axis is measured after identifying the longest diameter of a 
lymph node or nodal mass, and then measuring the longest perpendicular diameter to that as 
the short axis).  
 
b. A target lesion must also be evaluable for response:  To be evaluable, the lesion must also 
be MIBG or FDG-PET avid (if tumor known to be MIBG non-avid), or have a biopsy as 
required in the eligibility criteria.  If one soft tissue lesion present at enrollment is biopsied 
showing neuroblastoma or ganglioneuroblastoma at any time point, then all other soft tissues 
lesions present at enrollment are considered evaluable. Bone marrow positivity does not 
affect soft tissue evaluability. 
 
NOTE: Soft tissue components of bone lesions will be considered measurable lesions if > 
10mm in at least one dimension, and evaluable for response if MIBG avid (or 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, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the sum of diameters. 
 
 
11.1.2  Non-Target soft tissue lesions will include: 
a. Leptomeningeal tumor and tumor in cerebrospinal fluid cytology will be considered non-target 
lesions.  
b. Lesions that are considered likely to be active tumor by the treating physician based on clinical 
correlation (for example, hepatic and pulmonary nodules) 
 
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 soft tissue lesions (≥ 10mm) that are not MIBG avid or PET avid (if tumor known 
to be MIBG non-avid) and if biopsied did not show neuroblastoma or ganglioneuroblastoma. 
b. Non-measurable soft tissue lesions < 10mm or non-measurable 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.   


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11.1.4 The response of the CT/MRI lesions will be defined as outlined below: 
 
11.14.1   Complete Response (CR) 
Disappearance of all target CT/MRI lesions.   
  
11.1.4.2  Partial Response (PR) 
At least a 30% decrease in sum of diameters of CT/MRI lesions, (using longest diameter for non-nodal 
lesions and short axis for nodal lesions), taking as reference the measurement of target lesions 
performed at study enrollment. Non-target CT/MRI lesions must be stable to smaller in size.   No new 
lesions.  MIBG (PET-FDG 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 lesions (using longest diameter for non-nodal lesions 
and short axis for nodal lesions),  taking  as reference the smallest sum of diameters while on study (this 
includes the baseline if that is the smallest 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 tumor 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 CT/MRI lesions is also considered as a criteria for PD (guidance for 
substantial includes a 73% increase in volume, of 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 lesions which 
are stable in size, will be captured in MIBG response (or FDG-PET if tumor is MIBG non-avid) and will NOT 
be graded as CT/MRI progression.  CT/MRI would be graded as SD. 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 lesions) 
Neither sufficient shrinkage in sum of diameters to qualify for PR, and patient does not meet any criteria 
for PD. No new lesions.  Non-target 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 lesions only) 
Non-target lesions are still present; may be smaller or stable in size, and do not meet criteria for PD.  No 
new non-target tumor lesions (new lesions may be biopsied to rule out PD). 
 
11.1.4.6  Not involved (NI) 
 No target or non-target lesions 
 
11.1.4.7  Non-target lesions only   
Patient has no target lesions, but does have non-target lesions 
 
11.1.4.8  Not evaluable (NE) 
 CT/MRI scans are of inadequate quality as assessed by central reviewer, or scans are not repeated of all 
lesions 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 
 
11.1.4.9  Not done (ND) 
No CT/MRI scans were done at the given time point. 
 
11.2 
Response Criteria for Morphologic Bone Marrow Disease 
 
Routine morphology (with or without routine immunocytochemistry) will be used for baseline evaluation 
and all subsequent response evaluations performed while on protocol therapy, and at end of protocol 
therapy.  Central review will be performed on bilateral biopsies only unless tumor is seen only on 
aspirates. 


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Patients with ≤5% tumor on all samples of the bilateral bone marrow aspirate and biopsies at study entry 
will be evaluable for bone marrow response, but defined separately from patients with >5% at study entry.   
 
The percentage of tumor in an aspirate will be calculated as the number of tumor cells divided by the 
number of total nucleated cells. 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 (excluding Schwannian stroma).  
 
11.2.1 Complete Response (CR) 
Greater than 5% tumor cells seen on any one sample of bilateral aspirates/biopsies performed at study 
entry, with no tumor cells seen on bilateral aspirates and biopsies at one subsequent time point. 
 
11.2.2 Complete Response-Minimal Residual Disease (CR-MRD)   
Percentage tumor ≤ 5%  on all samples of bilateral aspirates/biopsies at study entry, with no tumor cells 
seen on  bilateral aspirates and biopsies at one subsequent time point after starting protocol therapy  If 
subsequent time points remain negative, then patient is classified as CR–MRD.  If subsequent time points 
are intermittently positive but with ≤ 10% tumor, then response should be reclassified as SD at the 
negative time points initially reported as CR-MRD. 
 
11.2.3 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 > 10% tumor on any one bone marrow sample AND there is a doubling in 
the amount of tumor compared to study entry (baseline).  
 
For example, a patient entering with ≤ 5% tumor in marrow must increase to > 10% tumor to have PD; a 
patient entering with 30% tumor must increase to ≥60% tumor.  If patients have in increase in tumor 
amount which is less than the amount specified for PD, the response will be classified as SD.  
 
Patients who enter on study with no tumor seen will be considered PD if ONE subsequent evaluation 
shows >10% tumor.  If ≤ 10% tumor is seen on one subsequent evaluation or intermittently, the response 
will be classified as SD.   
 
11.2.4 Stable Disease (SD) 
Stable disease will be defined as persistence of an amount of tumor in the bone marrow that does not 
meet criteria for progressive disease or CR or CR Minimal Residual Disease. (Note that patients who 
enter with any amount of tumor and have one subsequent negative bone marrow which is initially graded 
as a CR or CR-MRD and then on subsequent time points have 1-10% tumor noted would be then 
considered as SD at all time points, including the time point initially graded as CR/CR-MRD).  
 
11.2.5  Not Evaluable (NE) 
Patients for whom follow-up bone marrows 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. 
 
11.2.6  Not involved (NI)  
Patients with no evidence of neuroblastoma in the bone marrow at study entry, and remain negative on 
subsequent evaluations.  (Note that such patients may be reclassified as SD if they meet the SD criteria 
above with intermittent tumor in the bone marrow). 
 
11.2.7  Not done (ND) 
Bone marrow evaluation not done at a given time point. 
 
 
11.3. 
Response Criteria for MIBG Avid Lesions 
 
MIBG Response will be graded using the Curie scoring scale.106  The treating site will report the MIBG 
response using the Curie scoring, however the statistical endpoint of MIBG response will utilize the Curie 
score from the central reviewer.   


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MIBG scans will be scored for 10 regions: 9 anatomic regions for skeletal metastases, and a 10th region 
for any MIBG avid soft tissue disease.  
 
Each of the 10 regions will be given a score of 0-3, as defined below.   
 
Scoring of Skeletal Disease 
Regions  1 – 9 
Scoring 
MIBG uptake 
0 
No MIBG uptake 
1 
1 focal lesion  
2 
> 1 focal lesion  
3 
> 50% of a region  
 
 
 
 
 
The absolute extension score is obtained by adding the scores of all ten regions. The presence of an 
MIBG avid lesion, and NOT the “intensity” of MIBG-avidity, determines the scoring within a particular 
region.  
 
REGIONS 1-9 (SKELETAL 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 below). 
 
Region 10 (SOFT TISSUE DISEASE): Soft tissue disease within the neck, chest or abdomen/pelvis is 
scored within Region 10. Examples of soft tissue lesions may include MIBG avid cervical, paraspinous, 
adrenal, renal, retroperitoneal, or hepatic masses.  
 
SCORING SOFT TISSUE DISEASE: Score = 1 indicates an isolated soft tissue mass that encompasses 
< 50% of that region (chest or abdomen/pelvis). Score = 2 indicates > 1 soft tissue lesion in the neck, 
chest or abdomen/pelvis. A soft tissue score = 3 indicates MIBG avid soft tissue disease that 
encompasses > 50% of either the chest or abdomen/pelvis. (For example, a large adrenal mass in which 
the MIBG avidity encompasses > 50% of the abdomen/pelvis is scored a 3 for Region 10). Cervical soft 
tissue disease is included in the chest region.  


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If no MIBG-avid soft tissue lesions are present, then score 0 for Region 10.  
 
If a solitary soft tissue lesion extends into both the chest and abdomen/pelvic regions, score 3 for that 
lesion. For example, a large paraspinous mass that extends along the thoracic and lumbar spine would 
be scored a 3 for Region 10. Any corresponding metastatic bone disease within the thoracic or lumbar 
spine would be scored separately for the cervico-thoracic spine (Region 2) and lumbar spine (Region 4).  
 
Conjugate planar imaging will be used to score a given region. SPECT scans may be used as an adjunct, 
but only to help delineate the location of the MIBG avid lesion. 
 
The relative score is calculated by dividing the absolute score at each time by the corresponding pre-
treatment overall score. The relative score of each patient is calculated at each response assessment 
and classified as below:  
a. Complete response:  all lesions of 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 lesions on 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:  MIBG scan of inadequate quality as assessed by central reviewer. 
f.  Not involved: No MIBG avid lesions at study entry and subsequent response time points. 
g. Not done: MIBG scan not done at a given response time point. 
 
11.4   Response Criteria using FDG-PET scans (for MIBG non-avid patients) 
*This section included as a reference only and will NOT be used in NANT 2011-01 as all patients 
must be MIBG avid* 
 
Patients known to be non-avid for MIBG should have FDG-PET scans performed for monitoring response. 
FDG-PET avid lesions will be scored by the presence or absence of a lesion that is two times above 
background.   
 
11.4.1 Complete response (CR) 
Resolution of all FDG-PET uptake in all FDG-PET avid lesions identified at baseline and no new FDG-PET 
avid lesions. 
 
11.4.2  Partial response (PR) 
Reduction of number of lesions by FDG-PET by  ≥ 50%.  No new FDG-PET avid 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 lesions on FDG-PET scan.  Note: biopsy may be done to exclude causes of FDG-PET uptake other 
than tumor.  If biopsy 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 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 that is two times above background  
 
11.4.7  Not Done (ND) 
FDG-PET scan not done at that timepoint. 
 
On central review, FDG-PET avid lesions will be evaluated by both the Curie scoring method and by 
enumeration of lesions to grade response.       


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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 still be requested at all response evaluation time points and recorded 
in database as both actual and as “elevated” or “not elevated”.Catecholamines must be at least 3 
standard deviations above the mean for age to be classified as elevated.   
 
11.6 
Definition of Overall Response for Each Patient 
 
The criteria below will be used to define the overall response for each patient, with consideration of all three 
individual response parameters: CT/MRI, MIBG (FDG-PET if tumor is not MIBG avid), and Bone Marrow.  
 
11.6.1 Complete Response (CR) 
Response of CR or NI for MIBG (FDG-PET if tumor is not MIBG avid), CT/MRI and bone marrow.    
 
11.6.2  Complete Response-MRD (CR-MRD) 
Response of CR or NI for MIBG (FDG-PET if MIBG non-avid), CT/MRI response of CR or NI, with BM 
response of CR-MRD. 
 
11.6.3 Partial Response (PR) 
Response of PR in both CT/MRI and MIBG  (FDG-PET scan if tumor is not MIBG avid); or response of PR 
in either CT/MRI or MIBG (FDG-PET if MIBG non-avid) with response of CR, NI, or SD-NTL for other 
parameter or response of CR for MIBG with SD-NTL for CT response. Bone marrow response of either 
CR, CR-MRD, NI, or SD for patients with maximum amount of tumor <5% at that given time point.  
 
11.6.4 Progressive Disease (PD) 
Either one of the following will define an overall response of PD: 
a. At least one response parameter including CT/MRI, MIBG, and/or bone marrow and/or FDG-
PET response is PD.  If PD is found by one parameter, the other two parameters are not 
required to be evaluated to define an overall response of PD. 
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, or SD-NTL for other 
parameters.   
 
11.6.6 Minor response (MR) 
Complete response, Complete-MRD response, and/or partial response for one parameter (i.e. CT/MRI, 
MIBG (FDG-PET if MIBG non-avid),bone marrow), with response of stable disease for second parameter 
and any response other than PD or inevaluable for third parameter. 
 
11.6.7 Not evaluable (NE) 
Response of Not evaluable for one or more response parameters including CT/MRI, MIBG (FDG-PET if 
MIBG non-avid), or bone marrow, unless one parameter that had measurable/evaluable tumor at study 
enrollment. However, if one parameter is done and demonstrates PD this is defined as an overall response 
of PD.  In addition, response may be declared not evaluable if review by the  Study Management 
Committee/PI deems that there is insufficient data to grade response 
 
11.6.8 No Progression 
Baseline status at enrollment was NI or non-target lesions only for CT, NI for bone marrow, NI for MIBG 
(FDG-PET if MIBG avid) and there has NOT been PD at any site since on protocol therapy.  
 
11.6.9 Not done (ND) 
Response was not assessed at this timepoint. 
 
 


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11.6.10 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: 
 
Overall Response Assignment 
CT/MRI 
Response 
MIBG Response 
Bone Marrow 
Response 
Overall Response 
 
PD for any one parameter with any response (including Not Done or 
Inevaluable) for the other 2 parameters. PD may also be defined by clinical 
assessment of the treating physician only. 
 
PD 
CR 
CR 
CR 
CR 
CR for one parameter with either CR or NI for  other parameters 
 
CR 
MIBG response= CR or NI  
CT/MRI response =  CR or SD-No Target Lesions or NI  
 
 
CR-MRD 
CR-MRD 
 
CR or PR  or  
SD-No Target 
Lesions  
 
PR  
CR or  
CR-MRD or NI 
 
-OR- 
 
SD if < 5% tumor in 
bone marrow  
 
 
PR 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
CR  or PR or NI  
  
 
CR or 
CR-MRD or NI  
 
 
 
-OR- 
 
SD if ≤ 5% tumor in 
bone marrow at 
study entry 
 
 
 
 
 
 
 
 
PR 
SD for one parameter, with SD or NI or SD-NTL for other two parameters 
 
SD 
CR or CR-MRD or PR for  at least one parameter, SD for a second parameter, 
and any response other than PD or Not Evaluable for other parameter 
Minor Response 
Response of Not Evaluable for  
any one of the 3 parameters that had measurable/evaluable tumor at study 
enrollment and no PD for any parameter.  
Not Evaluable  
No response evaluations performed for any of the 3 parameters 
Not Done 
NI or non-target 
lesions only at 
enrollment  and no 
PD on subsequent 
timepoint 
 
NI at enrollment and no PD at 
subsequent time point 
NI at enrollment and 
no PD at subsequent 
time point 
 
 
No Progression  
 
*For patients who utilize FDG-PET in place of MIBG response, then substitute FDG-PET 
response for MIBG response in this table to define 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). 
 
An adverse event is defined as any unintended or abnormal clinical observation that is not of benefit to 
the patient.  Either the condition was not present prior to exposure to test medication, or it has worsened 
in intensity or frequency following exposure to test medication.  Adverse events will be graded according 
to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.   A copy of the 
CTCAEv4 can be downloaded from the CTEP home page (http://ctep.cancer.gov).   
 
12.2 
Expedited Adverse Event Reporting to the FDA 
 
Per CFR 312.32 (c), the sponsor of the IND, Steven DuBois, 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” with an associated 1571 form that will be 
consecutively numbered.  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. 
 
Each telephone call or facsimile transmission to the FDA shall be transmitted to the FDA division that has 
responsibility for review of the IND.  Following each facsimile transmission of an expedited adverse event 
report to the FDA, a hard copy version of the report shall be transmitted to the FDA division along with an 
amended 1571.   
 
12.3 
NANT Operations Center Role in Expedited Adverse Event Reporting to the FDA 
 
For purposes of this protocol, the expedited adverse event reports will be submitted to the FDA as above 
by the NANT Operations Center on behalf of the IND sponsor, Steven DuBois. The NANT Operations 
Center will also disseminate all expedited adverse event reports with NANT investigators, DraxImage, 
NDP, and Merck.  The IND sponsor, Steven DuBois, has also delegated to the NANT Operations Center 
the telephone/facsimile FDA notification responsibilities for unexpected fatal or life-threatening 
experiences.   
 
A cover letter to accompany expedited adverse event reports will be prepared by the NANT Operations 
Center in collaboration with the IND sponsor, Dr. DuBois. Contents will include: 
 
1. An assessment of the adverse event, its significance/relevance to the study, and 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. 


NANT 2011-01 Version Amendment #8  01-10-2018     78 
 
 
All IND submissions will be maintained in a master file at the NANT Operations Center. 
 
12.4 
NANT Site Investigator Role in Expedited Adverse Event Reporting 
 
For any serious adverse event, both expected and unexpected:  
• 
Contact the Study Chairperson and the NANT Operations Center to alert them to the existence of 
the serious adverse event within 1 working day, or 24 hours, of learning of the event.  
• 
Within 2 working days, or 48  hours,  of learning of the event complete the NANT 
SAE  form  (see  NANT  website www.nant.org  under protocol data forms/generic forms 
packet)  and email to NANTstaff@chla.usc.edu.  
• 
Follow-up information should be submitted as as an amended NANT SAE report 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 internal and external AE reports with their Institutional Review Boards 
according to local institutional policy.   
 
12.5  
Additional Adverse Event Reporting Requirements for Merck & Co, Jubilant DraxImage 
and NDP 
 
12.5.1 Merck & Co 
The NANT Operations Office will provide Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 
993-1220) with copies of all serious adverse experiences within two working days for patients randomized 
to Arm C.  Additionally, NANT has agreed to report any pregnancy occurring in association with use of 
vorinostat to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220). Details of pregnancy 
outcomes will also be reported.  Serious adverse experiences will be reported using MedWatch forms. 
 
NANT will also provide Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) with 
details of any vorinostat overdoses.  For the purposes of this overdose reporting, a vorinostat overdose 
will be considered any of the following:   
• 
Receipt of a duplicate dose on any protocol day; 
• 
Receipt of more than 14 days of vorinostat therapy; 
• 
Receipt of daily doses more than 30% higher than prescribed; 
• 
Receipt of an absolute daily dose of more than 400 mg.   
 
12.5.2  Jubilant DraxImage 
The NANT Operations Office will provide Jubilant DraxImage, Inc with copies of all serious adverse 
experiences associated with DraxImage’s MIBG product within two working days.  Serious adverse 
experiences will be reported using MedWatch forms. 
 
12.5.3  NDP 
Dr. Katherine Matthay is the IND holder for the use of NDP’s MIBG product.  The NANT Operations Office 
will provide Dr. Matthay with copies of all serious adverse experiences associated with NDP’s MIBG 
product within two working days.  Serious adverse experiences will be reported using MedWatch forms.   
 
12.5.4 Additional NANT Obligations 
The NANT Operations Office will also provide Merck, Jubilant Draximage and Dr. Matthay with a copy of 
all FDA Annual Progress Reports and bi-annual study progress reports. FDA Annual Progress Reports 
will cross-reference the Merck, DraxImage and NDP Investigational Compound Number (IND) at the time 
of submission.   
 
12.6 
Definitions of Adverse Event Terminology 
 
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. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     79 
 
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: 
 
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. 
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. 
 
12.7 
Reporting Secondary AML/MDS or Any Other Second Malignancy 
 
Within two working days of a diagnosis of AML/MDS or other secondary malignancy following treatment 
for cancer, submit the following to the NANT Operations Center: 
• 
A completed NANT SAE Form  
• 
A copy of the pathology report confirming the AML/MDS or other malignancy 
• 
A copy of the cytogenetics report (if applicable) 
 
The NANT Operations Center will report the secondary malignancy to the FDA via MedWatch form and to 
Steven DuBois (IND Sponsor), Draximage (if their product), NDP (if their product; via Dr. Matthay, IND 
holder for NDP’s MIBG product for use in neuroblastoma), and Merck (if on vorinostat arm of the trial).  
Reporting to Merck will be within two working days, as for any SAE.    
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     80 
 
13.0 
RECORDS AND REPORTING 
 
See separate Data Forms Packet which includes the data submission schedule in the members 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 scans). These forms and reports are faxed to the NANT 
Operations Center at 323-361-1803 or sent by email as electronic files to nantdata@chla.usc.edu 
at the end of each course of therapy (day 43-50 evaluation).   
2. For all patients on study, CT/MRI and MIBG scans done as baseline tumor evaluation at study 
entry are required to be submitted into the NANT PACS system or on CD for central review (after 
approval of NANT Operations Center).    Bone marrow slides from study entry may also be 
requested at the discretion of the Operations Center. 
3. For all patients the MIBG scans done at day 43-50 will also be submitted for central review.  The 
MIBG scans should be submitted after day 43-50 evaluation.  For patients who report a 
CR/PR/SD on CT/MRI, scans done at day 43-50 should be submitted for central review after day 
43-50 evaluation.  In questionable cases, the Operations Center may request CT/MRI scans for 
central review.  It is preferable that scans be submitted electronically into the NANT PACS 
system. However, when this is not possible scans can be submitted on CD to NANT Operations 
Center. 
4.  For patients who report a CR or CR-MRD in bone marrow, bone marrow slides will be submitted 
from study entry and from day 43-50 evaluation, and from the second bone marrow confirming 
CR if applicable.  
 
 
 


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71. Muhlethaler-Mottet A, Flahaut M, Bourloud KB, et al. Histone deacetylase inhibitors strongly sensitise 
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85. Rubin EH, Agrawal NG, Friedman EJ, et al. A study to determine the effects of food and multiple 
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15.0 
SAMPLE INFORMED CONSENT  
 
NANT 2011-01: STUDY OF SINGLE-AGENT 131I-MIBG, 131I-MIBG WITH VINCRISTINE AND 
IRINOTECAN, OR 131I-MIBG WITH VORINOSTAT FOR RESITANT/RELAPSED NEUROBLASTOMA 
 
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 
study doctor. 
 
You are being asked to participate in this study because you have been diagnosed with neuroblastoma, a 
type of solid cancer that usually affects children. Your cancer has either grown back (relapsed) or has 
never gone away (persistent tumor) after standard treatment. Standard treatment may have included 
chemotherapy, surgery, radiation therapy and/or high-dose chemotherapy with a stem cell transplant. 
 
The purpose of this study is to compare three different treatments aimed at maintaining or improving your 
response to previous treatments. This study involves the use of an investigational medicine called 
Metaiodobenzylguanidine (MIBG) alone and in combination with either Irinotecan and Vincristine or 
Vorinostat.  These combinations are also investigational, though the dose and side effects of these 
combinations have been tested in previous clinical trials.     
 
Once you are registered on this study, you will be randomly assigned to one of three treatments.  
You will either receive 131I-MIBG by itself or, 131I-MIBG with Vincristine and Irinotecan, OR 131I-MIBG 
WITH Vorinostat.  Patients on all treatment arms will receive the same dose of 131I-MIBG.  Patients on all 
treatment arms will receive blood stem cells as part of this therapy.     
 
Random assignment means that the treatment to which a patient is assigned is based on chance. It is like 
a flip of a coin, except assignment is done by a computer. Neither you or your doctor will choose which 
treatment you will receive. All patients will have an equal chance of being placed in either treatment 
group. During the study, if fewer patients are responding to one treatment arm, then that treatment arm 
will close early and only the two best treatment arms will continue.   
 
The three treatment arms are the following: 
 
131I-MIBG Alone:  
MIBG is taken up by neuroblastoma tumor cells. MIBG can be combined together with radioactive iodine 
(131I) in the laboratory to form the radioactive compound 131I-MIBG. The 131I-MIBG compound delivers 
radiation treatment to the neuroblastoma cancer cells throughout the body.  
 
131I-MIBG with irinotecan and Vincristine:   
This study will combine the two chemotherapy drugs, irinotecan and vincristine, that have been used 
together in some patients with neuroblastoma with the medicine called Metaiodobenzylguanidine (MIBG).  
The irinotecan / vincristine will be given during the same hospital stay as the 131I-MIBG. Giving the 
chemotherapy together with the 131I-MIBG may increase the number of patients who respond to 131I-
MIBG.   
 
131I-MIBG with Vorinostat:   
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. Giving vorinostat together with the 131I-MIBG may increase the number of patients who respond 
to 131I-MIBG.  


NANT 2011-01 Version Amendment #8  01-10-2018     88 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find out which of the three 131I-MIBG  therapies have a better tumor response rate after one 
treatment course.  
 
• 
To compare the side effects seen by giving 131I-MIBG alone, and 131I-MIBG in combination with 
Vincristine and Irinotecan and 131I-MIBG with Vorinostat 
 
• 
To describe the describe which of the three 131I-MIBG treatment regimens has the best tumor effect 
after two courses, including response in the bone marrow, MIBG lesions, soft tissue lesions and 
overall survival. 
 
• 
To describe how many patients who agree to send blood and bone marrow specimens for a special 
testing are found to have tumor cells by this new more sensitive test (called NB5 assay by TLDA) 
after the each of the three 131I-MIBG treatment regimens 
 
• 
To compare the exposure of whole body radiation from 131I-MIBG received on the three regimens using 
radiation measurements and blood markers of radiation. 
 
• 
To learn about a new computerized way of reading MIBG scans.    
 
• 
To learn whether the amount of a certain protein on neuroblastoma cells impacts whether a patient 
responds to 131I-MIBG therapy or not.   
 
The research is being done because: 
 
Currently there is no known effective treatment for your type of cancer.  
 
This study will compare three 131I-MIBG treatment regimens that have already been used for treatment of 
neuroblastoma and compare their effects on tumor response and associated side effects.  We are trying 
to see if one therapy is better for people with neuroblastoma.  
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
A total of 105 patients are expected to enroll on this study.  There will be 35 patients on each arm. All 
patients will be assigned randomly.   
 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Medical Tests Before You Begin the Study  
 
You will need to have the following exams, tests or procedures to find out if you can be in the study. 
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 study doctor. 
 
 
Physical exam  
Bone marrow tests# 
Blood tests 
Various scans* 
Pregnancy test 
Echocardiogram and EKG to check the heart function 
Urine tests 
Test of kidney function (laboratory testing)  


NANT 2011-01 Version Amendment #8  01-10-2018     89 
 
 
# Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is 
inside the bone. 
 
* Various scans that 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, then 
you will need the following tests and procedures during the study. They are part of regular cancer care.  
 
Physical exam  
Bone marrow tests 
Blood tests and scans 
Various tests 
Pregnancy test 
Echocardiogram and EKG to check the heart function 
Urine tests 
Test of kidney function (laboratory testing) 
 
You will also be expected to join a companion study to collect blood, bone marrow, and tumor tissue (if 
available) from patients with neuroblastoma.  Your study doctor will talk with you about this study.   
 
Treatment Plan  
 
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 could be 
used for your child’s stem cell infusion. 
 
Patients will then be randomized at study entry to one of three treatment arms.  Patients on Arm A will 
receive a single treatment course with 131I-MIBG alone.  Patients on Arm B will receive a single treatment 
course with 131I-MIBG, vincristine, and irinotecan.  Patients on Arm C will receive a single treatment 
course with 131I-MIBG and vorinostat.  After this course of treatment, we will check to see your response 
and then check to see how you are doing over time.  
 
 
A map of one treatment course on each treatment arm is shown here: 
 
TREATMENT ARM A:   131I-MIBG ALONE:  
Days 
 
 
    
 1 
 
 15 
         43-50 
 
Therapy 
                         M 
 
HSC 
           Eval 
 
 
131I-MIBG 
 
M 
Day 1 
Stem Cell Infusion  
HSC 
Day 15 
Evaluation 
Eval 
Day 43-50 
------------------------------------------------------------------------------------------------------------------------------------------ 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     90 
 
TREATMENT ARM B: 131I-MIBG + VINCRISTINE/IRINOTECAN:  
 
Cefixime 
C 
Days -1 through Day 6 
131I-MIBG 
M 
Day 1 
Irinotecan  
I 
Days 0 through 4 
Vincristine 
VCR 
Day  0 
Stem Cell Infusion  
HSC 
Day 15 
Evaluation  
Eval 
Day 43-50 
------------------------------------------------------------------------------------------------------------------------------------------- 
 
TREATMENT ARM C: 131I-MIBG + Vorinostat  
 
Vorinostat 
V 
Days -1 through +12 (14 total days) 
131I-MIBG 
M 
Day 1 
Stem Cells 
HSC 
Day 15 
Evaluation 
Eval 
Day 43-50 
 
 
Treatment with 131I-MIBG 
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 doctor will talk with you about where the different hospitals are that can give the 
131I-MIBG treatment. Your nurse and other members of the team that take care of you can help you plan 
for the trip to get this treatment. 
 
Patients will be admitted to an 131I-MIBG treatment center one day before starting 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 special precautions are taken to 
care for you during this time until the radiation level has gone down to a level where these precautions 
are no longer needed (usually 4 - 5 days).  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.  
 
Days 
-1 
0 
1 
2 
3 
4 
5 
6 
    15 
   43-50 
Therapy  
C 
C 
C 
C 
C 
C 
C 
C 
HSC 
Eval 
 
 
VCR 
 
 
 
 
 
 
 
 
 
 
I 
I 
I 
I 
I 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
Days 
-1 
0 
1 
2 
3 
4 
        5-12 
15 
43-50 
Therapy  
V 
V 
V 
V 
V 
V 
V 
HSC 
EVAL 
 
 
 
M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     91 
 
• 
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 through 
your urethra into the bladder to drain the radioactive urine from your body. This catheter will be removed 
3 –5 days following the treatment.  
 
You will also take a medicine by mouth (potassium iodide) 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. 
 
Treatment with Vincristine and Irinotecan (Treatment Arm B only)  
 
If you are randomized to treatment arm B, you will receive vincristine and irinotecan in addition to the 
131I-MIBG. All patients will get the same irinotecan and vincristine dose.  
 
Before chemotherapy starts on this arm, you will be given the antibiotic Cefixime (on Day -1) and will 
continue taking the Cefixime for a total of 8 days (until Day +6). Cefixime can be taken in tablet or liquid 
form. The purpose of the Cefixime is to reduce your chance of having bad diarrhea while getting the 
irinotecan. If there is trouble getting Cefixime, another antibiotic called cefpodixime can be used instead.  
After one day of Cefixime, you will start taking irinotecan and vincristine.  
 
Irinotecan is given daily for 5 days in a row (Day 0 through Day 4). Irinotecan is given each day by IV over 
60-90 minutes. Vincristine is given by IV over 5-15 minutes only on the first day irinotecan is given (Day 
0). Because the most common side effect of irinotecan is diarrhea, you will be instructed to take 
Loperamide (Imodium) after the first loose stool. You will be given written instructions on how much and 
how often this medicine should be taken. Additional medicines will be used if the diarrhea is severe.  
 
The day after vincristine and the first dose of irinotecan are given, you will be treated with 131I-MIBG (Day 
1). 
 
Treatment with Vorinostat (Treatment Arm C only)  
 
If you are randomized to treatment arm C, you will receive vorinostat in addition to the 131I-MIBG. 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.  All patients enrolled will get the 
same Vorinostat dose. You will receive vorinostat orally once daily for 14 days (Days -1 to +12). Two days 
after starting Vorinostat, 131I-MIBG will be given (Day 1).  
 
All Treatment Arms: 
All patients on this study will receive the same dose of 131I-MIBG on Day 1 and autologous blood 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 a NANT hospital, or at a pediatric transplant center that is more 
convenient for you that has been approved by your NANT doctor.   
 
If you develop a low white blood count, your may receive G-CSF (Neupogen) or pegfilgrastim in order to 
help your white blood cells recover faster after treatment. G-CSF (or pegfilgrastim) will be given either as 
an under the skin (subcutaneous) shot or through your IV (intravenous) once a day.  Pegfilgrastim, if 
given, is usually given as a one-time under the skin (subcutaneous) shot. 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. Your doctor will let you know if you will receive GSCF or pegfilgrastim, if needed.   
 
You can receive this therapy once as part of this study. 
 
When you have finished treatment on this study:   
 
After you stop treatment on your assigned treatment arm, 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 functions, 


NANT 2011-01 Version Amendment #8  01-10-2018     92 
 
tests will 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# 
Blood tests 
Various scans* 
Urine tests  
Pregnancy Testing 
 
Echocardiogram and EKG to check the heart function 
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this consent. 
 
Optional Tests in this Study 
You will be asked if you want to participate in the following tests that are being done to learn more about 
131I-MIBG therapy. This part of the study is voluntary.  The results of these tests would not be told to 
you or your doctor 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. You can decide not to let the doctors do these 
tests and will still be able to be treated as part of this clinical study. There are checkboxes on the next to 
last page of this consent form to mark whether you are willing to participate in these voluntary studies. 
 
• 
Evaluation of Blood Markers of Radiation Exposure  
 
Part of the research goal for this study is to look at changes in certain proteins and genes in the blood 
before and after you have been treated with on each arm of this study.  For this test, 12.5 mL of blood 
(2 and a half teaspoons) will be taken 4-5 times during the course of therapy to measure certain 
proteins and genes in the blood cells. You will not need separate clinic visits to participate in this part 
of the study.  The total amount of blood drawn for testing will be about 62.5 mL (about 12.5 
teaspoons) over approximately 16-17 days.  The blood can be drawn or taken from your central line 
(or port).  This amount of blood drawn over this time period is considered safe to donate.  Samples 
will be sent to Dana-Farber and Boston Children’s Hospital in Boston for research testing.  
 
• 
Evaluation of Transport Protein on Neuroblastoma Cells 
 
Part of the research goal for this study is to look to see if the amount of a specific transport protein on 
neuroblastoma cells corresponds to response to 131I-MIBG therapy.  If you give permission, 5 
pathology slides from previous tumor biopsies or tumor surgeries will be sent to Dana-Farber and 
Boston Children’s Hospital in Boston for research testing.  Only tumor material already collected will 
be used and no new biopsies will be performed to help with this research testing.   
 
• 
Evaluation of Automated MIBG Scoring System 
 
On this study, a new scoring system for MIBG scans will be evaluated using MIBG scans from 
patients who are willing to participate. You will not need to get extra MIBG scans to participate in this 
portion of the study.  If you agree, your scans will be forwarded to the University of Chicago for this 
automated MIBG scoring.   The researchers in Chicago will not have access to the reports from your 
treating institution.  
 
HOW LONG WILL I BE ON THIS STUDY?  
 
You will receive a single course of treatment on this study.   
 
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 oncologist or family doctor 
will give the researchers this information at regular intervals. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     93 
 
CAN I STOP BEING IN THE STUDY? 
 
Yes. If you are thinking about stopping the 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.  
 
The study doctor may 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 study looks at how common and serious side effects can be for each patient at a specific dose of a 
drug. In this type of study, some patients may have very serious side effects and could die as a result of 
these side effects.  For example, in rare instances, patients treated with 131I-MIBG for neuroblastoma or 
other diseases have died due to liver or lung damage.  You may be one of those patients who has serious 
side effects as a result of participating in this study.  
 
In this study, researchers will be looking at side effects and tumor responses seen in patients all taking 
131I-MIBG with different treatment combinations.  Since subjects will be assigned to different treatment 
arms, consisting of either 131I-MIBG alone or in combination with irinotecan/vincristine or vorinostat 
subjects will have differing tumor responses and side effects. The goal of this study is to see which 
treatment arm has the best response for your neuroblastoma while comparing the side effects of the 
different treatments.  
 
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 or itching). 
Many side effects go away soon after you stop taking the therapies, 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, including death 
from bleeding or infection due to low blood counts. 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 on the following pages. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     94 
 
Possible side effects of 131I-MIBG 
 
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out every 
100 children) 
Rare 
(happens to < 5 children out 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 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 side effects of Potassium Iodide 
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out 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.  
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     95 
 
Possible side effects of Vorinostat 
Likely 
(happens 
to 
21-100 
children 
out 
of 
every 
100 
children)  
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out 
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 
• 
Poor appetite 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
 
• Decrease in specific types of 
blood cells (white blood cells 
which can cause increased 
risk of infection 
• Weight loss 
• Effects on blood coagulation 
lab tests 
• Decreased kidney function 
• High blood sugar 
• Fever, with or without low 
blood counts  
• Chills 
• Hair loss 
• Constipation 
• Dehydration 
• Dry mouth 
• Heartburn 
• Taste changes 
• Infection 
• Low protein in the blood 
(albumin)  
• Changes in liver blood tests 
• Changes in blood salts 
• Muscle spasm or weakness 
• Dizziness 
• Abdominal pain 
• Cough 
• Shortness of breath 
• Blood clot 
• 
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.)   
 
 
 
Other side effects have been reported in patients receiving vorinostat, but it is unknown whether the 
vorinostat caused the side effect.  These side effects include: irregular heart rhythm; heart attack; blurry 
vision; trouble swallowing; gassiness; mouth sores; gum pain; swelling of arms/legs; trouble walking; 
chest pain; low blood sugar; aches and pains; tumor pain; trouble talking; changes in a blood test that 
measures blood clotting factors; headache; increased pressure in the brain; bleeding into the brain; 
stroke; confusion and memory changes; decreased skin sensation; fainting; tremor; anxiety; blood and/or 
protein in the urine; difficulties with urination; bleeding into the lungs; nose bleeds; trouble sleeping; stuffy 
nose; throat pain; increased sweating; nail changes; itchiness; other rashes; flushing; bruising; changes in 
blood pressure; and inflammation of blood vessels.   
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     96 
 
Possible side effects of Irinotecan  
 
Likely 
(happens to 21-100 children out of 100) 
Less Likely 
(happens to 5 -20 children out 
of 100) 
Rare 
(happens to less than 5 children 
out of 100) 
• 
Diarrhea (can be immediate) and 
may be associated with 
abdominal cramping, a runny 
nose, tearing, salivation, 
sweating, flushing (feeling of 
warmth and red cheeks), and 
difficulty adjusting your eyes to 
light.  
• 
Inflammation and/or sores in the 
mouth 
• 
Nausea and vomiting 
• 
Stomach pain 
• 
Loss of appetite 
• 
Fever 
• 
Loss of body water 
• 
Loss of strength and energy 
• 
An increase in the blood of a 
type of white blood cell called an 
eosinophil. 
These 
are 
sometimes 
associated 
with 
allergic reactions. 
• 
Elevation of the liver and bone 
enzymes  in the blood and of 
bilirubin (yellow pigment formed 
in the liver) 
• 
Decrease in the number of red 
and white blood cells and 
platelets made in the bone 
marrow 
• 
Hair loss 
• Increased blood tests for 
liver and kidney function  
• Constipation  
• Diarrhea that may occur 
later from 1 day to 2 
weeks after irinotecan 
which could cause 
excessive loss of water 
and salts from the body 
• Inflammation and/or sores 
in the mouth, throat and/or 
     esophagus 
• Headache 
• An upset stomach 
• Fewer red blood cells and  
platelets in the blood 
• Rash 
• Blood-clots**.  This is 
seen when Irinotecan is 
given with other drugs not 
used in this treatment 
plan. 
• Skin irritation and/or 
inflammation 
• Headache 
• Dehydration 
 
• Trembling  
• Blood in the urine  
• Mildly increased level of 
protein and glucose in the 
urine  
• Low amount of protein in the 
blood  
• Mouth sores  
• Allergic reaction, that may be 
life threatening.  
• Dizziness and low blood 
pressure  
• Sensation of warmth on face 
• Confusion and/or 
disorientation 
• Pain at the infusion site 
• Slow heart beat 
• Inflammation of the large 
intestine 
• Intestinal blockage 
• Inflammation of the lungs with 
cough and congestion 
• Risk to the unborn child in 
pregnant patients * 
 
* Birth defects and other serious abnormalities in the unborn baby have been noted with irinotecan in 
animal studies at doses similar to or less than those used in humans. The timing and frequency of these 
effects is as yet unknown. These may include multiple birth defects and abnormalities of  bone formation, 
** This toxicity is seen more commonly when irinotecan is given in combination with fluorouracil and 
leucovorin. It may rarely be a life threatening event. 
small size of baby at birth and increased risk of death of the unborn baby. Irinotecan is excreted in rat 
milk but this is unknown for humans. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     97 
 
Possible side effects of Vincristine (Oncovin): 
 
Likely 
(happens to 21-100 children 
out of 100) 
Less Likely 
(happens to 5 -20 children 
out of 100) 
Rare 
(happens to less than 5 children out of 100) 
• Hair loss 
• Constipation 
• Reversible nerve problem 
that may affect the way 
you walk or the feelings in 
your fingers and toes 
 
• Jaw pain 
• Headache 
• Feeling weak (in 
muscles)  
• Belly pain and bloating  
• Low blood counts that is 
mild and doesn’t last 
very long  
• Changes in feeling and 
sensation in the hands 
and feet including 
numbness, tingling and 
pain, clumsiness, wrist 
drop, foot drop, 
abnormal walking with 
foot slapping 
 
• Local damage to nearby tissue if 
vincristine leaks out of the vein and into 
the skin 
• Difficulty breathing 
• Your intestine stops working properly 
which can lead to a blocked intestine. 
• Drooping eyelids, double vision, and 
trouble seeing at night  
• Hoarse voice 
• Vocal cord paralysis 
• Low levels of body salts 
• Seizures 
• Defective sweating 
• Trouble walking or not being able to walk  
• Liver damage when used together with 
other chemotherapy drugs 
• Damage to the nerves to the eye leading 
to decreased vision and possible 
blindness 
• Trouble urinating, pain with urination, or 
having to urinate more often 
• Low blood pressure when going from 
sitting down to standing up which can 
make you dizzy. 
• Nerve damage with dizziness & a spinning 
sensation, uncontrolled eye movements 
and hearing loss 
 
Possible side effects of Cefixime: 
 
Likely 
(happens to 21-100 children 
out of 100) 
Less Likely 
(happens to 5 -20 children 
out of 100) 
Rare 
(happens to less than 5 children out of 100) 
 
• Diarrhea  
• Belly pain  
• Nausea and vomiting 
• Indigestion 
 
• Headache  
• Dizziness 
• Seizures  
• Allergic reaction 
• Hypersensitivity reactions 
• 
Low white blood cell, neutrophil and 
platelet counts, 
• 
High eosinophil count (one type of 
white blood cell), 
• Irritation of the colon  
• Increased blood tests of kidney and liver 
function 
• Hepatitis, yellowing of skin and whites of 
eyes 
• Redness and irritation of the skin and 
sometimes the eyes, lips and mouth.  There 
can also be skin peeling. 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     98 
 
Possible side effects of Cefpodoxime (Vantin-R) 
 
Likely 
(happens to 21-100 
children out of 100) 
Less Likely 
(happens to 5 -20 
children out of 100) 
Rare 
(happens to less than 5 children out of 100) 
 
• 
Diarrhea  
• 
Diaper rash 
 
 
• 
Belly pain  
• 
Nausea and vomiting 
• 
Headache  
• 
Seizures  
• 
Anaphylaxis 
• 
Chest pain 
• 
Hypersensitivity reactions 
• 
Low white blood cell, neutrophil and platelet counts, 
• 
High eosinophil count (one type of white blood cell), 
• 
Pseudomembranous 
colitis: 
causing 
abdominal 
cramping  watery diarrhea with  bloody stools, fever 
and a feeling of 
needing to go to the bathroom 
• 
High blood tests for liver and kidney function 
• 
Change in blood tests for blood clotting factors 
(prolonged) 
• 
Chest pain 
• 
Vaginal infection 
• 
Bone marrow failure: bone marrow does not produce 
enough new cells to replenish blood cells  
• 
Redness and irritation of the skin, eyes, lips and mouth.  
There can also be peeling of skin (a little to a lot)   
 
Possible side effects loperamide (Imodium): 
Sleepiness, trouble thinking, constipation, and nausea,  
 
Possible side effects of G-CSF (Neupogen) 
G-CSF is not an anti-cancer medicine.  It helps the growth of white blood cells that fight infection. 
Likely  
(happens to 21-100 
children out every 
100 children) 
Less Likely 
(happens to 5-20 
children out every 
100 children) 
Rare 
(happens to < 5 children out every 100 children) 
• Bone pain 
•Pain or irritation at 
injection site 
• Increased blood 
tests for alkaline 
phosphatase, LDH 
and uric acid 
• Low platelet count 
• Fever 
• Allergic reactions (more common with giving the drug IV than as 
an injection under the skin) 
• Skin rash, itching, puffiness in the face 
• Shortness of breath or wheezing 
• Low blood pressure, fast heart rate 
• Low grade fever 
• Enlargement of the spleen. 
• Rupture of the spleen 
• Worsening of existing skin rashes 
• Sickle cell crises in patients with sickle cell disease 
• High white blood cell count in the blood 
• Irritation of veins in the skin 
• Adult respiratory distress syndrome (life-threatening lung 
condition that prevents enough oxygen from getting to the lungs 
and into the blood)  
• Bone marrow dysfunction (MDS) or secondary leukemia in 
patients with very bad ongoing neutropenia (not as seen in 
cancer patients) and long term administration. 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     99 
 
Possible side effects of Pegfilgrastim: 
Pegfilgrastim is not an anti-cancer medicine.  It helps the growth of white blood cells that fight infection 
 
Likely  
(happens to 21-100 children out 
every 100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 100 
children) 
 
• Bone pain 
 
 
• 
Pain or irritation at 
injection site 
• 
Headache 
• 
Increased blood tests 
for alkaline phosphaste, 
lactate dehydrogenase 
and uric acid 
• 
Low platelet count 
 
 
• 
Low grade fever 
• 
Allergic reactions  
• 
Generalized redness and flushing 
• 
Enlarged spleen or rupture of the 
spleen splenic rupture 
• 
Pain or other crises in patients with 
sickle cell disease (SCD) 
• 
High white blood cell count in the 
blood 
• 
Adult respiratory distress syndrome 
(life-threatening lung condition that 
prevents enough oxygen from getting 
to the lungs and into the blood.)  
• Sweet’s Syndrome 
 
Possible side effects 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 needed 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.   
 
Possible side effects of stem cell infusion 
 
Likely  
(happens 
to 
21-100 
children out every 100 
children) 
Less Likely 
(happens 
to 
5-20 
children out every 100 
children) 
Rare 
(happens to < 5 children out 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 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     100 
 
Possible risks to unborn child 
 
Patients who agree to participate in this study should not become pregnant while on this study.  This 
study and the medicines used in this study may be hazardous to an unborn child.  Patients and their 
sexual partners should avoid sex and /or an effective method of contraception that is medically 
appropriate based on your personal doctor’s recommendation at that time. 
 
Possible risks to the caregiver(s) of the patient getting 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.   
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 side effects 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. 
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. 
 
Unknown risks 
The treatment combinations may have side effects that no one knows about yet. The researchers will let you 
and your child 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? 
 
Yes there are other options for treatment. Instead of being in this study, you have these options: 
 
o 
Treatment with chemotherapy medicines without MIBG. 
o 
Treatment with other experimental agents that may be available. 
o 
No neuroblastoma therapy at this time, with care to help you feel more comfortable. 
 
Please talk about these options with your doctor. 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     101 
 
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: 
• 
NANT Consortium 
• 
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), involved in keeping research safe for people. 
• 
Nuclear Diagnostic Products (NDP; alternate supplier of 131I-MIBG) 
• 
Draximage (alternate supplier of 131I-MIBG), a division of Draxis Specialty Pharmaceuticals, Inc  
• 
Merck (supplier of vorinostat) 
 
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. 
 
 
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.   
 
Irinotecan, vincristine, cefixime/cefpodoxime, loperamide, and G-CSF/Pegfilgrastim are commercially 
available agents. The cost of these drugs will be billed to your child and/or your child’s insurance 
company. The cost is normally covered by your child’s insurance company. 
 
Vorinostat will be provided by Merck, the company that makes this drug. However they do not cover the 
cost of getting Vorinostat ready and giving it to you, so you or your insurance company may have to pay 
for this.  
 
131I-MIBG will be supplied by Draximage or NDP, two companies that makes this drug, and will be paid for 
by the NANT consortium. Your insurance company will be charged for the cost of the administration of the 
drug.  
 
The optional studies will be done at no cost to if you agree to participate in this voluntary study.  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 MIBG 
treatment, parking, and baby sitter fees. 
 
Taking part in this study may lead to added costs that may 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 
Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this Web site. 
 
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. 


NANT 2011-01 Version Amendment #8  01-10-2018     102 
 
 
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 anytime. 
 
 
You will get a copy of this consent form. If you want more information about this study, ask your study 
doctor. 


NANT 2011-01 Version Amendment #8  01-10-2018     103 
 
CONSENTS FOR EXTRA STUDIES FOR RESEARCH 
 
The following tests are optional. You may still participate in the study even if you do not agree to 
these tests. 
 
Evaluation of Blood Markers of Radiation Exposure 
 
Circle YES, if you agree to let researchers take blood to evaluate blood markers of radiation exposure.  
These are extra blood draws. The results of these tests will be confidential and not made available to you 
or your treating physician. 
 
Circle NO, if you do not want researchers to take extra blood samples to evaluate blood markers of 
radiation exposure.   
 
 
 
YES 
 
 
NO 
 
Signature 
 
Participant: ________________  
 
Date: ______________ 
 
Evaluation of Transport Protein on Neuroblastoma Cells 
 
Circle YES, if you agree to allow pathology slides from previous neuroblastoma biopsies or surgeries to 
be sent to the Dana-Farber and Boston Children’s Hospital in Boston for research testing.     
 
Circle NO, if you do not want to allow your pathology slides to be sent for research testing.   
 
 
 
YES 
 
 
NO 
 
Signature 
 
Participant: ________________  
 
Date: ______________ 
 
 
Evaluation of Automated MIBG Scoring System 
 
Circle YES, if you agree to allow your MIBG scans to be forwarded to the University of Chicago for 
automated MIBG scoring.   
 
Circle NO, if you do not want to allow your MIBG scans to be forwarded to the University of Chicago for 
automated MIBG scoring.   
 
 
 
YES 
 
 
NO 
 
Signature 
 
Participant: ________________  
 
Date: ______________ 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     104 
 
SIGNATURE OF RESEARCH SUBJECT  
 
Your signature below indicates  
 
You have read this document and understand its meaning;  
 
You have had a chance to ask questions and have had these questions answered to 
your satisfaction;  
 
You consent/assent to your participation in this research study; and 
 
 
__________________________________________ 
Name of Subject 
 
 
 
 
 
 
__________________________________________ 
_____________________ 
Signature of Subject  
 
 
 
Date 
 
 
SIGNATURE OF PARENT(S)/LEGAL GUARDIAN(S) (If the subject is a minor) 
 
Your signature(s) below indicates  
• 
You have read this document and understand its meaning;  
• 
You have had a chance to ask questions and have had these questions answered to 
your satisfaction;  
• 
You agree to your child’s participation in this research study; and  
 
 
____________________________  
  _______________________________ 
Name(s) of Parent(s)/Legal Guardian(s)  
 
 
__________________________________________  _________________ 
Signature of Parent/Legal Guardian  
 
Date 
 
 
__________________________________________  _________________ 
Signature of Parent/Legal Guardian  
 
Date 
 
SIGNATURE OF INVESTIGATOR/PERSON OBTAINING CONSENT 
I have explained the research to the subject and/or the subject’s parent(s)/legal guardian(s) and 
have answered all of their questions.  I believe that they understand all of the information 
described in this document and freely give assent/consent/permission to participate. 
 
 
________________________________________ 
Name of Investigator/Person obtaining consent 
 
 
________________________________________ 
____________________ 
Signature of Investigator/Person obtaining consent 
Date 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     105 
 
SIGNATURE OF WITNESS (if applicable) 
My signature as Witness indicates that the subject and/or the subject’s parent(s)/legal 
guardian(s) voluntarily signed this assent/consent/permission form in my presence. 
 
 
________________________________ 
Name of Witness 
 
 
______________________________________________  ____________ 
 
Signature of Witness  
Date 
 
 
SIGNATURE OF INTERPRETER (if applicable) 
 
 
________________________________ 
Name of Interpreter 
 
 
______________________________________________  ____________ 
 
Signature of Interpreter  
Date 
 
 
Complete if applicable: 
Please check appropriate box and sign below. 
 
Investigator/person obtaining consent’s statement of certification for subjects less than seven 
years of age (assent): 
 
The undersigned, _____________________, hereby certifies that he/she has discussed all the 
information contained in the study consent to the subject, and has explained all the information 
in the study consent to the participant/patient, including any risks that may reasonably be 
expected to occur. The undersigned further certifies that the subject was encouraged to ask 
questions, that all questions were answered, and that assent was obtained. 
 
 Assent was not obtained for a subject under 18 years of age. (Please state the reason. 
Examples include: child is an infant; child is comatose; child lacks cognitive abilities to 
understand the information.) 
 
_____________________________________________________________________ 
 
_____________________________________________________________________ 
 
 
Date:_____________ 
 
Time:______________                     
 
Signature_________________________________________ 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     106 
 
Consent Addendum I: Tests that will be done on this study. 
 
 
Observation 
Before 
Entry 
Days -1 to Day +7 
of Course  
Days 8 to 43 of 
Course  
Day 43-50 of 
Course 
Physical Exam 
X 
Day 4 
Every other week 
X 
Blood Tests 
X 
Day 1* and Day 4 Up to two times a 
week 
 
X 
Urine tests 
(including Urine Catecholamines) 
X 
 
 
X 
Pregnancy test 
X 
 
 
X 
Heart tests (echocardiogram and 
EKG) 
X 
Day 4 EKG* 
 
X 
Bone Marrow Aspirate/biopsy 
X 
 
 
X 
CT, MRI and/or MIBG scans 
X 
 
 
X 
MIBG scan after MIBG 
treatment; no extra MIBG is 
given to you for this scan. 
 
After you get out 
of your radiation 
isolation room 
 
 
Blood samples for blood markers 
of radiation exposure (optional) 
 
Three or four 
blood draws over 
5-6 days 
 
One blood draw 
on Day 15 
 
Tumor slides sent for research 
(optional) 
 
X 
 
 
*only for patients on Treatment Arm C (131I-MIBG + Vorinostat) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     107 
 
Consent Addendum 2 
 
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 2011-01 Version Amendment #8  01-10-2018     108 
 
16.0  SAMPLE ASSENT FORM 
 
 
STUDY OF SINGLE-AGENT 131I-MIBG, 131I-MIBG WITH VINCRISTINE AND IRINOTECAN, OR 131I-
MIBG WITH VORINOSTAT FOR RESITANT/RELAPSED NEUROBLASTOMA 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
 
 
1. Dr. ____________________ is doing a research study. 
 
2. You have a kind of cancer called Neuroblastoma.  We are asking you to take part in a research study 
because doctors want to learn more about treating neuroblastoma using three different types of treatment 
choices.  You will only receive one of the treatments and which treatment you get will be decided by a 
computer.  You will get one medicine called MIBG for sure and then the other choices include 3 other 
medicines. 
Here are the three options: 
• 
MIBG all by itself 
• 
MIBG with two other medicines:  VINCRISTINE AND IRINOTECAN 
• 
MIBG with one other medicine:   VORINOSTAT  
Doctors are trying to see and to see what effects (both good and bad) these medicines have on patients 
and their cancer, and which medicines given together (or by themselves) are better in treating your 
neuroblastoma.  MIBG is a radioactive medicine that is given into the bloodstream (either through your 
central line or through a small tube placed in a vein in your hand or arm) Vincristine and Irinotecan are 
also medicines given into your blood stream. Vorinostat is a medicine that is given by mouth as a liquid or 
pill.  The MIBG goes mostly to where the cancer is in your body to give it radiation.  The doctors think that 
giving MIBG may kill neuroblastoma cancer cells and are trying to see if it works better by itself or when 
it’s given together with either Vincristine and Irinotecan or Vorinostat.  
 
3. If you agree to be in this study this is what will happen: 
 
You will get this therapy one time.    
 
MIBG (Given on all Treatment Arms):  
You will get MIBG, which is a radioactive medicine given into an IV over 1 hour.   Because of this 
radiation treatment you will need to stay in your 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 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. 
 


NANT 2011-01 Version Amendment #8  01-10-2018     109 
 
You will need to have a Urinary Catheter placed to help drain your urine while you are getting 
the 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 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.    
 
Vincristine and Irinotecan (Treatment Arm B only): 
You will get vincristine in your IV once on Day 0. You will get Irinotecan in your IV once a day for 
5 days (Day 0 through Day 4) 
 
 
 
Vorinostat (Treatment Arm C only): 
 
You will take vorinostat liquid by mouth once a day for 14 days.   
 
Stem Cells: 
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 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 will be given back to you like a blood 
transfusion after the MIBG and other treatment is finished.  This is called Stem Cell Infusion or 
Stem Cell Rescue.  We 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. 
 
Filgrastim/G-CSF:  
The G-CSF helps the blood cells grow back faster after treatment.  You will get G-CSF if your blood 
cells are low after getting MIBG.  G-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 until your blood cells have started to grow back.  We will know when the blood counts are high 
enough to stop the G-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 pee 


NANT 2011-01 Version Amendment #8  01-10-2018     110 
 
• 
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. 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 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 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. People also have good things that happen to them when they are in research studies. These are 
called “benefits”. The benefits to you of being in this research study are that 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. 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.   
 
7. 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 
MIBG and left the special room before the doctors said it was ok to leave, then you would still be 


NANT 2011-01 Version Amendment #8  01-10-2018     111 
 
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 MIBG but before you were 
given your stem cells back, the high dose of 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. 
 
8. 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.     Study doctor’s phone number: 
__________________. 
 
9. Optional Blood Samples 
Please check to show if you do or do not agree to allow us to take the 4 or 5 extra blood samples to 
learn more about the effect of MIBG on the body.  These blood samples are usually drawn from your 
central line.   
 
_________Yes, it is okay to take the extra blood samples. 
 
_________ No, it is not okay to take the extra blood samples. 
10. Optional Tissue Samples 
Please check to show if you do or do not agree to allow us to use some of your neuroblastoma tumor 
tissue already removed during previous surgeries or biopsies.  You will not have extra surgeries or 
biopsies just because you say “Yes” to this part of the study.   
 
_________Yes, it is okay to take the extra blood samples. 
 
_________ No, it is not okay to take the extra blood samples. 
11. Optional MIBG Scan Study 
Please check to show if you do or do not agree to allow us to send copies of your MIBG scans to a 
hospital that is testing a new way to read MIBG scans.  You will not have extra MIBG scans just 
because you say “Yes” to this part of the study.    
 
_________Yes, it is okay to send copies of my MIBG scans. 
 
_________ No, it is not okay to send copies of my MIBG scans. 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     112 
 
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 Subject: _________________________ 
 
 
 
 
 
 
 
 
 
 
________________________________________ 
______________________ 
Signature of Subject:  
 
 
 
 
Date 
 
 
_____________________________________  
______________________ 
Signature of Investigator 
 
 
 
 
Date 
 
 
_____________________________________  
______________________ 
Signature of Person Conducting Discussion  
 
Date  
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     113 
 
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.  
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     114 
 
APPENDIX II.  MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
For the most current list of medications, please refer to the following website: 
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm . 
 
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®) 
Alfuzosin (uroxatral®) 
Anagrelide (Agrylin®, Xagrid®) 
Atazanavir (Reyataz®) 
Arsenic trioxide (Trisenox®) 
Bedaquiline (Sirutro®) 
Astemizole  (Hismanal®) (Off US market) 
Clazapine (Clozaril® 
Azithromycin (Zithromax®, Zmax®) 
Dolasetron (Anzemet®) 
Bepridil Vascor® (Off US mkt) 
Eribulin (Havalen®) 
Chloroquine (Aralen®) 
Famotidine (Pepcid®) 
Chlorpromazine (Thorazine®) 
Felbamate (Felbatol®) 
Cisapride (Propulsid®) (Off US mkt) 
Fingolimod (Gilenya®) 
Citalopram (Celexa®, Cipramil®) 
Foscarnet (Foscavir®) 
Clarithromycin (Biaxin®) 
Fosphenytoin (Cerebyx®) 
Disopyramide (Norpace®) 
Gatifloxacin (Tequin®) 
Dofetilide (Tikosyn®) 
Femifloxacin (Factive®) 
Domperidone  (Motilium®) (Not on US mkt) 
Granisetron (Kytril®) 
Dronedarone (Multaq®) 
Iloperidone (Fanapt®) 
Droperidol (Inapsine®) (not on US mkt) 
Indapamide (Lozol®) 
Droleptan, (Dridol®) 
Isradipine (Dynacirc®) 
Erythromycin (E.E.S.®) 
Lapatinib (Tykerb®) 
Escitalopram (Cipralex®, Lexapro®) 
Levofloxacin (Levaquin®) 
Flecainide (Tambocor®) 
Lithium (Eskalith®) 
Halofantrine (Halfan®) 
Mirtazapine (Remeron®) 
Haloperidol (Haldol®) 
Moxepril/HCTZ (Uniretic®) 
Ibutilide (Corvert®) 
Nicardipine (Cardene®) 
Levomethadyl (Orlaam®) (Off US mkt) 
Nioltinib (Tasigna®) 
Mesoridazine (Serentil®) (Off US mkt) 
Ondansetron (Zofran®)  
Methadone (Dolophine®) 
Ofloxacin (Floxin®) 
Moxifloxacin (Avelox®, Avalox®) 
Oxytocin (Pitocin®) 
Pentamidine (NebuPent®, Pentam®) 
Paliperidone (Invega®) 
Pimozide (Orap®) 
Pasireotide (Signifor®) 
Probucol (Off US mkt) Lorelco® 
Promethazine (Phenergan®) 
Procainamide (Pronestyl®, Procan® ) 
Quetiapine (Seroquel®) 
Quinidine (Quinaglute®, Duraquin®) 
Ranolazine (Ranexa®) 
Sevoflurane (Ulane®) 
Rilpivirine (Edurant®) 
Sotalol (Betapace®) 
Risperidone (Risperdal®) 
Sparfloxacin (Zagam®) (Off US mkt) 
Saquinavir (Invirase®) 
Terfenadine (Seldane) (Off US mkt) 
Sertindole (Serlect) off US mkt 
Thioridazine (Mellaril®) 
Sunitinib (Sutent®) 
Vandetanib (Caprelsa®) 
Tacrolimus (Prograf®) 
 
Tamoxifen 
 
Telvancin (Vibativ®) 
 
Telithromycin (Ketek®) 
 
Tizanidine (Zanaflex®) 
 
Tolterodine (Detrol®) 
 
Vardenafil (Levitra®) 
 
Venlafaxine (Effexor®) 
 
Voriconazole (Vfend®) 
 
Vorinostat (Zolinza®) 
 
Ziprasidone (Geodon®) 
 


NANT 2011-01 Version Amendment #8  01-10-2018     115 
 
APPENDIX III.  VORINOSTAT DOSING NOMOGRAM 
For patients unable to swallow capsules, vorinostat will be given as a 50 mg/mL extemporaneous liquid 
preparation (see section 6.1.5 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 (eg. 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) 
 
Vorinostat 
180 mg/m2 
0.3-0.35 
60 mg 
0.36-0.39 
70 mg 
0.4-0.45 
80 mg 
0.46-0.55 
90 mg 
0.56-0.59 
100 mg 
0.6-0.65 
110 mg 
0.66-0.69 
120 mg 
0.7-0.75 
130 mg 
0.76-0.79 
140 mg 
0.8-0.85 
150 mg 
0.86-0.89 
160 mg 
0.9-0.95 
170 mg 
0.96-1.05 
180 mg 
1.06-1.09 
190 mg 
1.1-1.15 
200 mg 
1.16-1.19 
210 mg 
1.2-1.25 
220 mg 
1.26-1.29 
230 mg 
1.3-1.35 
240 mg 
1.36-1.39 
250 mg 
1.4-1.45 
260 mg 
1.46-1.55 
270 mg 
1.56-1.59 
280 mg 
1.6-1.65 
290 mg 
1.66-1.69 
300 mg 
1.7-1.75 
310 mg 
1.76-1.79 
320 mg 
1.8-1.85 
330 mg 
1.86-1.89 
340 mg 
1.9-1.95 
350 mg 
1.96-2.05 
360 mg 
2.06-2.09 
370 mg 
2.1-2.15 
380 mg 
2.16-2.19 
390 mg 
> 2.2 
400 mg 


NANT 2011-01 Version Amendment #8  01-10-2018     116 
 
APPENDIX IV: QUALITY CONTROL FOR FREE IODINE IN 131I-MIBG (DETECTION OF RADIOLYTIC 
DECOMPOSITION) 
 
Radiopharmaceutical 131I-MIBG from DraxImage or NDP 
 
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 SepPac cartridge, wet the sepPac with 5 ml ethanol.  The long tip of 
the SepPac must be connected to the flushes 
2. Rinse with 5 ml sterile water 
3. Add one drop to 1/20 mL MIBG to SepPac.  Dilute to around 0.5  uCi 
4. Flush SepPac 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 DraxImage product and greater than 93% 
for NDP 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 DraxImage product and 
greater than 93% for NDP product.  Record results on worksheet.  Contact physicians 
if there is an aberrant or low result. 
 
All centers administering 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.  


NANT 2011-01 Version Amendment #8  01-10-2018     117 
 
APPENDIX V: COMPOUNDS THAT INTERFERE WITH MIBG METABOLISM AND UPTAKE 
 
 
Drugs Known To Reduce Uptake of 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  
Uncertain (also enhances retention of previously stored 
norepinephrine and MIBG by blocking Ca
++ 
mediated 
release from vesicles)  
Tricyclic antidepressants  
Inhibition of catecholamine uptake  
Cocaine  
Inhibition of catecholamine uptake  
Drugs Expected To Reduce Uptake of MIBG  
Drug  
Mechanism  
Sympathomimetics  
Amphetamine and related compounds  
Beta-sympathomimetics
# 
 
Dobutamine, Dopamine, Metaraminol #: 
Systemic use. Effect unlikely with 
aerosol administration  
Depletion of storage vesicle contents.  
Atypical antidepressants  
Maprotiline  
Trazodone  
Inhibition of catecholamine uptake.  
Antipsychotics (major tranquilizers)  
Phenothiazines* 
Thioxanthines  
Butyrophenones  
*Occasionally used as antiemetic / 
antipruritic agents  
Inhibition of catecholamine uptake  
Antihypertensive / cardiovascular  
Adrenergic neuron blockers  
Depletion of storage vesicle contents. Competition for 
transport into vesicles.  
 


NANT 2011-01 Version Amendment #8  01-10-2018     118 
 
APPENDIX VI:  ADJUSTED BODY WEIGHT CALCULATION  
 
For patients whose actual body weight exceeds Ideal Body Weight (IBW) by more than 20%, the dose of 
stem cells, 131I-MIBG, vorinostat, and irinotecan may be based on Adjusted Body Weight (ABW) rather 
than actual body weight. 
 
IBW Formulas: 
1-17 yrs: height is in cm, weight is in kg 
IBW = (height2 x 1.65)/1000 
 
1-17 yrs 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 yrs 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) 
 


NANT 2011-01 Version Amendment #8  01-10-2018     119 
 
APPENDIX VII.  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA  
 
Be aware of your/your child's bowel movements. At the first sign that they are becoming softer than usual 
or if your child has any increase in the number of bowel movements over what is normal for him/her, start 
treating with loperamide (Imodium). If he/she does not start taking the loperamide right away, the 
diarrhea may become severe and last several days or require hospitalization.  
 
Please follow these directions carefully, using dosing guidelines below:  
 
• 
Take _____________ loperamide at the first sign of diarrhea.  
 
• 
Continue taking__________ loperamide every ____ hours until your normal pattern of bowel 
movements returns. Repeat the same doses and frequency if the diarrhea returns.  
 
• 
Do not give more than ___________ of loperamide in a 24 hour period.  
 
• 
Please call your doctor if you have any questions about taking loperamide, if your child's diarrhea 
is not under control after two days, or if he/she is feeling extremely weak, lightheaded, or dizzy.  
 
• 
Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit juices, soda, 
soup, etc.) while your child is participating in this study.  
 
• 
Side effects may include tiredness, drowsiness, or dizziness. If your child experiences these side 
effects, or if your child is urinating less frequently than usual, please contact your child's 
physician.  
 
• 
Do not give your child any laxatives without consulting with his/her physician.  
 
Loperamide dosing guidelines: 
Loperamide  1 teaspoon = 1mg; 1 caplet = 2mg 
 
Maximum dose of loperamide per day: < 6 years: 4mg/day; 6-11 years: 6mg/day; >11 years: 16 mg/day, 
using the non silicone-containing product. 
Weight:  > 43 kg: 
4 teaspoons or 2 caplets (4 mg) after the first loose bowel movement, 
followed by 2 teaspoons or 1 caplet (2mg) every2 hours. During the night the 
patient may take, 2 caplets (4mg) every 4 hours rather than1 caplet (2mg) 
every 2 hours.  
Weight: 30kg – 43kg: 
2 teaspoons or 1 caplet (2mg) after the first loose bowel movement followed 
by 1 teaspoon or one-half caplet (1 mg) every 2hours. During the night the 
patient may take, 1 caplet (2 mg) every 4 hours rather than one-half caplet 
every 2 hours. 
Weight: 20kg – < 30kg: 
2 teaspoons or 1 caplet (2mg)after the first loose bowel movement followed 
by 1 teaspoon or one-half caplet (1mg) every 3 hours. During the night, the 
patient may take 1 caplet (2mg) every 4 hours rather than one-half caplet 
every 3 hours. 
Weight: 13kg - < 20kg: 
1 teaspoon (1mg) after the first loose bowel movement followed by 1 
teaspoon (1mg) every 3 hours. During the night, the patient may take 1 
teaspoon (1 mg) every 4 hours rather than every 3 hours. 
Weight: < 13kg: 
Half teaspoon (0.5mg) after the first loose bowel movement followed by half 
teaspoon every 3 hours. During the night, the patient may take half teaspoon 
(0.5mg) every 4 hours rather than every 3 hours. 
 
 
 
 
 


NANT 2011-01 Version Amendment #8  01-10-2018     120 
 
APPENDIX VIII.  Interim Analyses using Bayesian Rules 
 
A.1 Overall Trial Design 
 
The pick-the-winner design includes the following three analyses (displayed in schematic below) 
• Perform interim analyses after 60 and 81 patients have been treated and evaluated.  The goal of 
these analyses will be to drop an inferior arm, if indicated, as well as to review the toxicities 
• Perform the final analysis after 105 patients have been treated and evaluated, with one 
exception: 
o 
if an arm is dropped as inferior after 60 patients, then the remaining 2 arms will be analyzed 
and compared after 35 patients are evaluable in those arms.  If the results are clear-cut, and 
one arm is superior, then the trial will stop; otherwise accrual will continue until 104 patients 
(42 in the 2 remaining arms) are randomized and evaluated. 
 
 
 
 
 
A.2  Methods Used for Establishing the (Bayesian) Rules for Dropping the Inferior Arm or 
Selecting the Superior Arm 
 
A.2.1  Notation and Distributions: 
 
At any given time in the trial,  
- 
let XA, XB, and XC represent the number of responders observed for regimens A (=MIBG alone), B 
(=MIBG + vincristine + irinotecan), and C (MIBG + Vorinostat), respectively,   
- 
let nA, nB, and nC, represent the total number of patients evaluated for response in arms A, B, and 
C, respectively,  
- 
and let  pA, pB, pC  denote the (true) probability of response (i.e. response rates) for regimens A, 
B, and C. 
 
Thus XA, XB, and XC are binomial random variables with parameters pA, pB, pC , and nA, nB, and nC. 


NANT 2011-01 Version Amendment #8  01-10-2018     121 
 
 
The Bayesian methodology says that pA, pB, pC  are not fixed numbers, but rather have a distribution, or 
range of possible values.   So we modeled these distributions as beta with parameters α and β.  For our 
calculations, we will assign the same mean value of 0.20 for all three distributions – but with very little 
confidence.    So for each p (which will be the same for each pA, pB, pC, separately) 
 
p ≈ Beta(α, β)  
where α/(α+β)=0.20 is the mean of the distribution and α+β=1.0 is like the “sample size”.     
 
We call this our prior distribution of p and pA, pB, pC.  
 
As we observe data (X responders out of n patients treated on each arm separately) then we incorporate 
these data into our distributions of the true response rate, p.  We calculate a new distribution which 
incorporates both our prior belief (or assumptions) and the data we have observed.  So now, after having 
some data, we have the following distribution for p: 
 
p|X ≈ Beta(α + X, β + (n-X))  
where the mean becomes (α+X)/((α+X)+(β+(n-X))) = c[X/n] + (1-c)[α/(α+β)] 
and where c=n/( α+β+n) and the effective sample size is α+β+n = n+1.     
 
We call this our posterior distribution of p.  
 
Since the data in the 3 arms of the study are independent and since we know the posterior distributions 
for each of the response probabilities, then it is easy to determine the posterior probabilities.  For this 
design, instead of calculating the posterior probabilities, we simulated the distributions with 2,000 
realizations for each comparison. 
 
A.2.2  Dropping an Arm / Deciding that the Response Rate is Inferior  
 
After 60 patients (and again after 81 patients, if necessary) we will determine:  
 
(a) Pr { pB – pA > 0.05 | XA, XB, nA, nB} and  Pr { pC – pA > 0.05 | XA, XC, nA, nC} and  
(b) Pr { pC – pB > 0.05 | XC, XB, nC, nB} and  Pr { pA – pB > 0.05 | XA, XB, nA, nB} and  
(c) Pr { pB – pC > 0.05 | XC, XB, nC, nB} and  Pr { pA – pC > 0.05 | XA, XC, nA, nC}.   
 
If the 2 probabilities on any line above are both > 0.85, then we will conclude that Arm A (based on line 
(a)) or Arm B (based on line (b)) or Arm C (based on line (c)) is inferior and based on this and other 
considerations, we will close this arm to future randomization.   These probabilities were determined 
based on 2,000 simulations. 
 
 
A.2.3  Deciding after 90 Patients that we have Sufficiently Strong Data to Stop and Pick the Best 
Regimen 
 
If an arm is dropped after 60 patients, then we will compare the 2 remaining arms after each has 35 
evaluable patients.  Without loss of generality, we will assume that Arm A has been dropped.  At that 
time, we will determine the posterior probabilities (where nC = nB= 35): 
 
Pr { pC – pB > 0.05 | XC, XB, nC, nB}   and   Pr { pB – pC > 0.05 | XC, XB, nC, nB} 
 
If either of these probabilities is > 0.90, then we will close accrual and declare “a winner”.  If not the study 
will continue until 104 patients have been randomized and are evaluable.  These probabilities were also 
determined based on 2,000 simulations. 
 
 
A.3  Evaluating the Characteristics (Statistical Properties) of the Proposed Design 
 
The decision to evaluate data at 60 and 81 patients for the possibility of dropping an inferior arm and at 
90 patients to select a superior arm early was based on logistic and practical reasons as well as 


NANT 2011-01 Version Amendment #8  01-10-2018     122 
 
preliminary simulations.  The choice of the values of 0.05, 0.85 and 0.90 for making the decisions was 
also based on preliminary simulations.   
 
To evaluate the performance of the proposed design, we considered a range of “true” fixed values of pA, 
pB, pC.  For convenience we always set the value of pA to be the lowest response rate and the value of pC 
to be the highest response rate.  For each configuration of (pA, pB, pC), we generated 2,500 trials of 105 
patients and evaluated the following design characteristics:   probability of correctly selecting the best 
arm,  probability of dropping the inferior arm,  probability of dropping the best arm,  average number of 
patients in the inferior arm.   The results are summarized in Table A below. 
 
 
Table A:  Probability* of Correctly Selecting the Best Arm and Dropping the Inferior Arm 
Response 
Rate in 
Inferior & 
Middle Arms 
Probability of Correctly 
Selecting Best Arm 
Probability of 
Dropping Inferior Arm 
Probability of 
Dropping Best Arm 
Average # of Patients in 
the Inferior Arm 
Difference in Response 
Rate between Middle & 
Best Arms 
Difference in 
Response Rate 
between Middle & 
Best Arms 
Difference in 
Response Rate 
between Middle & 
Best Arms 
Difference in Response 
Rate between Middle & 
Best Arms 
Inferi
or 
Middl
e 
+0.10 
+0.15 
+0.20 
+0.10 
+0.15 
+0.20 
+0.10 
+0.15 
+0.20 
+0.10 
+0.15 
+0.20 
0.10 
0.10 
87% 
94% 
98% 
21%** 
25% 
26% 
0.4% 
0.1% 
0.0% 
. 
. 
. 
0.15 
0.15 
81% 
92% 
97% 
25% 
26% 
30% 
0.4% 
0.4% 
<0.1% 
. 
. 
. 
0.20 
0.20 
78% 
90% 
96% 
25% 
29% 
32% 
1.2% 
0.5% 
0.3% 
. 
. 
. 
0.25 
0.25 
76% 
88% 
96% 
28% 
32% 
35% 
1.4% 
0.6% 
0.1% 
. 
. 
. 
0.30 
0.30 
76% 
86% 
95% 
27% 
32% 
34% 
1.5% 
0.5% 
0.2% 
. 
. 
. 
0.35 
0.35 
73% 
88% 
94% 
28% 
30% 
34% 
1.4% 
0.6% 
<0.1% 
. 
. 
. 
 
0.05 
0.15 
88% 
96% 
99% 
50% 
51% 
52% 
0.0% 
0.0% 
0.0% 
28 
28 
28 
0.10 
0.20 
88% 
95% 
98% 
44% 
48% 
50% 
0.2% 
0.1% 
0.0% 
29 
28 
28 
0.15 
0.25 
85% 
94% 
98% 
41% 
43% 
48% 
0.3% 
0.2% 
0.0% 
30 
29 
29 
0.20 
0.30 
85% 
92% 
97% 
41% 
45% 
46% 
0.4% 
0.1% 
0.0% 
30 
29 
29 
0.25 
0.35 
82% 
92% 
96% 
38% 
45% 
43% 
0.4% 
0.0% 
<0.1% 
30 
29 
30 
 
0.05 
0.20 
89% 
95% 
98% 
69% 
71% 
72% 
<0.1% <0.1% 
0.0% 
26 
25 
25 
0.10 
0.25 
86% 
92% 
98% 
60% 
65% 
68% 
0.0% 
0.1% 
0.0% 
27 
26 
26 
0.15 
0.30 
84% 
93% 
97% 
61% 
62% 
64% 
0.1% 
0.0% 
0.1% 
27 
27 
26 
0.20 
0.35 
85% 
93% 
97% 
57% 
60% 
61% 
0.2% 
0.1% 
0.0% 
28 
27 
27 
0.25 
0.40 
83% 
93% 
97% 
56% 
60% 
62% 
0.1% 
<0.1% 
0.0% 
28 
27 
27 
   * probabilities estimated based on 2,500 simulations and are reported as percents  
 ** in this box, for the probability of dropping the inferior arm, the percent reflects dropping either Arm A or Arm B (since 
their response rates are equal for these 6 lines)