Conditions: Multiple Myeloma
Keywords: Measles virus Sodium Iodide Symporter Cyclophosphamide Refractory multiple myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the clinical efficacy of MV-NIS (measles virus-sodium iodide symporter) therapy for people with relapsed/refractory myeloma when given with cyclophosphamide

Detailed description:
The drug used in this trial is a modified version of the measles virus used to vaccinate children. The virus has been altered by having an extra gene (piece of DNA) added to it to allow a protein called NIS to be inserted into it. NIS is normally found in the thyroid gland ( a small gland in the neck) and helps the body concentrate iodine. Having this additional gene will make it possible to track where the virus goes in the body.

Arms:
arm 1: None

Interventions: intervention 1: MV-NIS
Intervention descriptions: intervention 1: one dose in conjunction with a 4 day course intravenously

Protocol document:
Prot_SAP_000.pdf: 
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 UARK 2014-21: Phase II Trial of Oncolytic Virotherapy by Systemic Administration of 
Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with 
Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma 
 
Principal Investigator: 
Frits van Rhee MD, PhD 
Collaborators at Mayo Clinic: 
Angela Dispenzieri, MD 
Stephen J. Russell, MD, PhD 
Mark J. Federspiel. PhD 
Kah-Whye Peng, PhD 
 
Mayo Clinic:  200 First Street, SW; Rochester, MN 55905 
Telephone: (507) 284-2511; Fax: (507) 284-2230 
 
Myeloma Institute Clinical Sub-Investigators 
Mary Burgess, MD 
Faith Davies, MD 
Christoph Heuck, MD 
Aasiya Matin, MD 
Gareth Morgan, MD, PhD 
Carolina Schinke, MD 
Sharmilan Thanendrarajan, MD 
Maurizio Zangari, MD 
Translational Research Sub-Investigators 
Tarun Garg, PhD 
Joshua Epstein, DSc 
Ricky Edmondson, PhD 
Christoph Heuck, MD 
Donald Johann, Jr. MD 
Shmuel Yaccoby, PhD 
 
The Myeloma Institute 
University of Arkansas for Medical Sciences  
4301 West Markham St Slot 815; Little Rock, AR 72205 
Telephone:  (501) 686-8230;FAX:  (501) 686-5831 
Medical Monitor 
Sarah Waheed, MD 
The Myeloma Institute  
University of Arkansas for Medical Sciences 
 
Sponsor: University of Arkansas for Medical Sciences, IND 16193 
NCT02192775 


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TABLE OF CONTENTS 
LIST OF COMMON ABBREVIATIONS ........................................................................... 4 
SCHEMA DIAGRAM ....................................................................................................... 5 
1.0 
PROTOCOL SUMMARY ....................................................................................... 6 
2.0 
BACKGROUND AND RATIONALE ....................................................................... 7 
2.1. Introduction ........................................................................................................ 7 
2.2. MV-NIS: Description ........................................................................................... 8 
2.3. MM: Need for Alternative Therapies ................................................................. 10 
2.4. Safety of MV Vaccine in MM Patients Despite Suppression of Humoral 
Immunity .................................................................................................................... 11 
2.5. MM: Susceptibility to MV-NIS Oncolytic Virotherapy ........................................ 12 
2.6. Modulating the Anti-MV Immune Response by Cy in pre-clinical studies.37 ..... 13 
2.7. Pre-Clinical Data: MV-NIS Toxicity and Biodistribution Studies ....................... 14 
2.8. Experience with MV-NIS in MM Patients .......................................................... 19 
3.0 
OBJECTIVES ...................................................................................................... 28 
3.1. Primary Objectives ........................................................................................... 28 
3.2. Secondary Objectives ...................................................................................... 28 
4.0 
PATIENT ELIGIBILITY ........................................................................................ 29 
4.1. Inclusion Criteria .............................................................................................. 29 
4.2. Exclusion Criteria ............................................................................................. 31 
5.0 
TREATMENT PLAN ............................................................................................ 31 
5.1. Dose Escalation Schedule ............................................................................... 31 
5.2. Treatment Schedule ......................................................................................... 32 
5.3. MV-NIS Dose Escalation Rules (applicable to all steps of the Rapid Dose 
Escalation Phase) ...................................................................................................... 34 
5.4. MV-NIS Dose Escalation Rules (applicable to all steps of the Slow Dose 
Escalation Phase) ...................................................................................................... 34 
5.5. Dose De-Escalation ......................................................................................... 36 
5.6. Anticipated Toxicity .......................................................................................... 36 
5.7. DLT – Definition (Table 8). ............................................................................... 37 
6.0 
SCHEDULE OF EVALUATIONS (TABLE 9) ....................................................... 38 
7.0 
DOSAGE MODIFICATION BASED ON AEs ....................................................... 40 
7.1. Rules for Dose Escalation and De-Escalation .................................................. 40 
8.0 
ANCILLARY THERAPY ....................................................................................... 41 
8.1. Supportive Care ............................................................................................... 41 
8.2. Monitoring ........................................................................................................ 41 
8.3. Patient Education ............................................................................................. 41 
8.4. Disease Communication .................................................................................. 42 
8.5. Concurrent Enrollment ..................................................................................... 42 
9.0 
AE REPORTING AND MONITORING ................................................................. 42 
9.1. AE Information ................................................................................................. 42 
9.2. Assessment of Attribution ................................................................................ 43 
9.3. Expected vs. Unexpected ................................................................................ 43 
9.4. AE Grading....................................................................................................... 43 
10.0 TREATMENT/FOLLOW-UP DECISION AT EVALUATION ................................. 44 
10.1. 
Discontinuation of Therapy ........................................................................... 44 


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10.2. 
Subject Replacement .................................................................................... 44 
10.3. 
Response Monitoring .................................................................................... 44 
10.4. 
Observation: Study Non-Completion ............................................................. 45 
10.5. 
Discontinuation Due to Toxicity ..................................................................... 45 
10.6. 
Cancelations ................................................................................................. 45 
11.0 ANCILLARY STUDIES ........................................................................................ 45 
11.1. 
Assessment of Viremia ................................................................................. 45 
11.2. 
Assessment of Immune Competence ........................................................... 45 
11.3. 
Assessment of Peripheral Immune Response .............................................. 45 
12.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY ............................... 46 
12.1. 
Overview ....................................................................................................... 46 
12.2. 
Maximum Tolerated Dose (MTD) .................................................................. 46 
12.3. 
MTD determination ....................................................................................... 46 
12.4. 
General Statistical Considerations: ............................................................... 46 
12.5. 
Analysis Plans............................................................................................... 47 
13.0 SUBSET ANALYSES FOR WOMEN AND MINORITIES: ................................... 49 
14.0 REFERENCES .................................................................................................... 51 
APPENDIX I: GUIDELINES FOR MV-NIS ADMINISTRATION ..................................... 54 
APPENDIX II: RESPONSE CRITERIA AND SURVIVAL OUTCOME DEFINITIONS ... 57 
APPENDIX III: DRUG INFORMATION .......................................................................... 60 
APPENDIX IV: SUMMARY OF AEs .............................................................................. 66 
 
 


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LIST OF COMMON ABBREVIATIONS 
AE 
Adverse Event 
AUTO 
Autologous 
BM 
Bone Marrow 
CBC 
Complete Blood Count 
CD46 
CD46 Receptor 
CMP 
Complete Metabolic Panel 
CR 
Complete Response 
CTCAE 
NCI Common Terminology for Adverse Events 
Cy 
Cyclophosphamide 
DLCO 
Diffusion Capacity of the Lung for Carbon Monoxide 
ECHO 
Echocardiogram 
EFS 
Event-Free Survival 
FEV 
Forced Expiratory Volume 
GEP 
Gene Expression Profiling 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IFNαRKOxCD46 Ge 
Interferon α Receptor Knock Out Mice Transgenic for Human CD46 
IND 
Investigational New Drug  
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
ITL 
UAMS-MIRT Immunotherapy Research Lab 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MIRT 
Myeloma Institute for Research and Therapy 
MM 
Multiple Myeloma 
MUGA 
Multi Gated Acquisition Scan 
MV 
Measles Virus 
MV-Edm 
Edmonston Strain Measles Virus 
MV-NIS 
Recombinant Edmonston Measles Virus with Human NIS Gene 
NIS 
Sodium Iodide Symporter  
OS 
Overall Survival 
PB 
Peripheral Blood 
PBMC 
Peripheral Blood Mononuclear Cells 
PBSC 
Peripheral Blood Stem Cells 
PI 
Principal Investigator 
PO 
By mouth 
PR 
Partial Response; Proliferation 
PRN 
As needed 
qRT-PCR 
Quantitative Real-Time Polymerase Chain Reaction 
SC 
Subcutaneous 
TCID50 
Tissue Culture Infectious Dose 50 
99mTcO4 
Sodium Pertechnetate 
UARK/UAMS 
University of Arkansas for Medical Sciences 
UPE 
Urine Protein Electrophoresis 
WBC 
White Blood Count 
 


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SCHEMA DIAGRAM 
 
 
 


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1.0 
PROTOCOL SUMMARY  
 
Title:  UARK 2014-21: Phase II Trial of Oncolytic Virotherapy by Systemic 
Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express 
NIS, with Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma. 
 
Primary Objectives 
 
1.1. 
To determine the clinical efficacy of oncolytic virotherapy with Edmonston 
vaccine strain measles virus (MV-Edm) engineered to express the thyroidal 
sodium iodide symporter (MV-NIS) when administered in one dose with 4 days of 
cyclophosphamide (Cy) in patients with relapsed/refractory multiple myeloma 
(MM).  Efficacy will be measured by the International Myeloma Working Group 
(IMWG) criteria. 
 
1.2. 
To determine the safety and toxicity of the intravenous administration of MV-NIS 
administered in one dose with 4 days of Cy in patients with relapsed/refractory 
MM. 
 
1.3. 
To determine whether a 4 day course of Cy can enhance the efficacy of MV-NIS 
by transiently suppressing the anti-MV response in patients with relapsed or 
refractory MM. 
 
Secondary Objectives 
 
1.4. 
To determine the time course of viral gene expression and virus elimination, and 
the biodistribution of virally infected cells at various times points after infection 
with MV-NIS when administered IV with 4 days of Cy using sodium pertechnetate 
(available as the tracer 99mTcO4) with SPECT/CT -camera imaging (SPECT/CT). 
 
1.5. 
To monitor the humoral and cellular immune responses to the infused virus. 
 
1.6. 
To assess virus replication, viremia, viral shedding in urine and saliva, and virus 
persistence after systemic administration of MV-NIS. 
 
Population: This study is for patients with relapsed/refractory MM. After 7 patients are 
enrolled, an interim efficacy analysis will be performed, if positive, 9 additional patients 
will be enrolled.  Up to 45 subjects will be screened in order to obtain a goal of 16 
participants for this study. 
 
Phase:  II 
 
Sites: One 
 
Description of Intervention:  The MV–NIS will be administered intravenously in one 
dose in conjunction with a 4 day course of Cy to transiently suppress the anti-MV 
response. 
 
Study Duration:  Two years 
 
Subject Participation Duration:  Each subject will be on the study for 1 year. 


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2.0 
BACKGROUND AND RATIONALE 
 
2.1. 
Introduction 
 
MV-NIS is an attenuated MV, engineered to express the human thyroidal 
sodium-iodide symporter (Figure 1). The virus is selectively oncolytic, targeting 
and destroying tumor cells through CD46, a membrane regulator of complement 
activation that is known to be overexpressed on many human malignancies.1-3  
CD46 is the cellular receptor for MV-NIS, mediating both virus entry and 
subsequent cell killing through cell-cell fusion.4 The cytopathic effect of MV-NIS 
increases exponentially as the density of CD46 on target cells increases and is 
therefore dramatic at high CD46 densities (tumor) but minimal at low densities 
(normal tissues). NIS expression in MV-NIS infected cells permits noninvasive 
monitoring of virus spread by serial SPECT/CT imaging of radioiodine uptake. In 
addition, the anti-neoplastic activity of the virus can be amplified by administering 
131I , a potently ionizing beta emitting isotope of radioiodine.5  MM is an incurable 
malignancy of terminally differentiated plasma cells that is widely disseminated at 
diagnosis.6  Myeloma plasma cells over-express CD46 and are therefore highly 
susceptible to MV-NIS. Also, systemic virus administration is feasible in 
advanced MM since these patients have greatly reduced circulating titers of anti-
MV antibodies. MV-NIS demonstrated considerable oncolytic potency when 
administered intravenously to rodents bearing human MM xenografts.  Also, 
intratumoral spread of the virus could be monitored non-invasively by radioiodine 
imaging and the anti-neoplastic potency of the virus was significantly boosted by 
131I.  
 
 
 
Figure 1. The MV-NIS genome. Figure courtesy of Dr. Stephen Russell, Mayo Clinic. 
 
 
The Mayo Clinic therefore conducted a phase I clinical trial to evaluate the 
efficacy and safety of MV-NIS administered intravenously in a single dose, alone 
or preceded by a single dose of Cy which has shown that  a) MV-NIS is safe at 
all dose levels tested (3 patients have been treated at the maximum feasible 
dose of 1011 tissue culture infectious dose 50 (TCID50), and b) a single dose of 
Cy has no effect on the safety profile nor on the anti-MV antibody response. 
 
We now propose to conduct a phase II clinical trial to evaluate the efficacy and 
safety of single dose MV-NIS administered intravenously to patients with 
advanced MM in combination with Cy, administered daily for four days.  
 


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Other aims are: a) the determination of the lowest effective dose by this route, b) 
perform pharmacokinetic studies to determine the location of virus-infected cells, 
c) the time course of viral gene expression, and d) the evolution of the humoral 
and cellular immune response to MV and tumor antigens. Our overall hypothesis 
is that MV-NIS administered intravenously to patients with advanced MM on day 
2 of a four day intravenous Cy protocol will selectively propagate in myeloma 
deposits throughout the body, leading to tumor cell killing and reduction of tumor 
burden. This hypothesis will be tested by serial SPECT/CT imaging after MV-NIS 
therapy to monitor the changing number and location of virus-infected cells.  
 
2.2. 
MV-NIS: Description 
MV-NIS is a live tissue culture adapted MV engineered to express the human 
NIS gene. The virus propagates selectively in human cancer cells, leading 
directly to tumor cell killing. MV-NIS-infected tumor cells express NIS, a 
membrane ion channel that actively transports iodide and other monovalent 
anions such as sodium technetate (99mTcO4)  into the cell. Radioiodine and 
99mTcO4 uptake by cells expressing NIS provides a basis for in vivo imaging 
studies to reveal the profile of MV-NIS gene expression and the location of MV-
NIS-infected cells during virus spread and elimination. MV-NIS was constructed 
by inserting the NIS gene into a full-length infectious molecular clone of an 
attenuated MV-Edm  and propagates on Vero cells with kinetics equivalent to the 
parental strain.  
 
2.2.1. MV-NIS: Mechanism of tumor targeting 
 
MV-NIS is selectively oncolytic, targeting and destroying tumor cells 
through CD46, a membrane regulator of complement activation that is 
typically over-expressed on human malignancies.1-3 CD46 is the major 
cellular receptor for MV-NIS, mediating virus attachment entry and 
subsequent cell killing through cell-cell fusion. 4 The CD46 tropism of 
attenuated MV-Edm was acquired during tissue culture adaptation7 and 
distinguishes them from wild-type MVs, which enter cells primarily 
through two alternative receptors; SLAM, expressed on activated T cells, 
B cells and monocytes8  and NECTIN-4 expressed on epithelial cells. MV-
NIS has triple tropism for SLAM, NECTIN-4 and CD46.  
 
The cytopathic effect of MV-NIS increases exponentially as the density of 
CD46 on target cells increases. Killing is therefore minimal at the lower 
CD46 densities that typify normal tissues whereas it is dramatic at higher 
CD46 densities associated with the neoplastic phenotype. CD46 
regulates complement activation by acting as a co-factor for factor 
I-mediated cleavage of C3b and thereby protects the cells on which it is 
expressed from complement-mediated lysis.1,2  Numerous studies have 
demonstrated that CD46 is expressed at higher levels on human tumors 
of many different lineages than on their non-transformed counterparts. 1,3 
Thus, MV-NIS is a new class of antineoplastic agent that targets a widely 
expressed tumor phenotype; namely, a high membrane expression of 
CD46.  
 


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Gene expression profiling (GEP, Figure 2) and flow cytometry 
demonstrates that CD46 is highly expressed on myeloma cells. 
Furthermore, CD46 is encoded for on chromosome 1q which is often 
amplified in advanced MM.9,10 supporting the notion that MV-NIS may be 
especially useful for the treatment of more aggressive, relapsed MM. 
 
 
  
Figure 2. The MV-NIS receptor CD46 is highly expressed on all molecular subtypes11 of 
MM.  Shown are CD46 expression levels measured by GEP of CD138-positive purified 
cells from healthy donors (NPC, normal plasma cells) and MM patients of the following 
molecular subgroups:  CD-1, CD-2, HY (hyperdiploidy, LB (low bone disease), MY 
(myeloid, data not available), PR (proliferation), MF (MAF/MAF-B).  MM cell lines (MMCL) 
were also analyzed.  Parentheses indicate the number of subjects analyzed. 
 
 
2.2.2. MV-NIS: Radioiodine and 99mTcO4 uptake 
 
NIS is an intrinsic membrane protein of 643 amino acids that spans the 
plasma membrane 13 times with three potential sites for N-linked 
glycosylation. NIS is a symporter that imports two sodium ions with every 
iodide ion transported into the cell. NIS expression in thyroid follicular 
cells has been exploited for more than 50 years in clinical practice for 
thyroid imaging (with 123I or 99mTcO4) or ablation (with 131I) and for 
systemic therapy of well-differentiated thyroid malignancies. 12,13  It has 
recently been shown that radioiodine is efficiently trapped by 
experimental tumors transduced with a NIS gene. 5,14-19 Non-invasive 
assessment of NIS gene expression can then be achieved through 
SPECT/CT imaging of 123I or 99mTcO4 uptake, and tumor ablation can be 
achieved by administration of 131I as a source of ionizing radiation. The 
local bystander killing potential of NIS gene therapy is considerable 
because the average tissue path-length of the  particles emitted by 131I is 
approximately 6 cell diameters.20 Tumor cell lines and primary tumor cells 


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infected with MV-NIS show efficient uptake of radioiodine or 99mTcO4 that 
can be inhibited by perchlorate, a specific inhibitor of NIS. Moreover, in 
vivo uptake of radioiodine and 99mTcO4 by MV-NIS-infected tumor 
xenografts is readily detected by 123I or 99mTcO4 SPECT/CT imaging.  
 
2.3. 
MM: Need for Alternative Therapies  
 
There has been a steady improvement in outcome in patients treated on our 
Total Therapy (TT) programs. We have recently reported that a plateau emerges 
after 10 years in patients enrolled on TT1 who remain in uninterrupted remission. 
21  By incorporating bortezomib and thalidomide into induction, consolidation, and 
maintenance, the projected 10 year event free survival in TT3 is in excess of 
60%.22 These tremendous advances suggest that ‘cure’ is now well within reach 
for a significant proportion of MM patients. By systematically performing GEP on 
newly diagnosed MM patients enrolled in TT2 and TT3, 70 key genes, which are 
either highly up- or down-regulated, have been identified (GEP70) allowing for 
the calculation of a risk score that is highly correlated with outcome.10  Patients 
with so-called ‘low-risk MM’ do substantially better in TT3 compared with TT2 in 
terms of CR-duration and EFS. However, approximately 15% of newly diagnosed 
MM patients have a high-risk gene score associated with an unacceptably poor 
outcome. At disease relapse, the percentage of patients with a high-risk gene 
signature may be as high as 75%.10  Remission can easily be achieved in these 
high-risk patients, but disease control is of short duration due to rapid regrowth of 
chemotherapy-refractory MM cells, and overall survival remains poor. 
Furthermore, a new study calculating a risk score based on 80 genes which are 
either highly up- or down-regulated 48 hours after a bortezomib test dose, 
demonstrated that this score correlates significantly with outcome. 23  Importantly, 
the 80-gene GEP model (GEP80) also distinguished outcomes when applied at 
baseline. In the context of the validated 70-gene model (GEP70), the GEP80 
model identified 9% of patients with a grave prognosis among those with GEP70-
defined low-risk disease.  Interestingly, many of these high-risk associated genes 
map to chromosome 1. We and others have shown that amplification of 
chromosome 1q also confers a poor prognosis (Figures 3, 4).9,10 
 
Other poor cytogenetic indicators conferring worse outcome are deletions of 17p 
and hypodiploidy as recognized by the mSMART classification of high- versus 
low-risk MM promulgated by the Mayo Clinic. 24 Further, we have shown that 
MDS features in MM resulting from inherent genomic instability in the myeloma 
clone(s) also prognosticate for an adverse outcome. 25  It has long been 
recognized that LDH, in corollary to lymphoma, reflects tumor mass and is often 
associated with extramedullary MM disease. LDH is therefore also an important 
adverse prognostic factor.26  
 


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Figure 3. Amplification of the chromosome 1q region is a common phenomenon in MM and the 
copy number of 1q increases at the time of relapse. 
CR
EFS
OS
 
Figure 4. Patients with 3 or more copies of chromosome 1q have an increased relapse rate 
explaining poorer EFS and OS. 
 
 
2.4. 
Safety of MV Vaccine in MM Patients Despite Suppression of Humoral Immunity  
 
Wild-type MV causes a well-described illness characterized by fever, rash, upper 
respiratory tract symptoms and transient immunosuppression.27 The case fatality 
rate in the United States of America is 0.1 to 0.2 %, but is higher in 
underdeveloped countries where opportunistic infections secondary to MV 
immunosuppression are a more significant problem. At the other end of the 
spectrum, live attenuated MV vaccines have been used extensively. In the USA 
alone, more than 550 million doses of MV vaccine have been distributed to date. 
Several different members of the MV-Edm lineage have been used for 
vaccination, and all of them are capable of causing a mild MV-like illness in some 
variable percentage of vaccines.28  It is therefore anticipated that some MV-NIS-
treated patients may develop a MV-like illness. However, in the entire history of 
MV vaccination, no case of reversion of vaccine strain to wild-type MV has been 
documented, and only 6 deaths have been reported due to uncontrolled spread 
of the vaccine strain virus in severely immunocompromised individuals. In 
contrast to their effects in non-immune subjects, neither wild-type nor attenuated 
MVs cause a MV-like illness in patients previously exposed to the virus.28 
 
MM is unique amongst human malignancies in that because of the associated 
suppression of humoral immunity, systemic administration of a therapeutic virus 
is feasible, even if previous virus exposure has occurred. Successful deployment 
of oncolytic viruses for the treatment of disseminated malignancy requires 


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efficient delivery to tumor sites via the bloodstream, which can be inhibited by 
antiviral antibodies.29  Oncolytic virotherapy is therefore less likely to be effective 
when there is preexisting antiviral immunity. MM is characterized by profound 
suppression of humoral immune responses with hypogammaglobulinemia, 
typically affecting IgG, IgA and IgM fractions.30-32  Antibody titers against common 
vaccine antigens (e.g., MV, mumps, rubella, diphtheria and tetanus) are greatly 
reduced33,34 and immune responses following vaccination are considerably 
impaired.32,35.  At the Mayo Clinic stored serum samples from patients with 
heavily pretreated MM and age-matched controls were tested for anti-MV 
antibody titer and it was found that sera obtained from MM patients often 
contained very low levels of anti-MV antibody, in keeping with published 
observations.  
 
The MV-mumps-rubella (MMR II) vaccine (Merck) delivers 103 
to 104 
infectious 
units of live attenuated MV to each human recipient. Patients who undergo 
autologous or allogeneic stem cell transplantation lose immune memory for past 
exposure to infectious agents and vaccines and therefore require a re-
vaccination strategy which typically includes live-attenuated MV-mumps-rubella 
vaccine at 24 months post-transplant. Thirty-six MM patients (M:F – 23:13) who 
received their transplant and routine 2 year post-auto peripheral blood stem cell 
transplant (PBSCT) vaccination with MMR II were retrospectively studied at the 
Mayo Clinic. MMR II re-vaccination was delivered an average of 799 days 
(range: 539 - 1209) days after PBSCT. Follow-up time after re-vaccination 
averaged 755 days (range: 56 - 2345). Thirty-three of the 36 patients studied, 
remain alive. Most of these patients have experienced disease relapse requiring 
treatment. Eleven patients continue under observation without treatment since 
their original PBSCT. Overall, there was no significant change after re-
vaccination in the patients' absolute lymphocyte counts or immunoglobulin levels, 
nor was there significant change in the monoclonal protein levels. Importantly, no 
specific toxicities were documented following MMR administration. While 5 
patients did have a small decrease in monoclonal protein level, averaging only 
0.42g/dL (range: 0.1- 1.2) after re-vaccination, 2 out of the 5 were not recently 
treated for relapsed disease. One of these 5 patients continues to live relapse 
free without treatment and with a stable monoclonal protein. These data strongly 
suggest that conventional doses of MMR vaccine administered by intramuscular 
injection are safe, but inadequate for expression of oncolytic activity in patients 
with MM.  
 
2.5. 
MM: Susceptibility to MV-NIS Oncolytic Virotherapy 
 
Neoplastic plasma cells from MM patients express higher levels of CD46 
compared to normal marrow elements and unstimulated peripheral blood 
lymphocytes and MM cells are fully susceptible to infection by MV-NIS. In a 
laboratory study, CD138-positive myeloma cells from 5 patient bone marrow 
(BM) aspirates were infected with MV-NIS, and radioiodine uptake was 
measured 48 hours later. In addition to the classical MV cytopathic effect of cell-
cell fusion, the infected cells were shown to efficiently concentrate radioiodine 
achieving intracellular concentrations 50 fold higher than that of the incubation 
medium. Similarly, MV expressing a fluorescent GFP marker protein could 
efficiently fuse and kill MM cells but not non-transformed cells (Figure 5).36 


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Figure 5.  CD138-positive myeloma cells overexpress CD46 and are efficiently targeted 
by MV-GFP. Myeloma cells take up MV-GFP (A) and demonstrate much higher levels of 
MV receptor expression (B). CD138-negative,normal cells do not take up MV-NIS. 
 
 
Intravenous MV-NIS is a potent oncolytic agent in MM xenograft models. MM 
cells (ARH77, RPMI8226, KAS 6/1, MM1S) were implanted subcutaneously into 
the flanks of athymic or SCID mice and the mice were treated intravenously with 
MV-NIS or MV-Edm (identical sequence to MV-NIS but lacking the NIS gene). 
Intravenous administration of MV-Edm caused complete regression of ARH77 
xenografts and significantly slowed the progression of RPMI8226 xenograft 
growth. Moreover, a single intravenous dose of MV-NIS led to complete 
regression of large (0.5 mm diameter) KAS 6/1 xenografts.36 
 
2.5.1. Therapy models: Noninvasive imaging of MV-NIS 
 
Intratumoral spread of MV-NIS was non-invasively evaluated by serial -
camera imaging in 3 MM xenograft models. SCID mice bearing 
subcutaneous ARH77, KAS 6/1 or MM1 MM xenografts were injected 
intravenously with a single dose of MV-Edm or MV-NIS (2 x 106 IU). 
Three, 9 and 17 days later, 123I (18.5 MBq) was administered and -
camera imaging performed after 1 hour. All tumors treated with the 
control virus MV-Edm were negative by -photon imaging, whereas all 
MV-NIS treated tumors were able to concentrate radioiodine and could be 
visualized by -camera imaging. Analysis of the changing image intensity 
over the period of 17 days established that NIS expression peaks 
approximately 9 days after virus injection, presumably reflecting the 
maximum extent of the virus infection. 
 
2.6. 
Modulating the Anti-MV Immune Response by Cy in pre-clinical studies.37 
 
Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies 
whose titers increase progressively with each exposure, resulting in faster virus 
inactivation and further reductions in efficacy with each successive dose. A single 
dose of Cy at 370 mg/m2 was not sufficient to control the primary antiviral 
immune responses in mice, squirrel monkeys and humans. We therefore tested 
clinically approved multidose Cy regimens, which are known to kill proliferating 


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lymphocytes, to determine if more intensive Cy therapy can more effectively 
suppress antiviral antibody responses during virotherapy. In virus-susceptible 
mice, primary antibody responses to intravenously (IV) administered oncolytic 
MV or vesicular stomatitis virus were partially or completely suppressed, 
respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) Cy regimens 
initiated 1 day before virus. When MV- or vesicular stomatitis virus-immune mice 
were re-challenged with the respective viruses and concurrently treated with four 
daily systemic doses of Cy, their anamnestic antibody responses were 
completely suppressed and antiviral antibody titers fell significantly below pre-
booster levels. We conclude that the Cy regimen of four daily doses at 
370 mg/m2 should be evaluated clinically with IV virotherapy to control the 
antiviral antibody response and facilitate effective repeat dosing. 
 
2.7. 
Pre-Clinical Data: MV-NIS Toxicity and Biodistribution Studies 
 
2.7.1. Biodistribution in CD46 transgenic, interferon α/β receptor knockout 
(IFNRKO 
x CD46 Ge) mice 
 
Normal mice are not susceptible to MV infection, including wt-MV, MV-
Edm strain, and MV-NIS. However, mice transgenic for human CD46 
express the MV receptor and are permissive to infection. To further 
enhance the potential adverse effects of MV-NIS, mice were created 
which were both transgenic for CD46 and had a knock-out of the IFNR. 
IFNs are usually produced upon viral infection and render cells non-
permissive to viral replication.  As part of preclinical studies to evaluate 
MV-NIS, sensitive quantitative RT-PCR (qRT-PCR) methodology was 
developed in order to characterize tissue distribution of the virus in non-
tumor bearing transgenic IFNRKO 
x CD46 Ge mice that express human 
CD46 with human-like tissue distribution. Groups of male and female 
mice (10 mice/gender/treatment group) were given IV doses of vehicle or 
MV-NIS, 105 
TCID50, 107 
TCID50 or 107 
TCID50 + 125 mg/kg Cy.  MV-NIS 
tissue distribution was studied non-invasively by Micro-SPECT/CT 
imaging 4, 21 and 90 days after a dose of 0.5 mCi 123I. MV-NIS 
expression in tissues was measured 2, 5, 22 and 91 days after treatment 
(5 mice/gender/treatment group) by quantitative RT-PCR. Imaging 
studies showed that functional NIS was not detected in tissues other 
than those with normal expression after administration of MV-NIS. 
Highest concentrations of MV-NIS (> 10,000 MV-NIS RNA copies/ µg 
total RNA) appeared in lung, liver, spleen and blood of both male and 
female mice 2 days after administration of 107 
TCID50 +/- Cy. Cy did not 
delay clearance of MV-NIS from tissues. Blood concentrations 
remained high on day 5, and fell to undetectable levels in blood on day 91. 
Lung and liver concentrations fell to undetectable levels by day 91. 
Spleen concentrations were substantially lower on day 5 and day 22, and 
detectable in only 5 of 24 mice given high dose MV-NIS +/- Cy on day 91. 
277 – 44093 (median, 440) copies MV-NIS/ µg total RNA were detected 
in brain in 3/10 mice on day 2, 2/10 mice on day 5, 3 of 10 mice on day 
22, and 3 of 16 mice on day 91. The positive samples were detected only 
in mice treated with 107 
MV-NIS + Cy.  


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2.7.2. Toxicity of MV-NIS in IFNRKO 
x CD46 Ge mice 
 
Table 1 summarizes the test groups for MV-NIS murine studies.  
According to the protocol 144 IFNRKO 
x CD46 Ge mice (12/sex/dose 
group), approximately 6 to 8 weeks old on the first day of dosing were 
randomly divided into 6 dose groups and treated with one or both of the 
test articles (MV-NIS [NSC-731414] and Cy [NDC# 0015-0547-41]) or the 
control article (MV-NIS vehicle [5% sucrose, 50 mM Tris-HCl, pH 7.4, 
2mM MgCl2] diluted as per Test Article). Cy was at 125mg/kg given 2 
days prior (Day -2) to MV-NIS in order to modulate the immune response 
to MV-NIS. Cy and MV-NIS were given as a single intravenous bolus 
injection through the tail vein. On study days 2, 5, 22, and 91 six 
mice/dose group were euthanized and a complete necropsy examination 
was performed. Protocol-specified tissues were preserved in 10% neutral-
buffered formalin (NBF) and sent to Pathology Associates International’s 
Frederick, MD facility, which conducted the remainder of the analysis on 
those samples. 
 
Table 1. Summary of murine protocol groups 
Dose 
Group 
Cy (mg/kg) 
MV-NIS 
(TCID50) 
1 
0 
0* 
2 
125 
0* 
3 
0 
10
4 
4 
0 
10
5 
5 
0 
10
6 
6 
125 
10
6 
*MV-NIS Vehicle  
 
Mayo Clinic Toxicology Core ran the in-life portion of the studies, 
including monitoring clinical signs and weights daily the first week post 
article administration and weekly thereafter. At time of necropsy, final 
weights were taken, and mice were bled from the retroorbital plexus. 
Blood parameters analyzed included: hematology (white blood cell count, 
lymphocyte percent, monocyte percent, granulocyte percent, red blood 
cell count, mean corpuscular volume, hematocrit, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, red cell 
distribution width, hemoglobin, platelet count, mean platelet volume, and 
platelet 
distribution 
width); 
clinical 
chemistry 
(albumin, 
alkaline 
phosphatase, alanine aminotransferase, amylase, total bilirubin, blood 
urea nitrogen, calcium, phosphorus, creatinine, glucose, sodium, 
potassium, total protein, and globulin); and coagulation (prothrombin time 
and activated partial thromboplastin time). Plasma was also collected for 
anti-MV antibody titers. The in vivo portion of the study started March 7th, 
2005 and ended June 8th, 2005. There were no clinical signs or deaths 
considered to be related to the test articles MV-NIS or Cy. Body 
weights showed no signs of MV-NIS toxicity. Mice from Groups 4 and 5 


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developed robust anti-MV titers at the later time points of days 22 
and 91 post-virus administration. In contrast, the lowest dose of virus 
(1x104 
TCID50) in Group 3 mice induced poor to non-detectable titers post 
single administration, indicating that greater than 1x104 
TCID50 of MV-NIS 
is needed intravenously for the mice to mount an effective antibody 
response.  
 
In Groups 1, 3, 4, and 5, there were no toxicological findings in the 
hematology or coagulation that were considered to be related to the 
administration of MV-NIS. In clinical chemistry, there were sporadic mild 
elevations in ALT in 3 virus treated mice that were not correlated with any 
pathological changes in the liver. Total protein levels were mildly elevated 
in Groups 3, 4, and 5 as compared to control Group 1. This rise in total 
protein and/or globulin in virus-treated groups was likely due to the 
production of anti-MV immunoglobulin. Groups 4 and 5 BUN levels were 
mildly decreased as compared to control Group 1, but were not 
accompanied by any pathologic changes in the kidneys. These changes 
were considered related to the administration of MV-NIS, but not of 
significant toxicity.  
 
In Groups 2 and 6, there were no toxicological findings in coagulation that 
were considered to be related to the administration of MV-NIS. In 
hematology, the total WBC in Group 6 was depressed as compared to 
Group 2, suggesting that the additional challenge of MV-NIS to mice pre-
treated with Cy further suppressed the WBC. In clinical chemistry, there 
were sporadic mild elevations of creatinine considered to be related to the 
administration of MV-NIS, though the mice with elevated creatinine did 
not correspond to mice that showed changes in kidney pathology.  
 
Upon histological analysis of mouse tissues, there were no 
toxicologic findings in tissues considered to be related to the 
administration of MV-NIS. Mice receiving pre-treatment with Cy showed 
changes in the lymphoid organs (mandibular and mesenteric lymph 
nodes, thymus, and spleen), urinary bladder, BM, testes and ovaries that 
were considered to be related to the administration of Cy at the day 2 
sacrifice. The Cy-related changes showed evidence of recovery in later 
time points.  
 
2.7.3. Imaging study of iodine biodistribution in MV-NIS treated squirrel 
monkeys  
 
Two male squirrel monkeys (Saimiri sciureus) received a single 
intravenous dose of 108 
TCID50 MV-NIS. NIS expression in tissues was 
evaluated by noninvasive SPECT/CT imaging of 123I biodistribution at 
baseline and on days 3, 8, 15 and 22 after MV-NIS administration. 
Images were obtained at 1 and 2 hours after isotope administration. The 
isotope localized to the thyroid, stomach, salivary glands and 
bladder at all timepoints and the biodistribution did not change 
following MV-NIS administration.  
 


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2.7.4. Safety study of intravenous MV-NIS in squirrel monkeys with and without 
Cy  
 
This study was performed by IIT Research Institute (IITRI) in Chicago, IL 
through the NCI RAID program (Rapid Access to Intervention 
Development). According to the protocol, 12 male squirrel monkeys 
(Saimiri sciureus, 3/group) were intravenously dosed once with either MV-
NIS or control article (saline) on study day 1. Animals in Groups II and IV 
were intravenously dosed once with Cy on study day 2. Two monkeys per 
group were sacrificed on study day 29, and the remaining animals were 
sacrificed on study day 91. See table below.  
 
All monkeys were evaluated for mortality/morbidity twice daily throughout 
the treatment and observation periods. All monkeys were observed for 
abnormal clinical signs at least once daily. Body weights were recorded 
on days 1, 8, 5, 29, and 91 and body temperatures were recorded pretest, 
3 hours post-dosing on day 1 and on days 2 through 5 and 8. Clinical 
chemistry and hematology parameters were evaluated at the pretest and 
on days 3, 10, 15, 29, and 91. Thyroid hormone levels (TSH and T4 
levels) were evaluated on days 29 and 91. Cytokine levels (IL-1, IL-6, IL-
12 and TNF levels) were evaluated on days 1, 4, 8, 29 and 91. Anti-MV 
antibody levels were evaluated at the Mayo Clinic, Rochester, MN, on 
days 8, 15, 29, and 91. Samples containing epithelial cells and saliva 
were collected pretest and on days 1, 4 8, 29 and 91, and blood samples 
were collected on days 1, 4, 8, 29, and 91. MV-NIS levels were 
determined from these samples by PCR at the Mayo Clinic, Rochester, 
MN. Two monkeys/group were sacrificed on day 29, and the remaining 
animals were sacrificed on day 91. Tissues were collected, examined and 
fixed in 10% neutral buffered formalin at necropsy. Samples of all fixed 
tissues were embedded and put into blocks. Microscopic pathology was 
performed on all tissues. Statistical analysis of continuous data through 
day 29 were performed using analysis of variance with post-hoc 
comparisons made using Dunnett’s test with a minimum significance level 
of p≤ 0.05.  
 
There were no premature or unscheduled deaths during the study. 
No adverse clinical signs were observed during the study. No 
meaningful effects on body weights or body weight gains were noted 
during the study. There were no treatment-related effects noted for any 
clinical pathology parameters evaluated (hematology and clinical 
chemistry). No changes were observed in cytokine levels during the study. 
Lesions observed at necropsy included enlarged, dark-pigmented lymph 
nodes, small thymus and red focus on medial lobe of liver. All gross 
findings were interpreted as incidental and not treatment-related. No 
treatment-related histopathologic changes were observed.  
 
Table 2:  MV-NIS in squirrel monkeys with and without Cy  
 
Grp # 
MV-NIS 
(TCID50) 
Cy 
(mg/kg) 
Monkey
# 
Pre-
Dose* 
d1* 
d2* 
d8* 
d15* 
d29* 
d91* 


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I 
0 (Control) 
0 
775 
<100 
<100 
<100 
<100 
<100 
<100 
 
I 
0 (Control) 
0 
793 
<100 
<100 
<100 
<100 
<100 
<100 
 
I 
0 (Control) 
0 
803 
<100 
<100 
<100 
<100 
<100 
<100 
<100 
II 
0 (Control) 
31 
756 
<100 
<100 
1230 
<100 
<100 
<100 
 
II 
0 (Control) 
31 
770 
<100 
<100 
<100 
<100 
<100 
<100 
 
II 
0 (Control) 
31 
810 
<100 
<100 
<100 
<100 
<100 
<100 
<100 
III 
10e8 † 
0 
772 
<100 
1660 
<100 
1455 
<100 
<100 
 
III 
10e8 † 
0 
812 
<100 
<100 
<100 
<100 
<100 
<100 
 
III 
10e8 † 
0 
823 
<100 
66950 
<100 
896500 
8830 
<100 
<100 
IV 
10e8 † 
31 
817 
<100 
2270 
<100 
988500 
5880 
<100 
 
IV 
10e8 † 
31 
818 
<100 
53850 
955 
246500
0 
237987
0 
960 
 
IV 
10e8 † 
31 
819 
<100 
150250 
2520 
516000 
4590 
690 
<100 
TCID50, tissue culture infectious dose which will infect 50% of the cell monolayers challenged with the defined 
inoculum; Cy, cyclophosphamide; * Data represents copies of MV N-gene in 1.0µg RNA extracted from buccal cheek 
scrapes; † Dose = 108 or the highest dose available from Mayo Clinic Viral Vector Production Facility 
 
qRT-PCR on cheek swabs is summarized in Table 2. There was no virus 
detected at any time point for Groups I and II. However, in Groups III and 
IV there were low levels of viremia on day 1, which dropped by day 2, but 
increased significantly by day 8 to 15, but again dropped by days 29 and 
91. Anti-MV IgG antibodies remained undetectable in Groups I and II, but 
in Groups III and IV became detectable by day 15 and persisted through 
day 29 and 91.  
 
Based on the foregoing preclinical observations, it was concluded MV-
NIS is a highly promising CD46-targeted oncolytic agent that merits 
clinical testing in patients with MM. Not only does the virus have 
interesting and novel target specificity with associated single agent 
activity, but its biodistribution can also be non-invasively monitored in vivo 
allowing clinical validation of its ability to interact with its known molecular 
target, CD46.  
 
The risks associated with MV-NIS administration to MM patients were 
considered to be acceptable due to the vast knowledge base concerning 
the toxic effects of closely related viruses in the human population. Wild-
type MV causes a well-described illness characterized by fever, rash, 
upper respiratory tract symptoms and transient immunosuppression.27  
The case fatality rate in the United States of America is 0.1 to 0.2 %, but 
is higher in underdeveloped countries where opportunistic infections 
secondary to MV immunosuppression are a more significant problem. At 
the other end of the spectrum, live attenuated MV vaccines have been 
used extensively. In the USA alone, more than 550 million doses of MV 
vaccine have been distributed to date. Several different members of the 
MV-Edm lineage have been used for MV vaccination, and all of them are 
capable of causing a mild MV-like illness in some variable percentage of 
vaccines.38-44  It is therefore anticipated that some MV-NIS-treated 
patients may develop a MV-like illness. However, in the entire history of 
MV vaccination, no case of reversion of vaccine strain to wild-type MV 
has been documented, and only 6 deaths have been reported due to 


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uncontrolled spread of the vaccine strain virus in severely immune-
compromised individuals. In contrast to their effects in non-immune-
compromised subjects, neither wild-type nor attenuated MVs cause a MV-
like illness in patients previously exposed to the virus.40,45 Further studies 
in IFNRKO 
x CD46 Ge mice and new world primates, both with and 
without co-administration of Cy revealed no toxicities. Based on these 
pre-clinical observations a clinical trial was initiated at the Mayo Clinic 
with MV-NIS in MM. 
 
2.8. 
Experience with MV-NIS in MM Patients 
 
MV-NIS doses, and preliminary efficacy of MV-NIS administered intravenously 
with and without Cy in patients with relapsed or refractory MM.  
An ongoing clinical trial entitled Systemic Administration of Edmonston Strain of 
MV, Genetically Engineered to Express NIS, with or without Cy, in Patients with 
Recurrent or Refractory MM opened to patient enrollment on January 15, 2007 at 
the Mayo Clinic, and the first patient was registered 2/23/07. Overall, 31 patients 
have been enrolled, 30 have been treated and the trial is currently at Stage 
3/dose level 2. Stage 1 of the trial, which included 4 dose levels of single agent 
MV-NIS has been completed. Three patients each were treated with 105, 106, 107 
and 108 TCID50 MV-NIS.  For Stage 2, eight patients were treated with low dose 
(10mg/kg) Cy prior to MV-NIS at TCID50 dose levels of 107, 3x107, 9x107. Since 
MTD was not reached at maximum feasible dose of 109 TCID50 without Cy, the 
first patient treated with Cy received 107 TCID50. per FDA mandate, with the dose 
escalating by 3-fold rather than 10-fold. For Stage 3, a new manufacturing 
method was used to generate higher titers of MV-NIS and three patients have so 
far been treated with 1010 TCID50 MV-NIS (June 4, 2012) and three patients 
treated at the maximum feasible dose of 1011 TCID50 (July, 2013). Among the first 
20 evaluable patients (Stage 1 and Stage 2), no myeloma responses were seen, 
nor were any dose limiting toxicities observed. A summary of adverse events 
(AEs) are shown in Appendix IV. In the first cohort of 3 patients enrolled in 
Stage 3, receiving a single intravenous dose of 1010 TCID50 MV-NIS, there have 
been no dose limiting toxicities and one patient had a significant reduction in his 
monoclonal protein level during the first 10 days after virus administration. Three 
further patients have received a single intravenous dose of 1011TCID50 MV-NIS. 
Two of these three had neutralizing antibodies and there were no AEs and no 
responses. One patient had a low titer of MV antibody. This patient did have a 
marked response with shrinkage of a large skull plasmacytoma and reduction in 
paraprotein levels. Adverse effects included fever and transient 
thrombocytopenia.  
 
Characterization of NV-NIS gene expression using 123I and SPECT/CT imaging 
and correlation with disease distribution. 
Scans have been completed for 29 patients and tumor uptake was seen in 6, one 
in Stage 1, dose level 1 (Figure 6), one in Stage 2, dose level 1 (Figure 7), two 
in Stage 2 dose level 2 (data not shown), two in Stage 3 dose level 2 (data not 
shown). Neither the baseline PET or SPECT had uptake, but a lytic bone lesion 
was visible on bone windows of the CT. Factors predicting for positive 123I 
SPECT/CT scans included lower baseline WBC (3.2 versus 4.5, p=0.01) and 
viral dose (p=0.05).  


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Baseline FDG-PET/CT
Day +8 123I SPECT/CT
A
B
Baseline FDG-PET/CT
Day +8 123I SPECT/CT
Baseline FDG-PET/CT
Day +8 123I SPECT/CT
A
B
 
 
Figure 6. 123I uptake by an MV-NIS infected myeloma deposit (Pt#2, Stage 1, Dose Level 
1).  A. Pre-treatment FDG-PET/CT. B. Day 8, 123I SPECT/CT, 6-hour measure. 
 


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Day -1 123I SPECT/CT
Day +8 123I SPECT/CT
Day -1 123I SPECT/CT
Day +8 123I SPECT/CT
Day -1 123I SPECT/CT
Day +8 123I SPECT/CT
 
 
Figure 7. 123I uptake by an MV-NIS-infected myeloma deposit (Pt#13).  123I SPECT/CT, 
6-hour measurement at baseline and 8 days post MV-NIS administration.  Orange 
represents gastric contents; Yellow arrow shows 123I uptake by myelomatous vertebral 
lesion; Sputum and urine were also PCR positive 8 days post MV-NIS administration. 
 
Characterization of the time course of expression, replication, biodistribution, and 
shedding of MV-NIS and correlation of these parameters with CD46 expression 
in myeloma cells, dose level, & toxicity 
 
Viral clearance in first 6 hours: A protocol modification went into effect in the 
3rd quarter of 2010 that provided for measurement of viral clearance over first 24 
hours after MV-NIS treatment. PK studies are available for 6 patients treated at 
1010 (patients 10.1 to 10.3) and 1011 TCID50 (patients 11.1 to 11.3). These data 
are shown in Figure 8. At higher dose levels, more virus persists in the 
circulation and this was observed beyond 4 hours. 
 
Figure 8. Quantitative RT-PCR showed that more virus persists in the circulation 
of patients receiving higher dose levels of MV-NIS.  
Specificity of MV-NIS for myeloma cells: BM samples harvested pre-therapy 
were sorted into CD138-positive myeloma cells and CD138-negative non-
myeloma cells prior to infection with MV-GFP. Note the preferential infectivity of 
CD138 positive (myeloma cells) as compared to CD138 negative cells (other BM 
cells) in Figure 9. 


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Figure 9. Neoplastic CD138-positive myeloma cells (blue bars) from BM of trial patients 
Figure 9. CD138+ myeloma cels are preferentially infected by MV-GFP (red bars are 
CD138-negative marrow cells). 
 
 
Figure 10. Cell plot of N-gene qRT-PCR results by dose level and MV neutralization 
antibody titer for patients on study (Red, positive; Green, negative; White, not analyzed). 
 
Time course of viral shedding: To date, virus has been detected in sputum, 
urine and blood of some patients on days 3, 8 and 15, but not in day 42 BM 
samples (data not shown). The time points one is most likely to detect shed virus 
are days 8 and 15 (Figure 10). Viral persistence is rare at day 22 and beyond; 
the one exception was patient #7. Respiratory shedding (sputum swab) was most 
common, even at low doses of virus. In contrast, urine shedding was not seen 
until dose of 108 TCID50 & blood not until 109 TCID50.  


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There was a trend toward viral genome shedding into the urine among those 
patients with a lower CD46 density on their CD138-negative (non-myeloma BM) 
cells, 6,668 versus 8,367 CD46 copies/cell, p=0.05. Although the ex vivo 
infectivity of cells with MV-GFP was associated with CD46 density on cells, there 
was no apparent relationship between ex vivo infectivity and in vivo viral 
shedding.  
 
Characterization of humoral and cellular immune response to intravenously 
injected MV-NIS and correlation with toxicity, viremia, and NIS expression. 
 
Most patients had very low anti-MV antibody titers at baseline which boosted 
significantly by week 6, both by enzyme immunoassay (Diamedix assay, Figure 
11) and by plaque reduction virus neutralization (Figure 12). Antibody titers also 
boosted in patients 13 to 20 receiving Cy.  Patient 27 had a major response to 
MV-NIS. 
 
 
Figure 11. Anti-MV antibody titers (EU/mL) before (blue bars) and 6 weeks after 
(red bars) MV-NIS therapy. 20 EU/mL is considered seropositive. 
 


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Figure 12. Anti-MV antibody titers measured by plaque reduction neutralization assay 
before (blue bars) and 6 weeks after (red bars) MV-NIS therapy. 
 
Relationships between other baseline and 6 week immune parameters were 
studied (data not shown). At baseline patients had low lymphocytes (CD45 cells),  
helper T cells (CD4 cells), normal T cells (CD3), and B cells (CD19). At 6-weeks 
post therapy, there were significant, but modest increases in B cells and T helper 
cells (p<0.05). T-cell immunity to MV as measured by IFNγ ELISA and ELISPOT 
was severely impaired and there was no difference between baseline 
measurements and 6-weeks post treatment.  
 
2.8.1. 
Recent Developments  
 
In the ongoing clinical trial at Mayo Clinic MV-NIS was administered 
intravenously to 28 patients with advanced treatment refractory myeloma 
at doses up to 1011 TCID50, with or without low dose Cy. With its intensive 
in vivo imaging and lab correlative studies, this trial is the most 
comprehensive phase I/pharmacokinetic oncolytic virus study yet 
conducted.  MV-NIS has been very well tolerated at the doses tested and 
positive radioiodine imaging studies in 6 patients prove that circulating 
virus can extravasate and selectively amplify at sites of myeloma tumor 
growth, that NIS is a valid reporter gene for human applications, and that 
the intratumoral spread of the virus can be monitored independently even 
when it is co-administered with another drug.  However, there have also 
been significant limitations in the trial: 1) The very low dose of Cy tested 
in the clinical trial was insufficient to suppress the anti-MV antibody 
response or to impact the intratumoral spread of the virus, 2) the 
experience with the three patients treated at 1011 with the single 
responder being a patient with a low anti-MV antibody therapy 
emphasizes the need for suppressing MV antibody responses.  Further, 
the Mayo Clinic group has shown that higher intensity, clinically- 
approved, Cy protocols can efficiently and safely suppress the anti-MV 
antibody response in MV-susceptible mice (see section 2.6). Lastly, 
patients with high titers of anti-MV antibody will be excluded since studies 


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at the Mayo Clinic have shown that these patients neutralize MV-NIS and 
abrogate the oncolytic phase, Approximately 50% of patients do not have 
anti-MV antibody. 
 
In light of these observations and developments the following refinements 
of the clinical trial are now being pursued: 
 
a) Dose escalation will be started at doses of 1010 since doses up to 1011 
have been well tolerated.  This will commence after the completion of a 
Rapid Dose Escalation Phase to enroll 4 subjects starting at 108.  See 
Sections 5.1, 5.2, 5.3, 5.4. 
 
Due to manufacturing limitations, the original clinical studies (Stages 1 
and 2) previously used a maximum dose of 109 TCID50 MV-NIS, only 
three times higher than the minimum effective mouse dose (Figure 13). 
Figure 13 shows that the minimum effective dose was 105 (equivalent 
human dose 3 x 108) but tumor regression was delayed at this dose 
level. Rapid tumor control required a dose of 106 or higher (equivalent 
human dose >3 x 109). 
 
Even at this low clinical dose it was shown that MV-NIS can traffic via the 
bloodstream to the tumor, infect the tumor cells, amplify selectively in the 
tumor and then be eliminated by the immune system. There was 
therefore a strong rationale to push the dose of MV-NIS to higher levels 
and this is ongoing (Section 2.8).  
 
Recently developed improvements to Good Manufacturing Practice 
procedures will allow for the production and administration of higher titers 
of MV-NIS to MM patients. 
 
 
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
0
500
1000
1500
2000
2500
3000
UV-inactivated
104 MV-NIS
105 MV-NIS
106 MV-NIS
107 MV-NIS
Time After Therapy (days)
Tumor Volume (mm
3)


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Figure 13. MV-NIS to treat KAS6/1 MM xenografts.  Preclinical studies using 
intravenous MV-NIS to treat KAS6/1 MM xenografts are shown. Five groups of 10 
irradiated SCID mice age six to eight weeks were implanted subcutaneously with 
107 KAS-6/1 tumor cells in 100 L of normal saline in the right flank. When tumors 
reached 0.5 cm in diameter, control mice received a single intravenous injection of 
200 L of UV inactivated MV-NIS. Test mice received a single intravenous injection 
of live MV-NIS at a dose of 104, 105, 106 or 107 TCID50.  
 
 
b) Suppressing the anti-MV immune response by 4 days rather than one day 
of treatment with Cy to prevent immediate viral neutralization and hence 
intratumoral spread of the virus to enhance oncolytic efficacy 
 
c)   Only patients who have an anti-MV IgG antibody titer of <0.3 U/mL will be 
eligible for study. 
 
 
2.8.2. Improving immune suppression to allow for longer MV-NIS exposure 
 
The small dose of Cy employed in the ongoing clinical trial at the Mayo 
Clinic, administered 4 hours prior to virus infusion, had no discernible 
impact on anti-MV antibody responses. However, in parallel with the 
ongoing clinical trial Mayo Clinic investigators have evaluated more 
intensive Cy regimens in MV-susceptible transgenic mice and shown that 
4 days of Cy can suppress the anti-MV response. 
 
2.8.3. “High-dose” and “low dose” Cy regimens are potently suppressive to the 
primary anti-MV antibody response in MV-susceptible mice. 
 
IFNRKO x CD46 Ge mice aged 6-8 weeks were immunized by 
intraperitoneal challenge with MV-NIS administered once. Antibody titers 
were measured by immunofluorescence assay using Bion antigen 
substrate slides four weeks later. Various Cy dosing regimens were 
tested (5mg, 4mg, 3mg, 2.5 mg IP daily for four days) or 1.8 mg, 1.5 mg, 
1.3 mg by oral gavage daily for eight days) with the conclusion that 3 mg 
Cy IP per day for four days is the maximum that our mice can tolerate. 
The low dose regimen of 1.3 mg per day by oral gavage for eight days is 
also well tolerated. All mice were immunized with MV one day after 
initiation of Cy therapy and analysis of the anti-MV antibody titers was 
performed four weeks later (Table 3) showing that not only are these new 
regimens well tolerated, they are also potently suppressive to the primary 
anti-MV antibody response. Importantly, anti-MV antibodies were 
undetectable at the higher Cy dose.  
 
Table 3: CY Suppression of Primary anti-MV Antibody Response 
Mouse ID 
Saline 
+MV 
+ MV 
+ high dose Cy 
+MV 
+ low dose Cy 
1 
- ve 
40 
- ve 
- ve 
2 
- ve 
160 
- ve 
- ve 


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Additional experiments were conducted to test whether these Cy 
regimens could suppress the anamnestic antibody response. CD46 
transgenic, IFNRKO x CD46 Ge mice aged 6-8 weeks were immunized 
by intraperitoneal challenge with MV-NIS and antibody titers were 
measured four weeks at which time a booster dose of MV-NIS was 
administered with saline, low dose Cy or high dose Cy (7 to 8 animals per 
group). Both Cy regimens suppressed the anamnestic anti-MV antibody 
response, and the high dose regimen caused the titer to decay 
significantly from pre-booster levels (Figure 14).  
  
 
Figure 14. Booster doses of MV-NIS with Cy. White bars are pre-boost, 
grey bars are 4 weeks post-boost. 
 
When the dose is expressed in mg/m2, the area under the plasma 
concentration-time curve for Cy has been demonstrated to be essentially 
the same in all species tested, including mouse, hamster, dog, rat, 
monkey and man.46  The human equivalent of the “high dose” mouse 
protocol is therefore 400 mg/m2 daily by intravenous injection on four 
consecutive days and the low dose protocol equivalent is approximately 
170 mg/m2 daily by mouth for eight consecutive days. These two 
protocols are similar to well established human Cy schedules that have 
been used in MM patients.47-49 
 
3 
- ve 
160 
- ve 
40 
4 
- ve 
640 
- ve 
40 
5 
- ve 
160 
- ve 
- ve 
6 
- ve 
160 
- ve 
- ve 
7 
- ve 
160 
- ve 
- ve 
8 
- ve 
640 
 
160 


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The dose of Cy being administered prior to virus administration in Stage 2 
of our ongoing clinical protocol is 10 mg/kg, but at this dose there has 
been no impact on the anti-MV antibody response measured 6 weeks 
after virus challenge. The mouse equivalent of the standard four day 
intravenous (10 mg/kg or ~400 mg/m2 daily) human Cy protocol converts 
to a dose of 125 mg/kg daily, or approximately 3 mg daily per 25 gram 
mouse. Cy has been extensively used in MM treatment protocols, often in 
higher intensity than the protocol being tested here.47-49 
 
For example, the toxicity of Cy 600 mg/m2 IV days 1-4 (i.e. 50% higher 
intensity than the protocol tested above) has been reported.48 BM 
suppression was the major toxicity encountered in this study. The median 
leukocyte nadir was 200/L, and leukocyte nadirs of less than 500/L 
were seen in 69% of patients. Treatment-induced leucopenia resolved in 
15-18 days in most patients, but 34% of patients with nadir leukocytes 
<1000/L developed serious infections. Platelets decreased to a nadir of 
31,000/L. Of the 37 patients with pretreatment platelet counts of greater 
than 60,000/L, only 9 (24%) required platelet transfusion. This degree of 
myelosuppression is more than we would feel comfortable tolerating in 
our current study, and for that reason the 400mg/m2 days -1-2 will be 
employed which is the standard Cy regimen incorporated in the VDT-
PACE protocol used routinely for MM therapy at UAMS. Cy is an agent 
which is not toxic to stem cells, and any myelosuppression will be 
transient. 
 
3.0 
OBJECTIVES 
 
3.1. 
Primary Objectives 
 
3.1.1. To determine the clinical efficacy of oncolytic virotherapy with the 
optimum biological dose of the Edmonston vaccine strain measles virus 
(MV-Edm) engineered to express the thyroidal sodium iodide symporter 
(MV-NIS) when administered in one dose with 4 days of 
cyclophosphamide (Cy) in patients with relapsed/refractory multiple 
myeloma (MM).  Efficacy will be measured by the IMWG criteria. 
 
3.1.2. To determine the safety and toxicity of the intravenous administration of 
MV-NIS administered in one dose with 4 days of Cy in patients with 
relapsed/refractory MM. 
 
3.1.3. To determine whether a 4 day course of Cy can enhance the efficacy of 
MV-NIS by transiently suppressing the anti-MV response in patients with 
relapsed or refractory MM. 
 
3.2. 
Secondary Objectives 
 
3.2.1. To determine the time course of viral gene expression and virus 
elimination, and the biodistribution of virally infected cells at various time 


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points after infection with MV-NIS when administered IV with 4 days of 
Cy) using 99mTcO4 SPECT/CT imaging. 
 
3.2.2. To monitor the humoral and cellular immune responses to the injected 
virus with Cy 
 
3.2.3. To assess virus replication, viremia, viral shedding in urine and saliva, 
and virus persistence after systemic administration of MV-NIS when 
administered with Cy. 
 
Hypothesis:  A 4 day course of Cy therapy will suppress the T and B cell arms of the 
anti-MV immune response more effectively than a single dose, thereby enhancing the 
intratumoral spread of the virus and preferentially blocking the formation of anti-MV 
antibodies thus prolonging the oncolytic phase of the virotherapy. The proposed dose of 
Cy of 400mg/m2 for 4 days is extremely well-tolerated, and is in fact the Cy dose utilized 
in our current VDT-PACE regimen. The effect of Cy is transient and immune 
reconstitution will occur. We hypothesize that the prolonged oncolytic phase will be more 
effective in terms of tumor kill and promote myeloma cell death. Myeloma proteins will be 
presented to the immune system and induce an anti-myeloma tumor response. Thus it is 
hypothesized that administration of Cy and MV-NIS will enhance myeloma kill through a 
prolonged oncolytic phase, which will also allow in turn for the recruitment of immune 
effectors.  The oncolytic phase will be followed by cell death mediated by immune 
effectors. 
 
Since we do anticipate that 4 days of Cy will translate to a prolonged duration of viral 
replication, this does raise the concern that this enhanced viral replication could result in 
toxicity.  While doses of 1011 MV-NIS have safely been administered to patients without 
experiencing dose limiting toxicity (DLT), MV-NIS has not yet been given in the setting of 
the propsed Cy dose.  Therefore, we will begin this study by treating a small number of 
patients in a Rapid Dose Escalation Phase, with the goal of establishing that the there 
are no toxicity concerns with the proposed regimen.  This rapid escalation phase is 
outlined in Sections 5.1, 5.2, and 5.3.  These subjects will also receive 4 doses of Cy at 
400 mg/m2.  It is also important to note that viremia per se is not a dose limiting toxicity 
(DLT), and that any DLTs observed will be assessed in the context of viral titer to aid in 
the determination of causality. 
 
Upon completion of the initial Rapid Dose Escalation Phase, the study will progress to a 
Slow Dose Escalation Phase with MV-NIS dosing in a higher range.  Three patients per 
MV-NIS dose group will each receive MV-NIS at dose levels of 1x1010, 3x1010, 6x1010, or 
9x1010, all with 4 doses of Cy as outlined previously. A standard 3x3 clinical trial design 
will be used if dose-limiting toxicity is encountered. 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1. 
Inclusion Criteria 
 
4.1.1. MM patients relapsed after prior auto-PBSCT followed by further 
chemotherapy and must:  


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a) be “double refractory”, having failed immunomodulatory and 
proteasome inhibition therapy, 
OR 
b) have extramedullary disease, 
OR 
c) have high LDH (≥360 U/L) due to MM (rule out hemolysis, infection 
and contact PI for clarification if any doubt), 
OR 
d) have abnormal metaphase cytogenetics.  
4.1.2. ≥2 months must have elapsed after the last peripheral blood stem cell 
transplant prior to enrollment. 
4.1.3. Zubrod ≤ 2, unless solely due to symptoms of MM-related (bone) disease. 
4.1.4. Patients must have a platelet count of ≥ 20,000/µL within 30 days of study 
commencement (Day -1), unless lower levels are explained by extensive 
BM plasmacytosis or extensive prior therapy. 
4.1.5. Patients must be at least 18 years of age and not older than 75 years of 
age at the time of study commencement. 
4.1.6. Participants must have preserved renal function as defined by a serum 
creatinine level of ≤ 3 mg/dL within 30 days of study commencement.  
4.1.7. Participants must have an ejection fraction by ECHO or MUGA scan ≥ 
40% within 30 days prior to study commencement. 
4.1.8. Patients must have adequate pulmonary function studies > 50% of 
predicted on mechanical aspects (FEV1, etc) and diffusion capacity 
(DLCO) > 50% of predicted within 30 days prior to registration. If the 
patient is unable to complete pulmonary function tests due to MM related 
pain or condition, exception may be granted if the Medical Monitor and PI 
agree.  
4.1.9. Patients must have signed an IRB-approved informed consent and Health 
Insurance Portability and Accountability Act (HIPAA) authorization form. 
4.1.10. Patients must have anti-MV IgG titer of ≤ 0.3U/mL (Mayo Clinic assay). 
4.1.11. Patients must have a minimum of 2 x 106/kg CD34 stem cells stored. 
4.1.12. Patients must have a baseline ANC of ≥1000/L, unless due to 
involvement of the BM by myeloma (determined at the discretion of the PI). 
 
 


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4.2. 
Exclusion Criteria 
 
4.2.1. Patients may not be positive for the Human Immunodeficiency Virus (HIV). 
4.2.2. History of poorly controlled hypertension, diabetes mellitus, or any other 
serious medical illness or psychiatric illness that could potentially interfere 
with the completion of treatment according to this protocol or could be 
considered to be an exclusion criterion deemed by the PI. 
4.2.3. Patients must not have prior malignancy, except for adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, or other 
cancer for which the patient has not received treatment for one year prior 
to enrollment. Other cancers will only be acceptable if the patient’s life 
expectancy exceeds three years as determined by the PI.  
4.2.4. Pregnant or nursing women may not participate. Women of childbearing 
potential must have a negative pregnancy test documented within one 
week of study commencement. Women/men of reproductive potential may 
not participate unless they have agreed to use an effective contraceptive 
method for at least 8 weeks after virus administration. Acceptable methods 
include:  
Males: Vasectomy or condom 
Females: Hysterectomy; documented menopause; tubal ligation, oral, 
injectable, or implantable hormone contraception; intra-uterine device; 
barrier contraceptive with spermicide; vasectomized partner; or 
condom use by the partner. 
4.2.5. Exposure to household contacts including children who have not been 
vaccinated for MV or anyone with a known immunodeficiency syndrome. 
5.0 
TREATMENT PLAN 
 
5.1. 
Dose Escalation Schedule 
 
This study is designed to confirm the clinical efficacy of MV-NIS in 
relapsed/refractory MM, with the primary endpoint being clinical response 
measured by IMWG criteria. Dose escalation is planned, with the intent of 
determining the minimum effective dose, with a therapeutic efficacy defined as 
the achievement of CR in 3 of 3 treated subjects at a given dose level. Toxicity 
and pharmacokinetics (viral spread, expression and elimination) of MV-NIS will 
be evaluated at each level. Durability of the responses will be evaluated and in 
conjunction with the DSMB during an interim analysis and a determination will be 
made whether to proceed to a higher dose or whether the therapeutic effective 
dose has been reached and subsequent subjects will be treated at this level.  
The study will begin with the treatment of 4 subjects beginning at a MV-NIS dose 
of 108 TCID50, which will proceed through a Rapid Dose Escalation Phase.  Upon 
the completion of these 4 subjects (without DLT), the study will commence with a 
Slow Dose Escalation Phase starting at a MV-NIS dose of 1x1010 TCID50. 


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Table 4. Dose Escalation Schedule 
Step 
Treatment 
Number of patients 
to be enrolled 
RAPID DOSE ESCALATION PHASE USING LOWER DOSE MV-NIS 
A 
Day 0 MV-NIS 1x108 TCID50 
with Cy 400mg/m2 days -1 to 2 
1 
B 
Day 0 MV-NIS 3x108 TCID50 
with Cy 400mg/m2 days -1 to 2 
1 
C 
Day 0 MV-NIS 1x109 TCID50 
with Cy 400mg/m2 days -1 to 2 
1 
D 
Day 0 MV-NIS 3x109 TCID50 
with Cy 400mg/m2 days -1 to 2 
1 
SLOW DOSE ESCALATION PHASE UTILIZING HIGHER DOSE MV-NIS 
1 
Day 0 MV-NIS 1x1010 TCID50 
with Cy 400mg/m2 days -1 to 2 
3 
Interim Analysis 
2 
Day 0 MV-NIS 3x1010 TCID50 
with Cy 400mg/m2 days -1 to 2 
3 
3 
Day 0 MV-NIS 6x1010 TCID50 
with Cy 400mg/m2 days -1 to 2 
3 
4 
Day 0 MV-NIS 9x1010 TCID50 
with Cy 400mg/m2 days -1 to 2 
3 
 
5.2. 
Treatment Schedule 
 
A triple-lumen Cook catheter will be inserted prior to infusion of Cy in patients 
who do not already have central venous access (e.g. infusa-port, Cook, or similar 
catheter).  The virus will be administered by slow intravenous (IV) infusion (30 
minutes) in 100mL of normal saline under close observation in specially-
designated inpatient rooms.  
 
Patients who develop febrile or allergic responses to the MV-NIS infusion will be 
treated with acetaminophen (650 mg, PO), and diphenhydramine hydrochloride 
(50 mg IV or PO). For rigors, meperidine hydrochloride (50 mg IV) will be 
administered. Symptoms suggestive of anaphylaxis such as dyspnea, itching, 
dizziness or symptomatic hypotension will result in the abrupt cessation of the 
viral infusion and the start of aggressive supportive therapy with fluids, 
diphenhydramine, methylprednisolone (1mg/kg IV) and epinephrine (1mg 
subcutaneously). Administration of these medications will be tracked. 
 
 
 
 
 


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Table 5. Treatment Schedule. 
Dose 
Route 
Day 
Pre-medication prior to Administration of MV-NIS 
99mTcO4 
30 mCi 
IV 
Up to 30 days pre-MV-NIS (for baseline 
99mTcO4 scan) 
Cy 
400mg/m2  
IV 
Days -1 and 0 
(MV-NIS Administered after Cy on Day 0) 
MV-NIS Administration 
MV-NIS 
See Table 4 
IV 
Day 0 
After MV-NIS Administration 
Cy 
400mg/m2 
IV 
Days 1 and 2 
99mTcO4 
30mCi 
IV 
Days 3 and 8 
 
Table 6. Therapy for Acute Infusion Reactions. 
Agent 
Dose 
Route 
Reaction 
Acetaminophen 
650 mg 
PO 
Acute febrile reaction 
Diphenhydramine 
50 mg 
PO 
Acute febrile reaction 
Meperidine hydrochloride 
50 mg 
IV 
Rigors 
Methylprednisolone 
1 mg/kg 
IV 
Anaphylaxis 
Normal saline 
PRN 
IV 
Anaphylaxis 
Epinephrine 
1 mg 
SC 
Anaphylaxis 
 
 
Cy will be administered for 4 days as described above. It should be diluted as 
instructed in the product literature, added to 250 mL of 0.9% sodium chloride or 
5% dextrose in water and infused over 2 hours. On the day of MV-NIS 
administration, Cy will be administered prior to MV-NIS. 
 
Administration Location and Admission Logistics 
Subjects will receive the first dose of Cy as an outpatient in the Infusion 4 clinic 
on Day -1, and will be admitted to the inpatient unit on the evening of Day -1.  
The second dose of Cy will be administered in the inpatient unit on Day 0, 
followed by administration of MV-NIS.  Subjects will be observed overnight, and 
will receive the third dose of Cy the following morning in the inpatient unit.  
Subjects will be discharged, and will return to the Infusion 4 clinic on the following 
day (Day 2) for the fourth and final dose of Cy. 
 
The in vivo distribution of MV-NIS infected cells and the kinetics of virus spread 
and elimination will be monitored by whole body SPECT/CT imaging 1 hour after 
30 mCi of IV-administered 99mTcO4 and by serial measurements of viral RNA in 


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mononuclear cells derived from blood, saliva and urine (Viral N-gene RNA copy 
number/g RNA) per the schedule of evaluations outlined in section 6.  
 
99mTcO4 SPECT/CT images will be performed twice post MV-NIS in the following 
windows: 
a) Day 3 (3-7), and 
b) Day 8 (8-12) after MV-NIS infusion 
 
5.3. MV-NIS Dose Escalation Rules (applicable to all steps of the Rapid Dose Escalation 
Phase) 
 
5.3.1. Enrollment will proceed sequentially.  A 28-day waiting period (counted 
from Day -1 of the last subject in the previous dose cohort) will be 
observed between each step of the Rapid Dose Escalation Phase to 
observe for toxicity.  
 
5.3.2. The first subject will be enrolled and dosed with MV-NIS 1x108 TCID50 
with 4 doses of Cy at 400 mg/m2 (Step A). 
  
5.3.3. If no DLT is seen at this dose, the next subject will be enrolled and dosed 
with MV-NIS 3x108 TCID50 with 4 doses of Cy at 400 mg/m2 (Step B). 
 
5.3.4. If no DLT is seen at this dose, the next subject will be enrolled and dosed 
with MV-NIS 1x109 TCID50 with 4 doses of Cy at 400mg/m2 (Step C). 
  
5.3.5. If no DLT is seen, the next subject will be enrolled and dosed with MV-
NIS 3x109 TCID50 with 4 doses of Cy at 400mg/m2 (Step D). 
  
5.3.6. If at any step a DLT is observed, two additional subjects will be enrolled 
at the same step. 
  
5.3.7. If two DLTs are observed at any step, the dose will be de-escalated to the 
previous step and will enroll an additional 3 subjects. 
 
5.3.8. If any subject treated in the Rapid Dose Escalation Phase experiences 
CR, the determination will be made by the PI whether to accrue additional 
subjects at that dose level to observe for further CRs. 
   
5.3.9. Once all steps have been completed in the Rapid Dose Escalation Phase 
schedule, we will proceed with the Slow Dose Escalation Phase with 
higher dose MV-NIS. 
 
5.4. MV-NIS Dose Escalation Rules (applicable to all steps of the Slow Dose Escalation 
Phase) 
 
5.4.1. Subjects within a dose cohort will be enrolled sequentially at a maximum 
rate of one per 3 weeks. 
 
5.4.2. If CR is not observed in all 3 of 3 patients at a given step, AND If DLT is 
not seen in any of the 3 patients at a given step, then 3 additional patients 


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will be treated at the next dose level.  No subject will receive therapy at 
the new dose level until the completion of a 28-day waiting period 
(counted from Day -1 of the last subject in the previous dose cohort) to 
observe for toxicity.  
 
5.4.3. If DLT is seen in 1 of 3 patients treated at a given step, 3 additional 
patients will be entered, one by one, at the same step. 
 
5.4.4. If no additional DLT is observed at that dose level, then 3 additional 
patients will be treated at the next step. 
 
5.4.5. If 2 or more subjects out of 6 experience DLT at any step, MTD will have 
been exceeded. 
 
5.4.6. If MTD is exceeded at any step, an additional cohort of 3 participants will 
be enrolled at one dose level lower. 
 
5.4.7. If MTD is exceeded at the first dose level then the dose will be de-
escalated by one log 1 x 109. (vide infra)   
 
5.4.8. MTD will be defined as the highest dose at which no more than one out of 
six participants experiences DLT OR no DLT observed out of 3 patients at 
the maximum dose level, provided no DLT is observed at any of the 
previous dose levels (see sections 5.1, 5.7). In the case that no DLTs are 
observed in any of the dose levels, then the MTD will be the maximum 
dose delivered.  
 
5.4.9. If 3 of 3 treated subjects do not achieve CR at the highest dose step, and 
no DLT is observed, then escalation beyond this dose level will be 
considered. Further dose-escalation will only be considered in this 
scenario if no clinical efficacy has been observed.  If 9 x 1010 dose level 
(for step 4) is reached without dose limiting toxicity then the study will be 
re-evaluated with the DSMB in terms of further escalating the MV-NIS 
dose. Further, increases will need FDA and IRB approval before 
implementation 
 
5.4.10. An interim analysis of efficacy will be performed after enrollment of 6 
patients and a determination of whether or not to continue dose 
escalation will be made. 
 
5.4.11. Toxicity Observation Period: The first 4 weeks after therapy will be 
considered the toxicity observation period, where any DLTs observed in 
this timeframe will determine whether or not accrual can continue to the 
next dose level.  
 
5.4.12. About 45 subjects will be screened for study eligibility based on levels of 
anti-MV antibody.  Patients with anti-MV IgG levels >0.3U/mL are 
ineligible (see sections 4.1 and 4.2).  Patients whose anti-MV antibody 
levels exceed this threshold during screening will be replaced on study.    
 


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5.4.13. If a patient fails to complete the initial course of therapy (i.e. registers, but 
does not receive therapy or is lost to follow-up during the first 6 weeks), 
the patient will be regarded as not evaluable and an additional patient will 
be treated at the current dose level.  For these instances, a specific 
notation will be made for review by the IRB If more than one participant 
must be replaced at a dose level for reasons other than toxicity or 
ineligibility due to anti-MV IgG levels, the reasons will be reported to the 
FDA and the trial may be voluntarily halted pending comments by the 
FDA review team. 
 
5.5. 
Dose De-Escalation 
 
5.5.1. If two patients experience DLT at a dose level in the Rapid Dose 
Escalation Phase of the study, an additional 3 patients will be accrued at 
the previous dose level. 
 
5.5.2. If two or more patients experience DLT at the starting dose level (slow 
escalation phase), then the new dose level 1 will be 1 x 109.  Re-
escalation will occur according to escalation rules described in 5.4 except 
with this log-lower base. 
 
5.5.3. If two or more patients experience DLT at dose levels 2-4, an additional 
three patients will be accrued at the previous dose level. 
 
5.6. 
Anticipated Toxicity 
 
5.6.1. Acute febrile reaction to the intravenously administered virus may occur. 
Ancillary support is described in sections 8 and 11.  
 
5.6.2. MV-like illness (coryza, malaise, fever, rash, lymphadenopathy and 
transient suppression of the immune system). Patients will be educated 
about the symptoms of MV and asked to report immediately if any of 
these symptoms develop. The disease is self-limiting in normal adults but 
MM patients are immunocompromised, treatment will be implemented if 
the symptoms (including temperature > 38.5°C) persist for as long as 6 
days, and earlier at the treating physician’s discretion. Earlier treatment is 
strongly recommended if a typical MV exanthem appears. Treatment will 
include Immune Globulin (GamaSTAN, 15 mL maximum) and Ribavirin 
(10 mg/kg/day in 4 divided doses orally or 20 mg/kg/day 
intravenously).50,51 Administration of these medications will be tracked and 
a participant with persistent MV-like illness will be classified as having 
experienced a DLT (see Section 5.7).  Additional ancillary support is 
described in section 9. 


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Table 7. Therapy for MV Persistence. 
Agent 
Dose 
Route 
Reaction 
Immune Globulin 
(GamaSTAN) 
15 mL 
IM 
Persistent MV-like symptoms 
Ribavirin 
10mg/kg/day 
(in 4 divided doses) 
or 
20mg/kg/day 
(in 3 divided doses) 
PO 
 
 
IV 
Persistent MV-like symptoms 
or 
Persistent viremia 
see section 7.8) 
 
5.6.3. For other individuals, possible side effects may include nausea, vomiting, 
stomach ache and diarrhea, metallic taste in the mouth, fever, headache, 
or acne. Other rare, but serious side-effects include: burning mouth/throat, 
sore teeth/gums, mouth swelling, increased saliva, eye irritation/swollen 
eyelids, severe headache, goiter, signs of decreased thyroid gland 
function, confusion, numbness/tingling/pain/weakness of hands or feet, 
gastrointestinal hemorrhage. 
 
5.6.4. The planned Cy therapy may be associated with nausea, vomiting, 
diarrhea, fatigue, a drop in white blood count, hemoglobin and platelets. 
Since Cy will allow the MV to replicate longer at lower MV-NIS dose 
levels, we anticipate that this may lead to more severe symptoms of a 
MV-like illness.  
 
5.6.5. 99mTcO4 is well tolerated.  No acute toxicity is expected. 
 
5.7. 
DLT – Definition (Table 8). 
 
Category 
Description 
Renal 
Grade 3 (Serum creatinine > 3x ULN) 
Symptomatic MV infection 
Coryza, malaise, fever, rash, brassy cough; conjunctivitis; 
photophobia; and lymphadenopathy ≥ 6 days 
Neurological 
≥ Grade 2, excluding transient headache 
Pancytopenia 
Persistent pancytopenia (> 2 weeks duration) possibly or likely 
related to MV-NIS 
Autoimmune 
Any new serious autoimmune toxicity ≥ Grade 2 affecting vital 
organs (e.g. cardiac, renal, CNS) due to MV-NIS and occurring 
within 2 weeks of MV-NIS administration 
Other 
Any new Grade 3 or Grade 4 toxicity that is possibly or likely 
related to MV-NIS and is not reversible within 2 weeks 
OR 
Any treatment-related life-threatening event or treatment-related 
death 


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6.0 
SCHEDULE OF EVALUATIONS (TABLE 9) 
 
 
Pre-enrollment 
Pre-
therapy 
Post-therapy (relative to MV-NIS administration) 
Observation 
 
Tests and 
Procedures 
Day 
-120 to -1 
Pre 
Enroll-
ment 
Day 
-30 to -1 
Pre 
Enroll-
ment 
Day 
-30 to -1 
Post 
Enroll-
ment 
Day 0 
 
Day 3 
(3-7) 
 
 
Day 8 
(8-12) 
 
 
Day 15 
(13-17) 
 
 
Day 22, 
Day 29 
(±3) 
 
 
Week 
6 
(±7) 
 
3 months after 
treatment and 
every 3 months 
after for one year 
or until 
progression 
(+/- 2 weeks) 
1 
Informed 
Consent 
X 
 
X 
 
 
 
 
 
 
 
2 
History Exam, 
Weight, 
Performance 
Score 
 
X 
 
 
X 
X 
X 
X 
X 
X 
3 
AE Evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
4 
CBC 
 
X 
 
 
X 
X 
X 
X 
X 
X 
5 
CMP 
 
X 
 
 
X 
X 
X 
X 
X 
X 
6 
MMII, MMIII 
 
X 
 
 
 
 
 
 
X 
X 
7 
HIV screening 
(serology) 
 
X 
 
 
 
 
 
 
 
 
8 
BM asp/biopsy 
cIg DNA, 
cytogenetics, 
(6mL aspirate in 
EDTA for 
research) 
 
X 
 
 
 
 
 
 
X 
 
9 
CVL Placement 
(Cook, if no 
central venous 
access) 
 
X 
 
 
 
 
 
 
 
 
10 
(M) Viral 
shedding: 
mouth rinse 
sample & urine 
collection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
11 (M) Anti MV IgG 
X 
 
 
 
 
 
X 
 
X 
X 
(at 3 months only) 
12 
(M) MV 
Neutralizing Ab 
 
 
X 
 
 
 
X 
 
X 
X 
(at 3 months only) 
13 
(M) Viremia  
(PBMC) 
 
 
 
X 
15 min, 
30 min, 
1h, 2h, 
4h post 
MV-
NIS 
X 
X 
X 
X 
X 
X 
14 
Peripheral Blood 
100 mL for 
MV and anti-
tumor 
 T cell responses 
 
 
X 
 
 
 
 
 
X 
X  
(At 3 months only) 
15 
SPECT/CT 
 
 
X 
 
X 
X 
 
 
 
 
16  (M) Focal lesion 
biopsy 
 
 
 
 
X 
 
 
 
 
 
17 Pregnancy test 
 
X 
 
 
 
 
 
 
 
 


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Tests/Procedures to be performed: 
1. Informed Consent: Potential subjects will sign an informed consent for eligibility screening 
prior to the performance of the anti-MV IgM/IgG serology screening (item 11, below).  
Subjects to be enrolled will sign an additional informed consent for the study which will be 
obtained prior to performing any protocol-required tests or procedures: viral shedding (Mayo 
assay), MV neutralizing Ab (Mayo assay), Viremia (Mayo assay), peripheral blood for 
research/correlative studies, and SPECT/CT. 
2. Clinical exam: Including history and physical, weight and other metrics, and Zubrod 
performance status evaluation.  Assessed at all clinic visits: pre study (Day  -30 to -1), and 
Protocol Days 3, 8, 15, 22, 29, Week 6, and every 3 months for 1 year. 
3. AE Evaluation: Determination whether the subject has experienced AEs. To be assessed at 
baseline/pre-study (Day  -30 to -1), and on Protocol Days 0, 3, 8, 15, 22, 29, Week 6, and 
every 3 months for 1 year. 
4. Complete Blood Count (CBC):  Performed by the UAMS Clinical Laboratory pre study (Day  
-30 to -1), and Protocol Days 3, 8, 15, 22, 29, Week 6, and every 3 months for 1 year. 
5. Comprehensive Metabolic Panel (CMP): Performed by the UAMS Clinical Laboratory pre-
study (Day -30 to -1), and Protocol Days 3, 8, 15, 22, 29, Week 6, and every 3 months for 1 
year. 
6. Multiple Myeloma Panel II (MMII): Includes M-protein quantification and quantitative serum 
immunoglobulin measurements, free light chains and immunofixation.  Performed by the 
UAMS Clinical Laboratory pre-study (Day -30 to -1), and post therapy timepoints at 6 weeks, 
and every 3 months for 1 year. 
Multiple Myeloma Panel III (MMIII): Includes Totoal protein and M-protein quantification and 
immunofixation. measurements.  Performed by the UAMS Clinical Laboratory pre-study (Day  
-30 to -1), and post therapy timepoints at 6 weeks, and every 3 months for 1 year. 
7. HIV Screening: HIV serology screening to be performed pre-study (Day -30 to -1).  
8. Bone Marrow Aspirate and Biopsy: Both diagnostic and research specimens will be 
obtained pre-study (Day -30 to -1) and again post-study at 6 weeks.  Clinical tests include cIg 
DNA and cytogenetics.  Research specimen is a 6mL sample to be drawn from a unique site, 
and will be utilized by the UAMS-MIRT Immunotherapy Lab (ITL) for correlative studies.  See 
section 11.3 for details. 
9. CVL Placement:  A triple-lumen Cook catheter will be inserted prior to infusion of Cy in 
patients who do not already have central venous access (e.g. infusa-port, Cook, or similar 
catheter). To be performed prior to Cy dose 1. 
10. Viral Shedding (M):  For mouth rinse sample patient will gargle with 30mL of Scope 
mouthwash for 30 seconds and fluid will be collected;  A mid-stream urine sample (15mL) will 
also be collected.  Both will be shipped to Mayo Clinic for testing. To be assessed at 
baseline/pre-study (Day -30 to -1), and on Protocol Days 3, 8, 15, 22, 29, Week 6, and every 
3 months for 1 year. Testing beyond Day 15 may be omitted upon documentation of the 
cessation of viral shedding.  
11. Anti-MV IgG (M):  Serology to assess for titer of anti-MV antibodies.  Will be performed as a 
screening test (Day -120 to -1).  IgG titer will be the determining factor for subject eligibility.  
An anti-MV IgG level of ≤ 0.3U/mL is the threshold for enrollment.  A  blood  sample 
(approx.15mL) will be collected from the subjects venipuncture line and will be shipped to 
Mayo Clinic for testing. Follow-up testing to be performed post therapy on Day 15 and at 
Week 6 and at 3 months after end of study treatment.    
12. MV Neutralizing antibody (M): Functional assay to assess the ability of patient-derived 
circulating antibody to inhibit propagation of MV on Vero cell line (plaque assay).  Outcome 
does not affect subject enrollment eligibility, and is performed for research purposes only. A 
18 
Pulmonary 
Function  
Test 
 
X 
 
 
 
 
 
 
 
 
19 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 


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blood  sample (approx .15mL) will be collected and will be shipped to Mayo Clinic for testing.  
To be performed after enrollment (Day -30 to -1) and repeated post therapy on Day 15 and at 
Week 6 and at 3 months after end of study treatment. .   
13. Viremia (M):  Blood samples to measure viral titer.  Viremia will be assessed at baseline/pre-
study (Day  -30 to -1). On Protocol Day 0, viremia specimens will be drawn during the MV-
NIS infusion and immediately thereafter to assess the dynamics of viral titer increase.  Serial 
blood samples will be collected at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours (± 5 
minutes for all intervals) after infusion start.  Additional viremia testing will occur on Protocol 
Days 3, 8, 15, 22, 29, Week 6, and every 3 months for 1 year. Testing beyond Day 15 may 
be omitted if there is no evidence of increasing viral proliferation at Day 15.   
14. Peripheral Blood for anti-MV and anti-tumor T cell responses: Peripheral blood (100mL) 
will be collected at baseline/pre-study (Day -30 to -1) and again at post therapy Week 6 and 
at 3 months to assay for T cell responses to MV as well as tumor-associated antigens.  This 
testing will be performed in the ITL.  See section 11.3 for details. 
15. SPECT/CT: (Also known as gamma camera) will be performed at baseline/pre study (Day -
30 to -1) and again on post therapy Protocol Days 3 and 8 to assess viral homing to sites of 
myeloma tumor (such as lytic lesions).  One scan will be done pre-MV-NIS, and one each in 
the windows a) Day 3-7 and b) Day 8-12.   All scans will need to be performed ~ 1 hour post 
99mTcO4 administration. 
16. Focal Lesion Biopsy (M): Samples of this core biopsy will be sent to the Mayo Clinic for 
immunohistochemistry and molecular testing.  Only one focal lesion biopsy will be performed 
depending on the results of the SPECT/CT.  The biopsy will be done either in the time 
window for Day 3 or Day 8.  For the sake of convenience only the Day 3 time window has 
been noted in the study calendar. 
17. Pregnancy Test: Necessary in women of childbearing potential ≤ 7 days prior to registration. 
18. Pulmonary Function Test: To be performed at screening (Day -30 to -1). 
19. ECHO/MUGA: To be performed at screening (Day -30 to -1).  Either test is acceptable for 
cardiac clearance. 
 
Notes 
(M)  
Samples to be shipped to Mayo Clinic by ITL. These will be done on a research basis in  
 
Dr. Russell’s laboratory free of charge 
 
Subsequent timepoints may be omitted with the previous evaluation yields a negative 
 
result. 
 
These tests may be done sooner than Week 6 if the patient progresses and needs to 
start another treatment for MM prior to the Week 6 time point.  
  
Patients will be observed at 3 months (+/- 2 weeks) post treatment and every 3 months 
 
thereafter for a year or until progression—whichever is longer.  Lab tests may be done at 
 
home if the patient has progressed and is on observation for toxicity rather than efficacy. 
 
 
7.0 
DOSAGE MODIFICATION BASED ON AEs 
 
7.1. 
Rules for Dose Escalation and De-Escalation  
 
Described in sections 5.3, 5.4, 5.5. 


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8.0 
ANCILLARY THERAPY 
 
8.1. 
Supportive Care 
 
Patients may receive full supportive care during the study (pre-screening though 
study exit) including blood products, antibiotics, growth factors, and/or treatment 
of concurrent medical conditions and other newly diagnosed diseases at the 
discretion of the treating physician.  
 
8.2. 
Monitoring 
 
Patients will be closely monitored during infusion of the virus for acute febrile 
reaction to the intravenously administered virus. Patients who develop febrile or 
allergic responses to the infusion will be treated with acetaminophen (650 mg, 
po) and diphenhydramine hydrochloride (50mg IV or PO). For rigors, meperidine 
hydrochloride (50 mg IV) will be administered. Symptoms suggestive of 
anaphylaxis such as dyspnea, itching, dizziness or symptomatic hypotension will 
result in the abrupt cessation of the viral infusion and the start of aggressive 
supportive therapy with fluids, diphenhydramine, methylprednisone (1mg/kg IV) 
and epinephrine (1mg subcutaneously). Administration of these medications will 
be tracked. 
 
8.3. 
Patient Education 
 
Patients will be educated about the symptoms of MV (coryza, malaise, fever, 
rash, lymphadenopathy and transient suppression of the immune system28,29 ) 
and asked to report immediately if any of these symptoms develop.  
 
The incubation period of MV (rubeola) averages 10 to 12 days from exposure to 
prodrome and 14 days from exposure to rash (range, 7 to 18 days). Prodromal 
symptoms of severe, brassy cough; coryza; conjunctivitis; photophobia; and fever 
appear 3 to 4 days before the exanthem and increase daily in severity. The nose 
and eyes run continuously. Koplik's spots (blue-white spots with a red halo) 
appear on the buccal mucous membrane opposite the premolar teeth 24 to 48 
hours before the exanthem and remain for 2 to 4 days. 
 
The rash begins on the fourth or fifth day on the face and behind the ears, but in 
4 to 36 hours, it spreads to the trunk and extremities. It reaches maximum 
intensity simultaneously in all areas in approximately 3 days and fades after 5 to 
10 days. The rash consists of slightly elevated maculopapules that vary in size 
from 0.1 to 1.0 cm and vary in color from dark red to a purplish hue. They are 
frequently confluent on both face and body, a feature that is such a distinct 
characteristic of MV that eruptions of similar appearance in other diseases are 
termed morbilliform. The early rash blanches on pressure; the fading rash is 
yellowish-brown with a fine scale, and it does not blanch.  
 
The disease is self-limiting in normal adults but MM patients are 
immunocompromised, treatment will be implemented if the symptoms (including 
temperature > 38.5°C) persist for as long as 6 days, and earlier at the treating 
physician’s discretion. Earlier treatment is strongly recommended if a typical MV 


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exanthem appears. Treatment will include Immune Globulin (GamaSTAN, 15 mL 
maximum) and Ribavirin (10 mg/kg/day in 4 divided doses orally or 20mg/kg/day 
intravenously).50,51 Administration of these medications will be tracked and a 
participant with persistent MV-like illness will be classified as having experienced 
a DLT (see section 5.7) 
 
8.4. 
Disease Communication 
 
The disease is spread by respiratory droplets and can be communicated from 
slightly before the beginning of the prodromal period to 4 days after appearance 
of the rash; communicability is minimal after the second day of the rash. Though 
we would not expect the virus to be contagious to others since the majority of the 
U.S. population is vaccinated, it will be required that health care personnel wear 
a mask at the first sign of cough; coryza; conjunctivitis; photophobia; or fever in 
the patient.  
 
The vaccine strain of the MV (of which MV-NIS is a derivative) has been shown 
to be shed in the urine of normal children undergoing routine vaccination. Despite 
the presence of viral shedding of the vaccine strain of MV, transmission has not 
been documented. However, since other patients may be severely 
immunosuppressed, it will be required that MV-NIS-treated patients wear a mask 
while they are shedding virus (tested by qRT-PCR). 
 
As a safety precaution, we will also recommend that all caregivers and close 
personal contacts be previously immunized against the measles virus.  
Caregivers should contact their primary care physician to inquire about their 
vaccine status or titer.  
 
8.5. 
Concurrent Enrollment 
 
Patients enrolled in this study will not be eligible for concurrent enrollment in any 
other study involving a pharmacological agent (drugs, biologicals, 
immunotherapy, gene therapy) whether for therapeutic intent or symptom control. 
 
9.0 
AE REPORTING AND MONITORING  
 
This study will utilize the Common Terminology Criteria for AEs (CTCAE) v4.0 for AE 
monitoring and reporting. The CTCAE v4.0 can be downloaded from the CTEP home 
page (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). All appropriate treatment areas 
should have access to a copy of the CTCAE v4.0. 
 
9.1. 
AE Information 
 
AE monitoring and reporting is a routine part of every clinical trial. First, identify 
and grade the severity of the event using the CTCAE. Next, determine whether 
the event is expected or unexpected (refer to consent and/or product literature) 
and if the AE is related to the medical treatment or procedure. With this 
information, determine whether an AE should be reported as an expedited report, 
or as part of the routinely reported clinical data to FDA, and/ or IRB at continuing 
review. 


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Expedited AE reporting requires submission of a written report, but may also 
involve telephone notifications. Telephone and written reports are to be 
completed within the timeframes specified by UAMS Policy 10.2. All expedited 
AE reports should also be submitted to the Sponsor and local Institutional 
Review Board (IRB), per IRB policy 10.2 
 
9.2. 
Assessment of Attribution 
 
When assessing whether an AE is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
Definite - The AE is clearly related to the investigational agent(s). 
Probable - The AE is likely related to the investigational agent(s). 
Possible - The AE may be related to the investigational agent(s). 
Unlikely - The AE is doubtfully related to the investigational agent(s). 
Unrelated - The AE is clearly NOT related to the investigational agent(s) 
 
9.3. 
Expected vs. Unexpected 
 
 The determination of whether an AE is expected is based on agent-
specific AE information provided in the consent and/or protocol (Appendix 
II)  and/or drug handouts  
 Unexpected AEs are those not listed in the agent-specific AE information, 
and will be reported to the FDA following the guidelines outlined in 21 
CFR 312.32. 
 
9.4. 
AE Grading 
 
AEs shall be graded at each evaluation and pretreatment.  Symptoms/conditions 
are to be evaluated at baseline per CTCAE v4.0 grading unless otherwise stated 
in the table below: 
 
 
Table 10. AE Schedule of Evaluation 
Category 
AE/Symptoms 
Baseline 
Each  
evaluation 
BLOOD/BM 
Leukocytes (total 
WBC) 
X 
X 
Platelets 
X 
X 
METABOLIC/ 
LABORATORY 
Creatinine 
X 
X 
CONSTITUTIONAL 
Fever 
X 
X 
Rigors/chills 
X 
X 
DERMATOLOGIC 
Rash/ desquamation 
X 
X 
RESPIRATORY 
Cough 
X 
X 
GASTROINTESTINAL 
Baseline # of Stools 
X 
 
Diarrhea (patients w/o 
colostomy) 
X 
X 
Vomiting 
X 
X 


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Nausea 
X 
X 
 
Submit via appropriate Case Report Forms (i.e., paper or electronic as 
applicable) the following AEs experienced while on therapy: 
 
 Grade 2 AEs deemed possibly, probably or definitely related to the study 
treatment or procedure.  
 
 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure.  
 
 Grade 5 AEs (Death) 
 
o Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or procedure. 
 
o Any death more than 30 days after the patient’s last study treatment or 
procedure that is felt to be at least possibly treatment related must also 
be submitted as a grade 5 AE, with a CTCAE type and attribution 
assigned.  
 
 
10.0 
TREATMENT/FOLLOW-UP DECISION AT EVALUATION  
 
10.1. Discontinuation of Therapy 
 
The investigator may discontinue individual subjects from the study at any time 
for the following reasons: a) if the patient develops AEs that in the judgment of 
the investigator preclude continuaton on study; b) if a patient develops an 
intercurrent illness that is not consistent with the protocol requirements; c) if the 
patient is not compliant with the study plan; d) if a female subject becomes 
pregnant during the course of the study. 
 
10.2. Subject Replacement 
 
Indications for replacing a patient include: a) subject screening: if a patient is 
deemed ineligible due to anti-MV IgG titers (see section 4.1), an additional 
patient will be treated at the current dose level and, b) If a patient fails to 
complete the initial course of therapy (defined as study drug administration and 4 
weeks observation) for reasons other than toxicity (e.g. intercurrent illness, 
patient refusal, or patient non-compliance), the patient will be regarded as 
inevaluable and an additional patient will be treated at the current dose level (see 
section 5.4). If more than one participant must be replaced at a dose level for 
reasons other than anti-MV antibody levels or toxicity, the reasons will be 
reported to the FDA and the trial may be voluntarily halted pending comments by 
the FDA review team. 
 
10.3. Response Monitoring 
 


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For the purposes of this study, patients will be evaluated for clinical response  
(See Appendix II) at Week 6 and 3 months and every 3 months thereafter while 
on observation. (See Schedule of Evaluations Section 6.0). 
 
10.4. Observation: Study Non-Completion 
 
Patients who have disease progression, refuse further observation, or go on to 
receive alternate therapy will be monitored in Observation and will follow the test 
schedule per section 6.0 until 1 year after completing therapy. The exception to 
the rule is the case of a patient who progresses before the Week 6 evaluation 
AND receives alternate therapy to treat MM: these patients will remain on active 
monitoring through Week 6 despite receiving non-trial chemotherapy.  
 
10.5. Discontinuation Due to Toxicity 
 
Patients who discontinue treatment due to unacceptable toxicity will be actively 
monitored in Observation and will follow the test schedule per section 6.0 until 1 
year after completing therapy.  
 
10.6. Cancelations 
 
If a patient is registered to this trial and refuses further participation prior to 
receiving treatment (and is classified as a cancel), it is not necessary to provide 
follow-up information. No further follow-up information is necessary.  
 
11.0 
ANCILLARY STUDIES 
 
11.1. Assessment of Viremia  
 
Assessment of viremia and viral shedding will be performed on blood, saliva and 
urine per the schedule of evaluations (section 6.0) via qRT-PCR to determine 
virus RNA copy number and/or viral replication via co-culture on Vero cells for 
virus isolation. Testing will be performed in Dr. S.J. Russell’s laboratory at the 
Mayo Clinic. 
 
11.2. Assessment of Immune Competence 
 
Assessment of immune competence will be performed by evaluation of 
immunoglobulin levels. 
 
11.3. Assessment of Peripheral Immune Response 
 
Assessment of the peripheral immune response to viral administration will be 
evaluated per the schedule of evaluations by measuring anti-MV specific 
antibodies (IgG). Other research assays to investigate immune-mediated anti—
MV and anti-tumor response may be assessed via IFN secretion assays as well 
in the ITL research laboratory at UAMS. 


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12.0 
STATISTICAL CONSIDERATIONS AND METHODOLOGY  
 
12.1. Overview 
 
This is a Phase II study designed to confirm the clinical efficacy of MV-NIS in 
relapsed/refractory MM. The primary endpoint is clinical response measured by 
IMWG criteria. It should be emphasized that although dose escalation is planned, 
escalation of doses will be halted if therapeutic efficacy is observed in terms of 
achieving CR in 3 of 3 treated patients at a given dose level. Toxicity and 
pharmacokinetics (viral spread, expression and elimination) of MV-NIS will be 
evaluated at each level. Durability of the responses will be evaluated and in 
conjunction with the DSMB a determination will be made whether to proceed to a 
higher dose or whether the therapeutic effective dose has been reached and 
subsequent subjects will be treated at this level. 
 
12.2. Maximum Tolerated Dose (MTD) 
 
The MTD will be defined as the highest safely-tolerated dose level where at most 
one patient out of six experiences DLT or no DLT observed out of 3 patients at 
the maximum dose level, provided no DLT is observed at any of the previous 
dose levels (see section 5.7). In the case that no DLTs are observed in any of the 
dose levels, then the MTD will be the maximum dose delivered for each stage. 
 
12.3. MTD determination 
 
Sample Size, Accrual and Study Duration: The first dose level of this study in the 
Slow Dose Escalation Phase will accrue 3 patients.  If < 3 of 3 treated subjects 
achieve CR, then the study will proceed at the next dose level.  Each subsequent 
dose level will accrue an additional 3 patients, unless the primary endpoint of 3 of 
3 subjects achieving CR is met.  If this occurs, then additional subjects will be 
accrued at this dose level for a total enrollment of 16 subjects for this study 
(including the 4 subjects treated in the Rapid Dose Escalation Phase).  Upon 
completion of the first (1x1010) dose level cohort, an interim analysis assessing 
efficacy will be performed.  Escalation to the and second (3x1010), third (6x1010) 
and fourth (9x1010) dose level cohorts will occur if it is determined that the 
primary  efficacy  endpoint has not been achieved at the lower dose levels.   
 
 
We do anticipate that approximately 10% of patients may not complete the DLT 
evaluation phase due to disease progression, patient refusal etc.  These patients 
may be replaced as outlined previously. 
 
12.4. General Statistical Considerations:  
 
The trial is designed to provide data about pharmacokinetics (biodistribution, 
targeting, viral gene expression and viral elimination), safety and biological 
activity and efficacy of MV-NIS in patients with MM. Data related to toxicity and 
pharmacology will be presented using descriptive statistics due to the exploratory 
nature of the study. The data will be presented in table formats listing the mean, 
standard deviation and number of patients per group for continuous data, or 
listing count and percentages for categorical data as appropriate. All the relevant 


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data will be used both in exploratory and hypothesis generating fashions to 
examine factors related to toxicity and pharmacology. 
 
12.5. Analysis Plans 
 
12.5.1. Primary endpoints 
 
The clinical efficacy is response by IMWG criteria and minimum 
therapeutic dose will be determined as described above.  
 
A clinical response in this setting will be defined as noted in Appendix II. 
The number of responses (of all types) will be summarized by simple 
descriptive summary statistics across all patients in each group as well as 
by dose level. Dose escalation will be halted if 3 out of 3 patients achieve 
CR.  At that point the durability of the responses will be established and in 
conjunction with the DMSB it will be determined whether further 
individuals will be treated at this dose. Additionally, if any subject treated 
in the Rapid Dose Escalation Phase of this study achieves CR, the 
determination will be made whether to accrue additional subjects at that 
dose level (rather than proceeding with escalation to the Slow Dose 
Escalation Phase).  In all cases, response called at Week 6 will be 
evaluated and compared with a case-matched control cohort treated with 
salvage therapy. Further, simple summary statistics will be supplemented 
with Kaplan-Meier survival estimates and related confidence intervals. 
The effect of dose and ancillary dichotomized covariates such as age will 
be explored using log rank testing involving one covariate at a time. Again 
the small sample size restricts the generalizability of such testing, but the 
results will provide preliminary indications for subsequent research in 
Phase II clinical trials. 
 
The number and severity of toxicity incidents indicate the level of 
tolerance for MV-NIS administered with Cy in the therapy of MM. For 
each of the levels, non-hematologic toxicities will be evaluated via the 
CTCAE v4.0 standard toxicity grading. Non-hematologic toxicity 
measures will be assessed using continuous variables as the outcome 
measures (nadir and percent change from baseline values) as well as 
categorization via CTCAE v.4.0 standard toxicity grading. Frequency 
distributions and other descriptive measures will form the basis of the 
analysis of these variables. Further, tolerability of this regimen will be 
explored in an ancillary manner through time-related variables including 
time until any treatment related toxicity, time until treatment related grade 
3+ toxicity.  
 
Lastly, any enhancement of suppression of the anti-MV response in 
patients will be done by comparing anti-MV titers with previously treated 
patients without Cy at 1x1010 and 1x1011 dose levels. Simple comparative 
statistitics will be used. 


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12.5.2. Secondary endpoints  
 
Data will be collected for a number of laboratory correlative variables as 
discussed before including: a) virus replication, viremia, viral shedding in 
urine and respiratory secretions, and virus persistence, b) suppression of  
humoral and cellular immune responses to the injected virus, and c) the 
time course of viral gene expression and virus elimination, and the 
biodistribution of virally infected cells using  99mTcO4  SPECT/CT imaging. 
 
Descriptive statistics and scatterplots will form the basis of presentation of 
these variables. Correlations between the laboratory values and other 
outcome measures will be carried out by standard parametric and non-
parametric tests (e.g. Pearson’s and Spearman’s rho). Data obtained 
from SPECT/CT imaging of MV-NIS following 99mTcO4 administration will 
be used to determine the biodistribution and kinetics of virus spread and 
NIS gene expression in vivo and correlate it with tumor distribution. 
Where patterns of correlation are indicated, ordinary and partial 
correlation coefficients (controlling for dose levels) will be calculated. 
Inferential testing for significant shifts in the correlative laboratory data 
results across dose levels will be carried out only as a hypothesis 
generating exercise. 
 
At the end of the trial, the optimal dose level will be selected for future 
studies based on clinical efficacy, toxicity profile, antibody response, NIS 
imaging signal.  
 
12.5.3. Monitoring 
 
Members of the study team will review the study regularly to review the 
progress of this protocol and be kept aware of efficacy and toxicity issues. 
Indications for temporary stopping the study include: a) unexpected 
toxicity of any of the drugs; b) unexpected difficulties with production of 
MV-NIS; and c) unexpected difficulties with any of the assays required to 
monitor patient safety (qRT-PCR monitoring). 
 
12.5.4.  Early Stopping Rules 
 
Stopping rules will be put in place to protect the patients from excess 
toxicity.  The trial will be halted if serious treatment related toxicity or 
death occurs in 2 of the first 3 patients. If one serious treatment related 
toxicity or death occurs then a further 3 patients will be enrolled. The trial 
will be halted if >2 serious treatment related toxicities or deaths occur in 
the first 6 patients. An interim analysis will be performed after 6 patients 
and discussed with the DSMB.  If ≤2 serious treatment related toxicities or 
deaths occur in the first 6 patients then a further 3 patients will be enrolled. 
The trial will be halted if >3 serious treatment related toxicities or deaths 
occur in the first 9 patients. If ≤3 serious treatment related toxicities or 
deaths occur in the first 9 patients then a further 3 patients will be enrolled. 
The trial will be halted if >4 serious treatment related toxicities or deaths 
occur in the first 12 patients. If ≤4 serious treatment related toxicities or 


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deaths occur in the first 12 patients then a further 3 patients will be 
enrolled. The trial will be halted if >5 serious treatment related toxicities or 
deaths occur in the first 16 patients. 
 
13.0 
SUBSET ANALYSES FOR WOMEN AND MINORITIES: 
 
13.1. Eligibility 
 
This study will be available to all eligible patients, regardless of race, ethnic origin, 
and gender. There is no information currently available regarding differential 
effects of this regimen in subsets defined by race or gender, and there is no 
reason to expect such differences to exist. Therefore, although the planned 
analyses will, as always, look for differences in treatment effect based on gender 
and racial groupings, the sample size is not increased to provide additional 
power for subset analyses. 
 
13.2. Enrollment of Female Subjects 
 
Since women typically comprise 33% of this patient population, the number of 
women enrolled in this trial is expected to be approximately 5. 
 
13.3. Study Population Statistics 
 
Both men and women will be included in this study, in a 2:1 ratio, as this is a 
feature of the incidence of MM.  The study population will include non-Hispanic or 
Latinos of both White and African American races, at a ratio reflecting the patient 
population at our institution. 
 
Table 11. Study Cohort by Ethnicity, Race, and Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 
Not Hispanic or Latino 
6 
10 
16 
Unknown 
0 
0 
0 
Ethnic Category: Total of all subjects* 
6 
10 
16 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
2 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
5 
8 
13 
More than one race 
0 
0 
0 
Unknown 
0 
0 
0 
Racial Category: Total of all subjects 
6 
10 
16 
 


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Table 12. Definition of Ethnic and Racial Categories 
Ethnic Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central American, or other 
Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used in addition to 
“Hispanic or Latino.” 
Not Hispanic or Latino 
Racial Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples of North, 
Central, or South America, and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or the 
Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, 
the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been 
recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups of Africa. Terms 
such as “Haitian” or “Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original peoples of 
Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or North 
Africa. 


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14.0 
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9. Hanamura I, Stewart J, Huang Y, et al. Frequent gain of chromosome band 1q21 in plasma-
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12. Bushnell DL, Boles MA, Kaufman GE, Wadas MA, Barnes WE. Complications, sequela and 
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15. Mandell RB, Mandell LZ, Link CJ, Jr. Radioisotope concentrator gene therapy using the 
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2000;41:1898-904. 
17. Smit JW, Schroder-van der Elst JP, Karperien M, Que I, Romijn JA, van der Heide D. 
Expression of the human sodium/iodide symporter (hNIS) in xenotransplanted human 
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18. Spitzweg C, Dietz AB, O'Connor MK, et al. In vivo sodium iodide symporter gene therapy of 
prostate cancer. Gene Ther 2001;8:1524-31. 
19. Spitzweg C, O'Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC. Treatment of 
prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide 
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20. Thierens HM, Monsieurs MA, Brans B, Van Driessche T, Christiaens I, Dierckx RA. 
Dosimetry from organ to cellular dimensions. Computerized medical imaging and graphics : 
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21. Barlogie B, Anaissie E, Van Rhee F, et al. Total therapy (TT) for myeloma (MM) -10% cure 
rate with TT1 suggested by >10yr continuous complete remission (CCR): Bortezomib in TT3 
overcomes poor-risk associated with T(4:14)and DelTP53 in TT2. J Clin Oncol 
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22. Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in multiple 
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Haematol 2008;140:625-34. 
23. Shaughnessy JD, Jr., Qu P, Usmani S, et al. Pharmacogenomics of bortezomib test-dosing 
identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk 
feature in myeloma treated with Total Therapy 3. Blood 2011;118:3512-24. 
24. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic 
multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy 
(mSMART) consensus guidelines. Mayo Clin Proc 2009;84:1095-110. 
25. Arzoumanian V, Hoering A, Sawyer J, et al. Suppression of abnormal karyotype predicts 
superior survival in multiple myeloma. Leukemia 2008;22:850-5. 
26. Barlogie B, Smallwood L, Smith T, Alexanian R. High serum levels of lactic dehydrogenase 
identify a high-grade lymphoma-like myeloma. Annals of Internal Medicine 1989;110:521-5. 
27. Griffin D. Measles Virus. In: Fields B KD, Howley P, ed. Fields Virology. Philadelphia: 
Lippincott, Williams, & Wilkins; 2001:1551-85. 
28. Hilleman MR. Current overview of the pathogenesis and prophylaxis of measles with focus 
on practical implications. Vaccine 2001;20:651-65. 
29. Russell SJ. Replicating vectors for cancer therapy: a question of strategy. Semin Cancer 
Biol 1994;5:437-43. 
30. Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG. Randomised trial of 
intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple 
myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. 
Lancet 1994;343:1059-63. 
31. Jacobson DR, Zolla-Pazner S. Immunosuppression and infection in multiple myeloma. 
Semin Oncol 1986;13:282-90. 
32. Petersen J, Drivsholm A, Brandt M, Ambjornsen A, Dickmeiss E. B lymphocyte function in 
multiple myeloma: analysis of T cell- and monocyte-dependent antibody production. Eur J 
Haematol 1989;42:193-201. 
33. Bjerrum OW, Mansa B. Antibodies to common viruses in sera from patients with multiple 
myeloma. Acta pathologica, microbiologica, et immunologica Scandinavica Section B, 
Microbiology 1982;90:397-401. 
34. Heath RB, Fairley GH, Malpas JS. Production of Antibodies against Viruses in Leukaemia 
and Related Diseases. Br J Haematol 1964;10:365-70. 
35. Landesman SH, Schiffman G. Assessment of the antibody response to pneumococcal 
vaccine in high-risk populations. Reviews of infectious diseases 1981;3 Suppl:S184-97. 
36. Peng KW, Ahmann GJ, Pham L, Greipp PR, Cattaneo R, Russell SJ. Systemic therapy of 
myeloma xenografts by an attenuated measles virus. Blood 2001;98:2002-7. 
37. Liu YP, Suksanpaisan L, Steele MB, Russell SJ, Peng KW. Induction of antiviral genes by 
the tumor microenvironment confers resistance to virotherapy. Scientific reports 
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38. Katz S. Immunization of children with live attenuated measles vaccines: five years of 
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39. Anonymous. Update: vaccine side effects, adverse reactions, contraindications, and 
precautions recommendations of the Advisory Committee on Immunization Practices (ACIP). 
MMWR Morb Mortal Weekly Report 1996;45:1-35. 
40. Hilleman MR, Buynak EB, Weibel RE, Stokes J, Jr., Whitman JE, Jr., Leagus MB. 
Development and evaluation of the Moraten measles virus vaccine. JAMA 1968;206:587-90. 
41. Katz SL, Kempe CH, Black FL, et al. Studies on an attenuated measles-virus vaccine. VIII. 
General summary and evaluation of the results of vaccine. N Engl J Med 1960;263:180-4. 
42. Schwarz AJ, Boyer PA, Zirbel LW, York CJ. Experimental vaccination against measles. I. 
Tests of live measles and distemper vaccine in monkeys and two human volunteers under 
laboratory conditions. Journal of the American Medical Association 1960;173:861-7. 
43. Collard P, Hendrickse RG, Montefiore D, et al. Vaccination against measles. II. Clinical trial 
in Nigerian children. British medical journal 1961;2:1246-50. 
44. Aldous IR, Kirman BH, Butler N, Goffe AP, Laurence GD, Pollock TM. Vaccination aginst 
measles. III. Clinical trial in British children. British medical journal 1961;2:1250-3. 
45. Norby E. The paradigms of measles vaccinology. In: Meulen V MM, ed. Measles Virus. 
Heidelburgh: Springer-Verlag; 1995:167-80. 
46. Hill D. A Review of Cyclophosphamide. Springfield: Thomas; 1975. 
47. de Weerdt O, van de Donk NW, Veth G, Bloem AC, Hagenbeek A, Lokhorst HM. 
Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in 
patients with advanced multiple myeloma. The Netherlands journal of medicine 2001;59:50-
6. 
48. Lenhard RE, Jr., Kalish LA, Oken MM, Ettinger DS, Glick J. Timed-sequential high-dose 
cyclophosphamide and vincristine in the treatment of multiple myeloma. Cancer 
1994;73:2113-8. 
49. Szelenyi H, Kreuser ED, Keilholz U, et al. Cyclophosphamide, adriamycin and 
dexamethasone (CAD) is a highly effective therapy for patients with advanced multiple 
myeloma. Ann Oncol 2001;12:105-8. 
50. Barnard DL. Inhibitors of measles virus. Antiviral chemistry & chemotherapy 2004;15:111-9. 
51. Forni AL, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of 
clinical characteristics and therapy with intravenous ribavirin. Clin Infect Dis 1994;19:454-62. 
52. Duclos P, Ward BJ. Measles vaccines: a review of adverse events. Drug safety : an 
international journal of medical toxicology and drug experience 1998;19:435-54. 
53. Kaplan LJ, Daum RS, Smaron M, McCarthy CA. Severe measles in immunocompromised 
patients. JAMA 1992;267:1237-41. 
54. Watson JC HS, Dykewicz CA, Reef S, Phillips L. Measles, mumps, and rubella-vaccine use 
and strategies for elimination of measles, rubella, and congenital rubella syndrome and 
control of mumps: recommendations of the Advisory Committee on Immunization Practices 
(ACIP). MMWR Morb Mortal Weekly Report Recommendations and Reports/Centers for 
Disease Control 1996;47:1-57. 
55. Boddicker JD, Rota PA, Kreman T, et al. Real-time reverse transcription-PCR assay for 
detection of mumps virus RNA in clinical specimens. Journal of clinical microbiology 
2007;45:2902-8. 
 
 


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APPENDIX I: GUIDELINES FOR MV-NIS ADMINISTRATION 
BY NURSING STAFF 
Drug Information 
 
MV-NIS is a live, tissue culture-adapted MV engineered to express the human thyroidal sodium 
iodide symporter (NIS). The virus was constructed by inserting the NIS gene (cDNA) into a full-
length infectious molecular clone of an attenuated MV-Edm. This virus is not a vaccine. MV-NIS 
propagates on Vero cells with kinetics equivalent to the parental strain of virus. It propagates 
selectively in human cancer cells that it infects by binding preferentially to CD46, a membrane 
protein that is overexpressed in tumor cell lines including MM. The virus is directly cytopathic to 
tumor cells leading to the formation of multinucleated syncytia that die by apoptosis. MV-NIS 
infected tumor cells express NIS, a membrane ion channel that actively transports iodide into 
cells. Radioiodine uptake by cells expressing NIS provides the basis for in vivo radioiodine (or 
99mTcO4)  imaging that can reveal the profile of MV-NIS gene expression and the location of MV-
NIS infected cells during virus spread and elimination.  
 
Preparation and storage:  
 
MV-NIS will be prepared at the Virus and Vector Production Laboratory (VVPL) of the Molecular 
Medicine Program at Mayo Clinic and stored at ≤ -65C. The virus will be shipped to UAMS, 
thawed, and mixed with normal saline prior to administration according to good practice 
guidelines for any Biohazard Level 1 biological. A leak proof box, preferably equipped with a 
gasket seal lid, should be used for transport of MV-NIS from one location to another. 
 
The MV-NIS product will be dispensed with intravenous tubing attached that is primed 
with the base solution used for preparation of the medication. The product will be 
dispensed in leak-proof packaging and contain a label indicating safe handling 
precautions are required.  
 
The drug, dose, dilution, drug diluent, final product concentration, labeling and 
documentation of the preparation are checked by a pharmacist prior to dispensing.  
Administration:  
 
The MV-NIS product will be administered by slow IV infusion (30 minutes) in 100mL of normal 
saline under close observation in the Inpatient Unit.  
 
Personal protective equipment (PPE), including gloves, gowns, mask, and eye 
protection should be worn when handling the MV-NIS product. Protective eyewear must 
be worn at all times that the product is handled, and, in the event that splashing or 
spraying is anticipated, a mask or protective shield must be used. Protective eyewear 
should cover the eyes and areas above and below the eyes, and protection to the sides 
of both eyes. Face shields that extend from over the eye area to below the chin may be 
used. 
 
Prior to administration of MV-NIS, two persons qualified to administer chemotherapy 
shall verify the drug and dose against the orders and the protocol, and the identity of the 
patient to receive the MV-NIS.  


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 
The chemotherapy-prepared RN or prescriber educates the patient and/or family about 
the MV-NIS the patient will be receiving.  
 
MV-NIS administration is documented against the Medication Administration Record 
(MAR) in EPIC. A chemotherapy-prepared RN is responsible to review the Order to 
Infuse in EPIC with each dose to assure that there is agreement with the MAR and the 
label on the medication.  
 
Non-chemotherapy-prepared RNs and LPNs are able to do the following:  
o 
Monitor the intravenous site for patency  
o 
Monitor the infusion rate of intravenous cytotoxic medications  
o 
Interrupt and resume infusions  
o 
Discontinue infusions when completed.  
Other precautions – Inpatient Setting:  
 
Utensils (e.g., bedpans, urinals) are cleaned with an institutionally approved detergent 
and rinsed twice following each use.  
 
The toilet is covered with a white professional towel (plastic side up) and flushed twice. 
The white professional towel is disposed of in a red biohazard bag or biohazard waste 
container.  
 
Disposable patient care items contaminated with blood or body secretions are placed in 
a red biohazard bag or biohazard waste container.  
 
Soiled linen is placed in a clear plastic bag or a designated plastic chemotherapy bag 
and then put into a regular linen bag.  
 
Eating and drinking are prohibited in the patient’s room during the infusion, and extreme 
precautions are taken while handling needles and other sharp instruments. 
 
The patient should wear a surgical mask when outside of his/her hospital room while on 
UAMS grounds as long as persistent viral shedding is documented. 
 
All spills should be reported. 
 
A spill kit shall be kept available in the Inpatient Unit at all times. Cytotoxic Spill kits are 
available from the Department of Occupational Health and Safety.   
 
In case of a blood or body fluid exposure, thoroughly wash skin with soap and water; 
backbleed when appropriate; thoroughly rinse mucous membranes with water. Promptly 
report all exposures to management and Employee Health Services. Within 48 hours of 
the exposure, an Employee Incident Report should be completed. 
 
Known potential toxicities of MV-NIS: 
 
The virus was rescued from a derivative of the Edmonston B vaccine strain of MV and we 
anticipate that the most common toxicities will be similar to those experienced after the 
administration of the MV vaccine. The main reaction associated with MV vaccination is a mild 
MV-like syndrome that occurs in 2-3% of recipients usually 1 week after vaccination. Thus 
patients might experience moderate fever up to 39.4C and rash (minimal) within the first 5 to 12 
days after virus infusion. However it should be noted that this vaccine related MV-like illness has 
been described only in MV-naïve subjects. 
 
Not uncommon reactions: 
 
Moderate to high fever lasting 1 – 2 days, starting within a week or two of vaccination 
 
A rash, lasting 1 – 2 days 
 
Cough and rhinitis 
 
Erythema multiforme 


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 
Arthritis 
 
Unexpected and rare reactions associated with the vaccine: 
 
Allergic reactions including anaphylaxis 
 
Reactions at the injection site such as a wheal, flare or urticaria 
 
Thrombocytopenia 
 
Diarrhea 
 
Giant cell pneumonia 
 
Inclusion body encephalitis 
 
Guillain-Barré syndrome 
 
Vasculitis  
 
Otitis media  
 
Optic neuritis  
 
Ataxia  
 
Viral transmission between patient and his/her contacts is thought to be unlikely, unless the 
patient develops florid MV infection. The vaccine strain of the MV (of which MV-NIS is a 
derivative) has been shown to be shed in the urine of normal children undergoing routine 
vaccination. Despite the presence of viral shedding of the vaccine strain of MV, there has been 
only 1 case of symptomatic MV presumptively transmitted from a vaccinated individual.52  
However, since other patients on the UAMS grounds may be severely immunosuppressed, we 
will require that MV-NIS treated patients wear a surgical mask when outside of their hospital 
room on UAMS grounds while they are shedding virus (tested by qRT-PCR). 
    
We will be particularly vigilant for symptoms suggestive of either giant cell pneumonia or 
inclusion body encephalitis that have been rarely observed in immunocompromised patients 
who were administered the vaccine. If symptoms suggestive of persistent MV or either 
pneumonitis or encephalitis develop, the patients will be treated aggressively with Immune 
Globulin (GamaSTAN) and ribavirin and all the supportive care necessary as the situation might 
dictate. 
 


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APPENDIX II: RESPONSE CRITERIA AND SURVIVAL OUTCOME DEFINITIONS 
 
Timing of Response Evaluation 
Response will be evaluated according to the Schedule of Evaluations listed above (section 6.0)  
Definition of Measurable Disease 
Measurable protein criteria of the serum are defined as serum M-protein of IgG, IgA, IgD, IgE 
Isotype ≥ 1.0 gm/dl (10.0 g/L).   Measurable protein criteria of the urine are defined as urine M-
protein (Bence-Jones Protein) > 200 mg/24 hours. 
Participants with IgM peaks must have either  20% bone marrow plasmacytosis or >3 lytic 
lesions on skeletal survey. 
Non-Secretory Disease:  Participants without quantifiable M-proteins but with 20% bone 
marrow plasmacytosis will be assessed using plasma cell percentages.  These participants will 
be evaluated for CR, no CR, and progression/relapse using the criteria above. 
Response Criteria: 
 
Multiple Myeloma:  For the purpose of establishing one set of criteria for both Phase II and 
Phase III multiple myeloma studies, the following definitions will be used.  These definitions are 
based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for 
Multiple Myeloma43. 
Measurable Disease:  Measurable, quantifiable protein criteria must be present.  Acceptable 
protein criteria are:  
 
Serum M protein ≥ 1 g/dL (≥ 10 g/L), quantified by using densitometry on serum protein 
electrophoresis (SPEP).  
AND / OR 
 
Urine M protein [Bence-Jones Protein] ≥ 200 mg/24 hrs (> 0.2 g/24 hrs), quantified by 
24-hour urine protein electrophoresis (UPEP).  
OR 
 
Patients who have both serum M protein levels < 1 g/dL AND urine M protein levels < 
200 mg/24 hrs at baseline may be followed by serum free light chain (FLC) assay if 
involved free light chain level ≥ 10 mg/dL (≥ 100mg/L). 
Oligosecretory and Non-secretory Disease:  Patients that do not meet the criteria for 
measurable disease above may only be assessed for the following objective statuses: Stringent 
Complete Response, Stable, and Progression. 
Objective Status: 
Stringent Complete Response (sCR):   
 
Meets all of the criteria for Complete Response (CR) and   
 
normal serum free light chain ratio and 
 
absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence 
Complete Response (CR): 
 
Disappearance of all evidence of serum and urine M proteins on immunofixation 
electrophoresis studies and 


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 
≤ 5% plasma cells in bone marrow and 
 
disappearance of any soft tissue plasmacytomas 
Very Good Partial Response (VGPR): 
 
Meets all of the criteria for Partial Response (PR) and 
 
Serum and urine M proteins detectable by immunofixation but not on 
electrophoresis or  
 
≥ 90% reduction in serum M protein and urine M protein < 100 mg/24 hrs. 
Partial Response (PR): 
 
≥ 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by ≥90% or to < 200 mg/24 h 
 
If the serum and urine M-protein are unmeasurable at baseline, a ≥50% 
decrease in the difference between involved and uninvolved FLC levels is 
required in place of the M-protein criteria 
 
If serum and urine M-protein are not measurable, and serum free light assay is 
also not measurable, ≥50% reduction in plasma cells is required in place of M-
protein, provided baseline bone marrow plasma cell percentage was ≥ 30% 
 
In addidion to the above listed criteria, if present at baseline, a ≥ 50% reduction 
in the size of of soft tissue plasmacytomas is also required 
Stable Disease (SD): 
 
Patient does not meet criteria for Stringent Complete Response, Complete 
Response, Very Good Partial Response, Partial Response, or Progression. 
Progression (PD):  Any one or more of the following: 
 
Serum M protein increase ≥ 25% from lowest response value (or an increase of ≥ 
1 g/dL if serum M protein was ≥ 5 g/dL at baseline), with an absolute increase of 
≥ 0.5 g/dL and/or 
 
Urine M protein increase ≥ 25% from lowest response value, with an absolute 
increase of ≥ 200 mg/24 hrs and/or 
 
Only in patients without measurable serum and urine M-protein levels at 
baseline: ≥ 25% increase from lowest response value in the difference between 
involved and uninvolved serum free light chain level, with an absolute increase of 
>10 mg/dL 
 
Only in patients without measurable serum and urine M-protein levels and 
without measurable disease by free light chain levels, bone marrow plasma cell 
percentage increase ≥ 25% from lowest response value, with the absolute 
plasma cell % ≥ 10%  
 
Definite development of new  bone lesions or soft tissue plasmacytomas, or 
definite increase in size of existing bone lesions or soft tissue plasmacytomas 
(see Appendix III: Notes h.)  
 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to multiple myeloma 
 
NOTES: If a disease assessment indicates that a patient is experiencing a Stringent 
Complete Response, Complete Response, Very Good Partial Response, Partial 
Response, or Progression, this should be confirmed by a second disease assessment 
and this should be done prior to the institution of any new therapy.  The second disease 
assessment may be done at any time. 
 
CR, sCR, VGPR, and SD categories also require no known evidence of progressive or 
new bone lesions if radiographic studies were performed.  


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VGPR and CR categories require serum and urine studies regardless of whether 
disease at baseline was measurable on serum, urine, both, or neither. Radiographic 
studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be confirmed.  
For PD, serum-M component increases of more than or equal to 1 g/dL are sufficient to 
define relapse if starting M-component is ≥ 5 g/dL. 
*Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only 
measurable disease is by serum FLC levels: CR in such patients indicates a normal FLC 
ration of 0.26 to 1.65 in addition to CR criteria listed above. VGPR  in such patients 
requires a > 90% decrease in the difference between involved and uninvolved FLC 
levels. 
†Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be 
used only in patients without measurable disease by M protein and by FLC levels; “25% 
increase” refers to M protein, FLC, and bone marrow results, and does not refer to bone 
lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” 
does not need to be a confirmed value. 
The size of the soft tissue plasmacytomas is defined as the sum of the products of the 
cross-diameters of each plasmacytoma.  The size of the bone lesions will be determined 
in a similar manner.  A definite increase in the size is defined as a ≥ 50% increase (and 
at least 1 cm2) of this sum 
Survival Outcomes 
Overall Survival:  measured as the time from initial registration to death from any cause. 
Event-Free Survival:  measured as the time from initial registration to progression/relapse of 
disease or death from any cause. 


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APPENDIX III: DRUG INFORMATION 
 
MV-NIS 
 
MV-NIS is a live, tissue culture adapted MV engineered to express the human thyroidal sodium 
iodide symporter. The virus was constructed by inserting the NIS gene (cDNA) into a full-length 
infectious molecular clone of an attenuated MV-Edm. This virus is not a vaccine. MV-NIS 
propagates on Vero cells with kinetics equivalent to the parental strain of virus. It propagates 
selectively in human cancer cells that it infects by binding preferentially to CD46, a membrane 
protein that is overexpressed in tumor cell lines including MM. The virus is directly cytopathic to 
tumor cells leading to the formation of multinucleated syncytia that die by apoptosis. MV-NIS 
infected tumor cells express NIS, a membrane ion channel that actively transports iodide into 
cells. Radioiodine uptake by cells expressing NIS provides the basis for in vivo radioiodine 
imaging that can reveal the profile of MV-NIS gene expression and the location of MV-NIS 
infected cells during virus spread and elimination.  
 
Preparation and storage: MV-NIS will be prepared at the Virus and Vector Production 
Laboratory (VVPL) of the Molecular Medicine Program at Mayo Clinic and stored at ≤ -65C. 
The virus will be thawed and mixed with normal saline prior to administration. (See Appendix I) 
 
Administration: The virus will be administered by slow intravenous (IV) infusion (30 minutes) in 
100mL of normal saline under close observation in the inpatient unit. (See Appendix I) 
 
Known potential toxicities: MV-NIS has not been tested in the clinic and therefore, we do not 
know the potential toxicities. However, the virus was rescued from a derivative of the 
Edmonston B vaccine strain of MV and we anticipate that the most common toxicities will be 
similar to those experienced after the administration of the MV vaccine.52 The main reaction 
associated with MV vaccination is a mild MV-like syndrome that occurs in 2-3% of recipients 
usually 1 week after vaccination. Thus patients might experience moderate fever up to 39.4C 
and rash (minimal) within the first 5 to 12 days after virus injection. However it should be noted 
that this vaccine related MV-like illness has been described only in MV-naïve subjects. 
 
Not uncommon reactions: 
 
Moderate to high fever lasting 1 – 2 days, starting within a week or two of vaccination 
 
A rash, lasting 1 – 2 days 
 
Cough and rhinitis 
 
Erythema multiforme 
 
Arthritis 
 
Unexpected and rare reactions associated with the vaccine: 
 
Allergic reactions including anaphylaxis 
 
Reactions at the injection site such as a wheal, flare or urticaria 
 
Thrombocytopenia 
 
Diarrhea 
 
Giant cell pneumonia 
 
Inclusion body encephalitis 
 
Guillain-Barré syndrome 
 
Vasculitis  
 
Otitis media  


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 
Optic neuritis  
 
Ataxia  
 
We will be particularly vigilant for symptoms suggestive of either giant cell pneumonia or 
inclusion body encephalitis that have been rarely observed in immunocompromised patients 
who were administered the vaccine. 53  If symptoms suggestive of persistent MV or either 
pneumonitis or encephalitis develop, the patients will be treated aggressively with Immune 
Globulin (GamaSTAN) and ribavirin and all the supportive care necessary as the situation 
might dictate.54 
 
Risks to caretakers and other Clinic Patients 
Viral transmission between patient and his/her contacts is thought to be unlikely, unless the 
patient develops florid MV infection. The vaccine strain of the MV (of which MV-NIS is a 
derivative) has been shown to be shed in the urine of normal children undergoing routine 
vaccination. Despite the presence of viral shedding of the vaccine strain of MV, there has been 
only 1 case of symptomatic MV presumptively transmitted from a vaccinated individual.55 
However, since other patients on UAMS grounds may be severely immunosuppressed, we will 
require that MV-NIS-treated patients wear a surgical mask when outside of their hospital room 
on UAMS grounds while they are shedding virus (tested by qRT-PCR).  
 
 
Sodium Pertechnetate - 99mTcO4 
 
PHARMACOLOGY: The pertechnetate ion distributes in the body similarly to the iodide ion, but 
is not organified when trapped in the thyroid gland. Pertechnetate tends to accumulate in 
intracranial lesions with excessive neovascularity or an altered blood-brain barrier. It also 
concentrates in the thyroid gland, salivary glands, gastric mucosa, and choroids plexus. 
However, in contrast to the iodide ion, the pertechnetate ion is released unchanged from the 
thyroid gland.  After intravascular administration, the pertechnetate ion remains in the circulatory 
system for sufficient time to permit blood pool measurement, organ perfusion, and major vessel 
studies. It gradually equilibrates with the extravascular space. A small fraction is promptly 
excreted via the kidneys.  
  
Indications 
 
Sodium Pertechnetate 99mTcO4 is used IN ADULTS as an agent for: 
 Brain Imaging (including cerebral radionuclide angiography) 
 Thyroid Imaging 
 Salivary Gland Imaging 
 Placenta Localization 
 Blood Pool Imaging (including radionuclideangiography) 
 Urinary Bladder Imaging (direct isotopic cystography) for detection of vesico-ureteral 
reflux 
 
Nasolacrimal Drainage System Imaging (dacryoscintigraphy) Sodium Pertechnetate 99mTcO4 is 
used IN PEDIATRIC PATIENTS as an agent for: 
 Brain Imaging (including cerebral radionuclide angiography) 
 Thyroid Imaging 
 Blood Pool Imaging (including radionuclide angiography) 


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 Urinary Bladder Imaging (direct isotopic 
 cystography) for the detection of vesico-ureteral reflux 
 
CONTRAINDICATIONS 
None known. 
 
Known potential toxicities 
 
Allergic reactions including anaphylaxis have been reported infrequently following administration, 
however, no toxicity is expected from the diagnostic doses of 99mTcO4 to be used in this study. 
 
WARNINGS 
 
Radiation risks associated with the use of Sodium Pertechnetate 99mTcO4 are greater in 
pediatric patients 
than in adults and, in general, the younger the patient the greater the risk owing to greater 
absorbed radiation doses and longer life expectancy. These greater risks should be taken firmly 
into account in all benefit risk assessments involving pediatric patients. Only use generator 
eluant specified for use with the 
Ultra-TechneKow™ DTE Generator. Do not use any other generator eluant or saline from any 
other source. 
 
PRECAUTIONS 
 
As in the use of any radioactive material, care should be taken to minimize radiation exposure to 
the patient consistent with proper patient management and to insure minimum radiation 
exposure to occupational workers. Radiopharmaceuticals should be used only by physicians 
who are qualified by training and experience in the safe use and handling of radionuclides and 
whose experience and training have been approved by the appropriate government agency 
authorized to license the use of radionuclides. 
After the termination of the nasolacrimal imaging procedure, blowing the nose and washing the 
eyes with sterile distilled water or an isotonic sodium chloride solution will further minimize the 
radiation dose. Since the eluate does not contain an antimicrobial agent, it should not be used 
after 12 hours from time of generator elution.  
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
No long-term animal studies have been performed to evaluate carcinogenic or mutagenic 
potential or 
whether Sodium Pertechnetate 99mTcO4 may affect fertility in males or females.  
 
Pregnancy Category C 
 
Animal reproductive studies have not been conducted with Sodium Pertechnetate 99mTcO4. It is 
also not known whether Sodium Pertechnetate 99mTcO4 can cause fetal harm when 
administered to a pregnant woman or can affect reproductive capacity. Sodium Pertechnetate 
99mTcO4 should be given to pregnant women only if the expected benefits to be gained clearly 
outweigh thepotential hazards. Ideally, examinations using radiopharmaceutical drug products - 
especially those elective in nature - in women of childbearing capability should be performed 
during the first ten days following the onset of menses. 


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Nursing Mothers 
 
Technetium 99mTcO4 is excreted in human milk during lactation, therefore, formula-feedings 
should be substituted for breast-feedings. 
 
Dosage and Administration 
 
Sodium Pertechnetate 99mTcO4 is usually administered by intravenous injection, but can be 
given orally. 
 
For imaging the urinary bladder and ureters, (direct isotopic cystography), the sodium 
perytechnetate 99mTcO4 injection is instilled aseptically into the bladder via a urethral catheter, 
following which the catheter is flushed with approximately 200 mL of sterile saline directly into 
the bladder. The dosage employed varies with each diagnostic procedure. If the oral route is 
elected, the patient should fast for at least six (6) hours before and two (2) hours after 
administration. When imaging the nasolacrimal drainage system, instill the sodium 
pertechnetate 99mTcO4 injection by the use of a device such as a micropipette or  
similar method which will ensure the accuracy of the dose.  
 
How Supplied 
 
Sodium pertechnetate 99mTcO4 injection is supplied as a Molybdenum Mo 99/Technetium Tc 
99m generator in sizes of molybdenum Mo 99 from 30.7 GBq up to 614.2 GBq, 830 mCi up to 
16,600 mCi, as of the date and time of calibration specified on the generator label, in 
approximately 30.7 GBq, 830 mCi increments. The Technetium 99mTcO4 Generator consists of:  
1. Sterile generator  
2. Sodium Chloride Injection source  
3. Sterile evacuated vials (10 and 20 cc sizes)*  
4. Sterile needles  
5. Elution vial shield (initial order only if needed)  
6. Finished drug labels  
7. Package insert  
 
Preparation and Storage 
 
Store generator at room temperature (18-25 °C).  
CAUTION: Avoid freezing.  
These radionuclides will be obtained, prepared, stored and delivered to the only by the 
Department of Nuclear Medicine using methods and procedures that are standard and routine 
to that department.  
 
Cyclophosphamide (Cytoxan) 
 
Preparation and Storage: Injectable powder is stored at room temperature. The temperature is 
not to exceed 90°F.  
a. Reconstituted parental solutions are stable for 24 hours at room temperature or 14 days if 
refrigerated. Dissolve the 100, 200, 500 mg, 1 g and 2 g vials in 5, 10, 25, 50 and 100 mL 
of sterile water, respectively, resulting in a solution of 20 mg/mL.  Shake vials vigorously 


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and warm slightly in lukewarm water to facilitate dissolution. The lyophilized form is more 
easily soluble.  
 
Known potential toxicities:  
 
Hematologic: Leukopenia, with nadirs about 8-14 days after administration and recovery 18-25 
days. Anemia 
 
Dermatologic: Alopecia. 
 
 
Gastrointestinal: Nausea and vomiting (begins 6-10 hours after administration). 
 
Hepatic: Increased AST, ALT. 
 
Neurologic: Headache, dizziness. 
 
Pulmonary: Rarely, interstitial pulmonary fibrosis. 
 
Cardiovascular: Cardiomyopathy, thrombosis/embolism. 
 
Renal: Hemorrhagic cystitis (onset of cystitis may be delayed from 24 hours to several weeks).  
 
Other: Metallic taste during injection, nasal congestion, testicular atrophy, amenorrhea, may be 
long term, rarely anaphylaxis, teratogenesis, may cause secondary neoplasms, secondary 
AML/MDS (risk is uncommon but may be increased when given in combination with an 
anthracycline, especially if one or both drugs are given at higher than standard doses), 
secondary tumors.  
 
 
 
Availability: Commercially available in 100, 200, 500 mg, 1 g and 2g vials. 
 
Cyclophosphamide is an alkylating agent. 
 
Nursing Guidelines: 
 
Leukopenia nadir occurs 8-14 days after administration and recovery is usually 18-25 days. 
Monitor CBC.  
 
Instruct patient to drink 2-3 liters of fluid per day for 2-3 days following treatment and to void 
frequently, not greater than every 3 hours to facilitate keeping the bladder clear of drug.  
 
Instruct patient to report any urinary urgency, frequency, dysuria or hematuria.  
 
Advise patient of possible strong metallic taste associated with cyclophosphamide and suggest 
hard candy with a strong flavor (cinnamon, peppermint) to alleviate it.  
 
Administer antiemetics as necessary to minimize nausea and vomiting, which usually occurs 6-8 
hours after administration.  
 
Report and record any complaint of lightheadedness, facial “heat sensation”, diaphoresis during 
administration.  


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Use of an ice cap may be helpful in preventing or limiting alopecia.  
 
Corticosteroids, phenothiazine, imipramine and allopurinol may inhibit cyclophosphamide 
metabolism and modify its effect. They may also increase BM suppression. 
 
Advise female patients of possible menstrual changes or amenorrhea. 
 


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APPENDIX IV: SUMMARY OF AEs 
Phase I Goal: Estimate MTD of this Combination 
Patient Status Listing 
Obs 
Data 
Center 
ID 
Date 
on 
Date off 
Replaced 
Group 
Dose Level 
Expected 
End of 
Cycle 1 
Current 
Dose 
Level 
AE Data 
Submitted 
Dose 
Limiting 
Toxicity 
1 3324593 02/23/2007 03/19/2007 
 Stage 1 
MV-NIS Dose Level 1 03/23/2007 
 
Yes 
No 
2 6328484 03/23/2007 05/08/2007 
 Stage 1 
MV-NIS Dose Level 1 04/20/2007 
 
Yes 
No 
3 3024984 04/19/2007 05/30/2007 
 Stage 1 
MV-NIS Dose Level 1 05/17/2007 
 
Yes 
No 
4 6121247 01/17/2008 03/04/2008 
 Stage 1 
MV-NIS Dose Level 2 02/14/2008 
 
Yes 
No 
5 6459047 01/31/2008 03/17/2008 
 Stage 1 
MV-NIS Dose Level 2 02/28/2008 
 
Yes 
No 
6 6469760 03/27/2008 05/12/2008 
 Stage 1 
MV-NIS Dose Level 2 04/24/2008 
 
Yes 
No 
7 6353196 05/08/2008 06/25/2008 
 Stage 1 
MV-NIS Dose Level 3 06/05/2008 
 
Yes 
No 
8 6126892 06/27/2008 08/14/2008 
 Stage 1 
MV-NIS Dose Level 3 07/25/2008 
 
Yes 
No 
9 6360266 10/10/2008 11/21/2008 
 Stage 1 
MV-NIS Dose Level 3 11/07/2008 
 
Yes 
No 
10 5272446 04/08/2009 05/21/2009 
 Stage 1 
MV-NIS Dose Level 4 05/06/2009 
 
Yes 
No 
11 5470267 04/24/2009 04/28/2009 
Yes Stage 1 
MV-NIS Dose Level 4 05/22/2009 
 
Yes 
 
12 7069965 06/04/2009 07/07/2009 
 Stage 1 
MV-NIS Dose Level 4 07/02/2009 
 
Yes 
No 
13 4458079 10/16/2009 12/02/2009 
 Stage 1 
MV-NIS Dose Level 4 11/13/2009 
 
Yes 
No 
14 5459036 01/15/2010 03/01/2010 
 Stage 2 
MV-NIS Dose Level 1 02/12/2010 
 
Yes 
 
15 6040166 05/20/2010 07/07/2010 
 Stage 2 
MV-NIS Dose Level 1 06/17/2010 
 
Yes 
 
16 6427326 05/26/2010 07/07/2010 
 Stage 2 
MV-NIS Dose Level 1 06/23/2010 
 
Yes 
 
17 7098506 11/12/2010 12/27/2010 
 Stage 2 
MV-NIS Dose Level 2 12/10/2010 
 
Yes 
 
18 6248674 01/07/2011 02/23/2011 
 Stage 2 
MV-NIS Dose Level 2 02/04/2011 
 
Yes 
 
19 6460890 01/14/2011 02/28/2011 
 Stage 2 
MV-NIS Dose Level 2 02/11/2011 
 
Yes 
 
20 6035553 05/25/2011 07/20/2011 
 Stage 2 
MV-NIS Dose Level 3 06/22/2011 
 
Yes 
 
21 5479089 07/12/2011 09/01/2011 
 Stage 2 
MV-NIS Dose Level 3 08/09/2011 
 
Yes 
 
22 7262514 11/14/2011 02/08/2012 
 Stage 1 
MV-NIS Dose Level 5 12/12/2011 
 
Yes 
No 
23 5408341 12/09/2011 01/20/2012 
 Stage 1 
MV-NIS Dose Level 5 01/06/2012 
 
Yes 
No 
24 6116386 04/24/2012 06/01/2012 
 Stage 1 
MV-NIS Dose Level 5 05/22/2012 
 
Yes 
No 
25 7326935 11/02/2012 01/03/2013 
 Stage 1 
MV-NIS Dose Level 5 11/30/2012 
 
Yes 
No 
26 7210900 02/01/2013 
 
Yes Stage 1 
MV-NIS Dose Level 6 03/01/2013 
 
Yes 
No 
27 6167970 04/26/2013 06/06/2013 
 Stage 1 
MV-NIS Dose Level 6 05/24/2013 
 
Yes 
No 
28 6199727 05/24/2013 07/16/2013 
 Stage 1 
MV-NIS Dose Level 6 06/21/2013 
 
Yes 
No 
29 6084741 07/26/2013 
 
 Stage 1 
MV-NIS Dose Level 6 08/23/2013 
 
Yes 
Yes 
 


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Follow Up 
 
Obs 
Data 
Center 
ID 
Follow Up Date 
Follow Up 
Status 
Prog Date 
Prog 
Status 
Date off 
Reason 
End 
Treatment 
1 3324593 
09/30/2007 
Dead 
03/19/2007 
Prog 
03/19/2007 
Dx Prog 
2 6328484 
03/05/2012 
Alive 
05/07/2007 No Prog 
05/08/2007 
Complete Rx 
3 3024984 
10/30/2007 
Dead 
05/30/2007 
Prog 
05/30/2007 
Dx Prog 
4 6121247 
08/24/2008 
Dead 
03/04/2008 
Prog 
03/04/2008 
Dx Prog 
5 6459047 
10/12/2008 
Dead 
03/17/2008 
Prog 
03/17/2008 
Dx Prog 
6 6469760 
04/17/2009 
Alive 
04/17/2009 No Prog 
05/12/2008 
Complete Rx 
7 6353196 
03/21/2009 
Dead 
08/05/2008 No Prog 
06/25/2008 
Complete Rx 
8 6126892 
07/09/2009 
Alive 
08/13/2008 
Prog 
08/14/2008 
Dx Prog 
9 6360266 
07/30/2009 
Dead 
11/20/2008 
Prog 
11/21/2008 
Dx Prog 
10 5272446 
08/17/2012 
Alive 
07/24/2009 
Prog 
05/21/2009 
Complete Rx 
11 5470267 
05/18/2009 
Dead 
04/28/2009 No Prog 
04/28/2009 
Other Med Prob 
12 7069965 
07/07/2009 
Alive 
07/07/2009 
Prog 
07/07/2009 
Dx Prog 
13 4458079 
02/12/2010 
Dead 
01/10/2010 
Prog 
12/02/2009 
Complete Rx 
14 5459036 
10/22/2011 
Dead 
03/01/2010 
Prog 
03/01/2010 
Complete Rx 
15 6040166 
02/22/2011 
Dead 
05/20/2010 No Prog 
07/07/2010 
Complete Rx 
16 6427326 
06/03/2011 
Alive 
08/26/2010 
Prog 
07/07/2010 
Complete Rx 
17 7098506 
03/21/2011 
Dead 
11/19/2010 
Prog 
12/27/2010 
Complete Rx 
18 6248674 
12/27/2011 
Dead 
02/23/2011 
Prog 
02/23/2011 
Dx Prog 
19 6460890 
12/13/2011 
Dead 
02/28/2011 
Prog 
02/28/2011 
Complete Rx 
20 6035553 
05/24/2012 
Alive 
07/20/2011 
Prog 
07/20/2011 
Complete Rx 
21 5479089 
03/12/2012 
Dead 
09/01/2011 
Prog 
09/01/2011 
Complete Rx 
22 7262514 
05/31/2012 
Dead 
02/06/2012 
Prog 
02/08/2012 
Complete Rx 
23 5408341 
02/12/2013 
Alive 
06/01/2012 
Prog 
01/20/2012 
Complete Rx 
24 6116386 
08/19/2012 
Dead 
07/27/2012 
Prog 
06/01/2012 
Complete Rx 
25 7326935 
06/07/2013 
Alive 
01/03/2013 No Prog 
01/03/2013 
Complete Rx 
26 7210900 
05/23/2013 
Alive 
05/23/2013 No Prog 
 
 
27 6167970 
07/17/2013 
Alive 
06/06/2013 No Prog 
06/06/2013 
Complete Rx 
28 6199727 
07/16/2013 
Alive 
06/16/2013 No Prog 
07/16/2013 
Complete Rx 
29 6084741 
09/12/2013 
Alive 
09/12/2013 No Prog 
 
 
 
 
 
Cycle 1 AEs by Dose Level 


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Group=Stage 1 doselevl2=MV-NIS Dose Level 1 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
3324593 
Creatinine increased 
1 
UNLIKELY 
No 
 
Dehydration 
3 
UNLIKELY 
No 
 
Fever 
1 
UNLIKELY 
No 
 
Hemoglobin decreased 
3 
UNLIKELY 
No 
 
Platelet count decreased 
2 
POSSIBLE 
No 
6328484 
Cough 
1 
POSSIBLE 
No 
 
Fever 
1 
POSSIBLE 
No 
 
Hemoglobin decreased 
1 
UNLIKELY 
No 
 
Leukocyte count decreased 
2 
POSSIBLE 
No 
 
Neutrophil count decreased 
2 
POSSIBLE 
No 
 
Platelet count decreased 
1 
POSSIBLE 
No 
3024984 
Actvtd prtl thromboplastin tm prolonged 
2 
POSSIBLE 
No 
 
Cough 
1 
UNLIKELY 
No 
 
Creatinine increased 
1 
NOT RELATED 
No 
 
Hemoglobin decreased 
4 
UNLIKELY 
No 
 
Nausea 
3 
NOT RELATED 
No 
 
Neutrophil count decreased 
1 
UNLIKELY 
No 
 
Platelet count decreased 
3 
UNLIKELY 
No 
 
Vomiting 
3 
NOT RELATED 
No 
 
Duodenal hemorrhage 
2 
UNLIKELY 
No 
 
  
Cycle 1 AEs by Dose Level 
Group=Stage 1 doselevl2=MV-NIS Dose Level 2 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
6121247 
Creatinine increased 
1 
NOT RELATED 
No 
 
Hemoglobin decreased 
3 
NOT RELATED 
No 
 
Leukocyte count decreased 
3 
NOT RELATED 
No 
 
Neutrophil count decreased 
3 
NOT RELATED 
No 
 
Platelet count decreased 
2 
NOT RELATED 
No 
6459047 
Creatinine increased 
2 
UNLIKELY 
No 
 
Hemoglobin decreased 
2 
UNLIKELY 
No 
 
Hypercalcemia 
3 
UNLIKELY 
No 


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Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
 
Leukocyte count decreased 
1 
POSSIBLE 
No 
 
Nausea 
3 
UNLIKELY 
No 
 
Neutrophil count decreased 
1 
POSSIBLE 
No 
 
Platelet count decreased 
2 
POSSIBLE 
No 
 
Vomiting 
1 
UNLIKELY 
No 
6469760 
Hemoglobin decreased 
3 
POSSIBLE 
No 
 
Leukocyte count decreased 
2 
POSSIBLE 
No 
 
Nausea 
2 
POSSIBLE 
No 
 
Neutrophil count decreased 
3 
POSSIBLE 
No 
 
Platelet count decreased 
3 
POSSIBLE 
No 
 
Vomiting 
2 
POSSIBLE 
No 
 
 
Cycle 1 AEs By Dose Level 
Group=Stage 1 doselevl2=MV-NIS Dose Level 3 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
6353196 
Hemoglobin decreased 
2 
UNLIKELY 
No 
 
Leukocyte count decreased 
3 
POSSIBLE 
No 
 
Neutrophil count decreased 
3 
PROBABLE 
No 
 
Platelet count decreased 
1 
UNLIKELY 
No 
6126892 
Hemoglobin decreased 
2 
UNLIKELY 
No 
 
Leukocyte count decreased 
3 
PROBABLE 
No 
 
Neutrophil count decreased 
2 
PROBABLE 
No 
 
Platelet count decreased 
1 
UNLIKELY 
No 
6360266 
Cough 
1 
UNLIKELY 
No 
 
Creatinine increased 
2 
NOT RELATED 
No 
 
Diarrhea 
2 
POSSIBLE 
No 
 
Hemoglobin decreased 
2 
NOT RELATED 
No 
 
Leukocyte count decreased 
2 
NOT RELATED 
No 
 
Nausea 
1 
POSSIBLE 
No 
 
Neutrophil count decreased 
3 
UNLIKELY 
No 
 
Platelet count decreased 
4 
NOT RELATED 
No 
 
 
Cycle 1 AEs By Dose Level 


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Group=Stage 1 doselevl2=MV-NIS Dose Level 4 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
5272446 
Hemoglobin 
decreased 
1 
POSSIBLE 
No 
 
Leukocyte count 
decreased 
2 
POSSIBLE 
No 
 
Neutrophil count 
decreased 
2 
POSSIBLE 
No 
7069965 
Anorexia 
3 
NOT RELATED 
No 
 
Bone pain 
3 
NOT RELATED 
No 
 
Chills 
1 
UNLIKELY 
No 
 
Cough 
1 
NOT RELATED 
No 
 
Creatinine increased 
1 
NOT RELATED 
No 
 
Diarrhea 
1 
UNLIKELY 
No 
 
Hemoglobin 
decreased 
1 
 
No 
 
Hypercalcemia 
3 
NOT RELATED 
No 
 
Leukocyte count 
decreased 
1 
POSSIBLE 
No 
 
Nausea 
3 
UNLIKELY 
No 
 
Platelet count 
decreased 
3 
NOT RELATED 
No 
 
Rash desquamating 
1 
POSSIBLE 
No 
4458079 
Creatinine increased 
1 
 
No 
 
Fever 
1 
 
No 
 
Hemoglobin 
decreased 
3 
UNLIKELY 
No 
 
Leukocyte count 
decreased 
1 
 
No 
 
 
Cycle 1 AEs By Dose Level 
Group=Stage 1 doselevl2=MV-NIS Dose Level 5 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
7262514 
Aspartate aminotransferase 
increased 
2 
POSSIBLE 
No 
 
Chills 
1 
UNLIKELY 
No 
 
Cough 
2 
UNLIKELY 
No 


UARK 2014-21 
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Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
 
Creatinine increased 
2 
UNLIKELY 
No 
 
Fever 
1 
UNLIKELY 
No 
 
Hemoglobin decreased 
4 
POSSIBLE 
No 
 
Hyperkalemia 
3 
NOT RELATED 
No 
 
Hyperuricemia 
4 
NOT RELATED 
No 
 
Hyponatremia 
3 
UNLIKELY 
No 
 
Infection(gr 0/1/2 ANC) 
3 
UNLIKELY 
No 
 
Leukocyte count decreased 
2 
POSSIBLE 
No 
 
Nausea 
1 
POSSIBLE 
No 
 
Neutrophil count decreased 
2 
POSSIBLE 
No 
 
Platelet count decreased 
4 
NOT RELATED 
No 
 
Renal failure 
3 
UNLIKELY 
No 
 
Vomiting 
1 
POSSIBLE 
No 
5408341 
Creatinine increased 
2 
UNLIKELY 
No 
 
Diarrhea 
1 
POSSIBLE 
No 
 
Hemoglobin decreased 
2 
UNLIKELY 
No 
 
Hypothyroidism 
1 
UNLIKELY 
No 
 
Leukocyte count decreased 
2 
NOT RELATED 
No 
 
Nausea 
1 
POSSIBLE 
No 
 
Neutrophil count decreased 
3 
UNLIKELY 
No 
 
Platelet count decreased 
2 
UNLIKELY 
No 
6116386 
Chills 
2 
DEFINITE 
No 
 
Creatinine increased 
2 
POSSIBLE 
No 
 
Fever 
1 
DEFINITE 
No 
 
Hemoglobin decreased 
3 
POSSIBLE 
No 
 
Leukocyte count decreased 
3 
POSSIBLE 
No 
 
Nausea 
2 
POSSIBLE 
No 
 
Neutrophil count decreased 
3 
UNLIKELY 
No 
 
Platelet count decreased 
3 
PROBABLE 
No 
 
Restrictive cardiomyopathy 
3 
UNLIKELY 
No 
 
Vomiting 
2 
POSSIBLE 
No 
7326935 
Cough 
1 
UNLIKELY 
No 
 
Diarrhea 
1 
UNLIKELY 
No 
 
Hemoglobin decreased 
2 
 
No 
 
Platelet count decreased 
2 
 
No 
 


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Cycle 1 AEs By Dose Level 
Group=Stage 1 doselevl2=MV-NIS Dose Level 6 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
7210900 
Hemoglobin decreased 
2 
UNLIKELY 
No 
 
Leukocyte count decreased 
3 
 
No 
 
Nausea 
1 
UNLIKELY 
No 
 
Neutrophil count decreased 
4 
PROBABLE 
No 
 
Platelet count decreased 
1 
PROBABLE 
No 
 
Rash desquamating 
1 
POSSIBLE 
No 
 
Cytokine release syndrome 
2 
PROBABLE 
No 
 
Pain 
2 
PROBABLE 
No 
 
Upper respiratory infectn(gr 
0/1/2 ANC) 
2 
POSSIBLE 
No 
6167970 
Diarrhea 
2 
PROBABLE 
No 
 
Fever 
1 
PROBABLE 
No 
 
Hemoglobin decreased 
1 
PROBABLE 
No 
 
Leukocyte count decreased 
1 
PROBABLE 
No 
 
Nausea 
2 
PROBABLE 
No 
 
Neutrophil count decreased 
2 
PROBABLE 
No 
 
Platelet count decreased 
1 
PROBABLE 
No 
 
Vomiting 
2 
PROBABLE 
No 
6199727 
Cough 
1 
 
No 
 
Diarrhea 
2 
POSSIBLE 
No 
 
Fever 
1 
PROBABLE 
No 
 
Hemoglobin decreased 
2 
DEFINITE 
No 
 
Leukocyte count decreased 
2 
DEFINITE 
No 
 
Nausea 
2 
POSSIBLE 
No 
 
Neutrophil count decreased 
3 
POSSIBLE 
No 
 
Platelet count decreased 
4 
DEFINITE 
No 
 
Vomiting 
2 
POSSIBLE 
No 
6084741 
Chills 
1 
UNLIKELY 
Yes 
 
Fever 
2 
UNLIKELY 
Yes 
 
Hemoglobin decreased 
3 
NOT RELATED 
Yes 
 
Leukocyte count decreased 
3 
NOT RELATED 
Yes 
 
Neutrophil count decreased 
3 
NOT RELATED 
Yes 
 
Platelet count decreased 
4 
UNLIKELY 
Yes 
 


UARK 2014-21 
August 21, 2015 
Version 11 
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Cycle 1 AEs By Dose Level 
Group=Stage 2 doselevl2=MV-NIS Dose Level 1 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
5459036 
Creatinine increased 
1 
 
 
 
Hemoglobin decreased 
2 NOT RELATED 
 
 
Nausea 
1 NOT RELATED 
 
 
Neutrophil count decreased 
2 
POSSIBLE 
 
6040166 
Fracture 
3 NOT RELATED 
 
 
Hemoglobin decreased 
3 
UNLIKELY 
 
 
Hyperglycemia 
2 
UNLIKELY 
 
 
Joint pain 
3 
UNLIKELY 
 
 
Leukocyte count decreased 
4 
UNLIKELY 
 
 
Lymphocyte count decreased 
4 NOT RELATED 
 
 
Neutrophil count decreased 
4 
UNLIKELY 
 
 
Platelet count decreased 
4 
UNLIKELY 
 
 
Rash desquamating 
1 
 
 
6427326 
Hemoglobin decreased 
1 NOT RELATED 
 
 
Leukocyte count decreased 
2 
 
 
 
Nausea 
1 
 
 
 
Neutrophil count decreased 
1 
 
 
 
Platelet count decreased 
1 NOT RELATED 
 
 
Treatment related secondary 
malignancy 
3 NOT RELATED 
 
 
 
 
 
Cycle 1 AEs By Dose Level 
Group=Stage 2 doselevl2=MV-NIS Dose Level 2 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
7098506 
Creatinine increased 
2 
NOT RELATED 
 
 
Hemoglobin decreased 
2 
UNLIKELY 
 
 
Leukocyte count decreased 
2 
NOT RELATED 
 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 74 of 80 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
 
Nausea 
1 
POSSIBLE 
 
 
Neutrophil count decreased 
3 
UNLIKELY 
 
 
Platelet count decreased 
2 
UNLIKELY 
 
 
Rash desquamating 
1 
POSSIBLE 
 
6248674 
Cough 
1 
NOT RELATED 
 
 
Diarrhea 
1 
NOT RELATED 
 
 
Hemoglobin decreased 
2 
NOT RELATED 
 
 
Leukocyte count decreased 
1 
 
 
 
Nausea 
2 
NOT RELATED 
 
 
Platelet count decreased 
1 
NOT RELATED 
 
 
Vomiting 
1 
 
 
6460890 
Cough 
1 
 
 
 
Diarrhea 
1 
UNLIKELY 
 
 
Hemoglobin decreased 
1 
NOT RELATED 
 
 
Leukocyte count decreased 
2 
 
 
 
Lymphocyte count decreased 
3 
UNLIKELY 
 
 
Neutrophil count decreased 
1 
 
 
 
Platelet count decreased 
1 
NOT RELATED 
 
 
 
Cycle 1 AEs By Dose Level 
Group=Stage 2 doselevl2=MV-NIS Dose Level 3 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
6035553 
Cough 
1 NOT RELATED 
 
 
Creatinine increased 
2 
UNLIKELY 
 
 
Diarrhea 
1 NOT RELATED 
 
 
Hemoglobin decreased 
1 
UNLIKELY 
 
 
Left ventricular failure 
3 
POSSIBLE 
 
 
Leukocyte count decreased 
3 
POSSIBLE 
 
 
Lymphocyte count decreased 
3 
POSSIBLE 
 
 
Nausea 
1 
UNLIKELY 
 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 75 of 80 
 
Data 
Center 
ID 
Toxicity 
Grade 
Relationship 
Study 
Meds 
Dose 
Limiting 
Toxicity 
 
Neutrophil count decreased 
3 
POSSIBLE 
 
 
Platelet count decreased 
2 
POSSIBLE 
 
5479089 
Cough 
1 
UNLIKELY 
 
 
Fever 
1 
POSSIBLE 
 
 
Hemoglobin decreased 
2 
UNLIKELY 
 
 
Leukocyte count decreased 
3 
POSSIBLE 
 
 
Nausea 
2 
POSSIBLE 
 
 
Neutrophil count decreased 
3 
PROBABLE 
 
 
Platelet count decreased 
2 
UNLIKELY 
 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
Group=Stage 1 doselevl2=MV-NIS Dose Level 1 
 
 
Grade 
1 2 3 4 
N N N N 
Body#System 
Toxicity 
1 2 2 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
 3 
 
 
Neutrophil count decreased 
 1 1 
 
Platelet count decreased 
 2 2 1 
Renal /Genitourinary 
Creatinine increased 
1 1 
 
 
Constitutional Symptoms 
Fever 
2 
 
 
 
Dermatology/Skin 
Rash desquamating 
2 1 
 
 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 76 of 80 
 
Group=Stage 1 doselevl2=MV-NIS Dose Level 2 
 
 
Grade 
1 2 3 4 
N N N N 
Body#System 
Toxicity 
3 1 3 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
1 
 1 
 
Neutrophil count decreased 
1 1 
 1 
Platelet count decreased 
1 1 3 1 
Renal /Genitourinary 
Creatinine increased 
1 3 
 
 
Constitutional 
Symptoms 
Chills 
1 
 
 
 
Gastrointestinal 
Nausea 
1 1 
 
 
Vomiting 
1 1 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
Group=Stage 1 doselevl2=MV-NIS Dose Level 3 
 
 
Grade 
1 2 3 
N N N 
Body#System 
Toxicity 
3 1 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
 2 
 
Neutrophil count decreased 
 1 1 
Platelet count decreased 
2 
 1 
Gastrointestinal Nausea 
 1 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 77 of 80 
 
Group=Stage 1 doselevl2=MV-NIS Dose Level 4 
 
 
Grade 
1 
2 
N 
N 
Body#System 
Toxicity 
 
1 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
1 
 
Renal 
/Genitourinary 
Creatinine increased 
1 
 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
 
Group=Stage 1 doselevl2=MV-NIS Dose Level 5 
 
 
Grade 
1 2 3 
N N N 
Body#System 
Toxicity 
1 2 1 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
 1 
 
Neutrophil count decreased 
 
 1 
Platelet count decreased 
3 1 1 
Infection/Febrile 
Neutropenia 
Febrile neutropenia 
 
 1 
Renal /Genitourinary 
Creatinine increased 
2 
 
 
Constitutional Symptoms 
Fever 
1 
 
 
Dermatology/Skin 
Rash desquamating 
1 
 
 
Gastrointestinal 
Diarrhea 
1 
 
 
Nausea 
 
 2 
Vomiting 
1 
 1 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
 
 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 78 of 80 
 
Group=Stage 1 doselevl2=MV-NIS Dose Level 6 
 
 
Grade 
1 
2 
N 
N 
Body#System 
Toxicity 
2 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
1 
 
Neutrophil count decreased 
 
1 
Pulmonary 
Cough 
1 
 
Constitutional 
Symptoms 
Chills 
1 
 
Fever 
1 
 
Gastrointestinal 
Diarrhea 
 
1 
Nausea 
 
1 
Vomiting 
 
1 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
 
Group=Stage 2 doselevl2=MV-NIS Dose Level 1 
 
Grade 
1 2 3 4 
N N N N 
Body#System 
Toxicity 
7 1 1 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
 
 1 
 
Lymphocyte count decreased 
 
 3 2 
Neutrophil count decreased 
 
 1 
 
Platelet count decreased 
2 
 
 2 
Pulmonary 
Cough 
1 
 
 
 
Renal /Genitourinary 
Creatinine increased 
3 
 
 
 
Other 
Treatment related secondary 
malignancy 
 
 4 
 
Constitutional Symptoms 
Fever 
 
 1 
 
Gastrointestinal 
Diarrhea 
1 
 
 
 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 79 of 80 
 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
 
Group=Stage 2 doselevl2=MV-NIS Dose Level 2 
 
 
Grade 
1 2 3 4 
N N N N 
Body#System 
Toxicity 
3 3 1 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
 1 2 
 
Lymphocyte count decreased 
 
 3 
 
Neutrophil count decreased 
 2 1 
 
Platelet count decreased 
1 2 3 1 
Metabolic/Laboratory 
Hypercalcemia 
 
 1 
 
Neurology 
Syncope 
 
 1 
 
Pulmonary 
Cough 
1 
 
 
 
Renal /Genitourinary 
Creatinine increased 
 1 
 
 
Gastrointestinal 
Nausea 
2 
 
 
 
 
 
Summary of All AEs Cycle 2 and beyond by Dose Level 
 
Group=Stage 2 doselevl2=MV-NIS Dose Level 3 
 
 
Grade 
1 2 3 4 
N N N N 
Body#System 
Toxicity 
4 1 1 
 
Hematology 
Hemoglobin decreased 
Leukocyte count decreased 
1 3 2 
 
Lymphocyte count decreased 
 
 
 1 
Neutrophil count decreased 
1 3 
 
 
Platelet count decreased 
1 4 1 
 
Infection/Febrile Neutropenia 
Upper respiratory infectn(gr 0/1/2 ANC) 
 
 1 
 


UARK 2014-21 
August 21, 2015 
Version 11 
Page 80 of 80 
 
 
Grade 
1 2 3 4 
N N N N 
Metabolic/Laboratory 
Hypokalemia 
 
 1 
 
Hyponatremia 
 
 1 
 
Pulmonary 
Cough 
1 
 1 
 
Renal /Genitourinary 
Creatinine increased 
3 
 
 
 
Gastrointestinal 
Nausea 
1 1