Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 48
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of vaccine therapy when given with or without cyclophosphamide and to see how well they work in treating patients with multiple myeloma that has come back (recurrent) or has not responded to previous treatment (refractory). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vaccine therapy together with cyclophosphamide may be a better treatment for multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) when administered with or without cyclophosphamide in patients with relapsed or refractory multiple myeloma. (Phase I) II. To evaluate the confirmed response rate of MV-NIS alone in patients with relapsed or refractory multiple myeloma who have exhausted all therapeutic options. (Phase II, Cohort A) III. To evaluate the confirmed response rate of MV-NIS alone in patients who are relapsing from very good partial response (VGPR) or complete response (CR) and have not received myeloma directed therapy for at least 12 weeks. (Phase II, Cohort B)

SECONDARY OBJECTIVES:

I. To determine the safety and toxicity of the intravenous administration of an Edmonston vaccine strain measles virus engineered to express the thyroidal sodium iodide symporter (MV-NIS) when administered with or without cyclophosphamide in patients with relapsed or refractory multiple myeloma. (Phase I) II. To evaluate the confirmed response rate of MV-NIS in patients with relapsed or refractory multiple myeloma. (Phase I) III. To further evaluate the adverse event profile of MV-NIS in patients with relapsed or refractory multiple myeloma. (Phase II) IV. To evaluate overall survival, failure-free survival and progression-free survival. (Phase II)

TERTIARY OBJECTIVES:

I. 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 with or without cyclophosphamide) using 99m-technetium (Tc) gamma camera imaging. (Phase I and II) II. To assess virus replication, viremia, viral shedding in urine and respiratory secretions, and virus persistence after systemic administration of MV-NIS (when administered with or without cyclophosphamide). (Phase I and II) III. To monitor humoral responses to the injected virus. (Phase I and II) IV. To explore the anti-myeloma efficacy (i.e. clinical response rate, time to progression, progression free survival, duration of response) of the virus using standard myeloma response criteria as well as immunoglobulin free light chain measurements. (Phase I and II)

OUTLINE: This is a phase I, dose-escalation study of MV-NIS followed by a phase II study. Patients are assigned to 1 of 2 treatment arms (Stage 1 or Stage 2) in phase I and assigned to Stage 1 in phase II.

STAGE 1 (MV-NIS ALONE, closed to accrual on 12/17/2009 and reopened 10/13/2011): Patients receive MV-NIS intravenously (IV) over 1 hour on day 1.

STAGE 2 (MV-NIS AND CYCLOPHOSPHAMIDE, temporarily closed to accrual on 10/13/11): Patients receive cyclophosphamide IV over 30 minutes and then MV-NIS IV over 1 hour 2 days later.

After completion of study treatment, patients are followed up at 6 weeks, 12 weeks, and then every 3 months for 1 year.

Arms:
arm 1: Patients receive MV-NIS IV over 1 hour on day 1. (Closed to accrual on 12/17/2009 and reopened 10/13/2011) arm 2: Patients receive cyclophosphamide IV over 30 minutes and then MV-NIS IV over 1 hour 2 days later. (Temporarily closed to accrual on 10/13/11)

Interventions: intervention 1: Cyclophosphamide intervention 2: Laboratory Biomarker Analysis intervention 3: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given IV intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 


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Index 
 
 
Schema 
1.0 
Background 
2.0 
Goals 
3.0 
Patient Eligibility 
4.0 
Test Schedule 
5.0 
Stratification Factors 
6.0 
Registration /Randomization Procedures 
7.0 
Protocol Treatment 
8.0 
Dosage Modification Based on Adverse Events  
9.0 
Ancillary Treatment 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/ Follow-up Decision at Evaluation of Patient 
14.0 
Pharmacologic/Ancillary Studies 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations for Quality Control 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Appendix I - Guidelines For MV-NIS Administration By Nursing Staff 
Appendix II - Pre-Screening Process, Oral Script Contact Letter, and Minimal Risk HIPPA Consent 
Consent Form 
 
 


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Phase I Schema 
 
Prior to discussing protocol entry with the patient, call the Mayo Clinic Cancer Center Registration 
Office (507-284-2753) to confirm study status and insure that a place on the protocol is currently 
available to the patient. 
 
Registration 
(see section 6.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle = 6 weeks 
 
* Stage 1 (MV-NIS alone) will be evaluated first; once MTD of stage 1 is determined, subsequent patients will 
be accrued to Stage 2 (cyclophosphamide + MV-NIS); see Section 7.0.-STAGE 1 CLOSED TO ACCRUAL 
ON DECEMBER 17, 2009. STAGE 2 TEMPORARILY CLOSED ON October 13, 2011, AND STAGE 
1 RE-OPENED FOR 2 MORE DOSE LEVELS and Phase II expansion 
 
 
Mayo Drug Names/Abbreviations 
Generic name: MV-NIS 
(recombinant Edmonston measles virus carrying 
the human NIS gene ) 
Mayo abbreviation: MV-NIS 
 
Generic:Cyclophosphamide 
Brand name(s) Cytoxan® 
Mayo abbreviation: CTX 
 
Generic 
Technetium 99m 
Mayo Abbreviation: 99m-
Tc 
 
 
99m-Tc dose with gamma camera imaging any day before MV-NIS treatment  
   
Stage 1* 
MV-NIS 
(dose escalation) 
Stage 2* 
CTX 10mg/kg (day -2) 
MV-NIS*(day 1) 
(at MTD) 
  99m-Tc Day, 8, 15 after MV-NIS (and possibly 2 other dates based on biodistribution) 
Unacceptable 
Toxicity, disease 
progression, refusal, or 
alternate therapy at 
any time 
Observation  


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Phase II Schema 
 
 
Registration 
(see section 6.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle = 6 weeks 
 
Mayo Drug Names/Abbreviations 
Generic name: MV-NIS 
(recombinant Edmonston measles virus 
carrying the human NIS gene ) 
Mayo abbreviation: MV-NIS 
 
Generic 
Technetium 99m 
Mayo Abbreviation:  99m-Tc 
99m-Tc dose with gamma camera imaging any day before MV-NIS treatment  
   
 
MV-NIS 
 
  99m-Tc Day 8, 15 after MV-NIS (and possibly 2 other dates based on biodistribution) 
Unacceptable 
Toxicity, disease 
progression, refusal, or 
alternate therapy at 
any time 
Observation  


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1.0 
Background 
 
1.1 
Introduction 
 
MV-NIS is an attenuated measles virus, engineered to express the human thyroidal 
sodium-iodide symporter (NIS).  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. CD46 is the cellular 
receptor for MV-NIS, mediating both virus entry and subsequent cell killing through cell-
cell fusion. The cytopathic effect of MV-NIS increases exponentially as the density of 
CD46 receptors on target cells increases and is therefore dramatic at high CD46 receptor 
densities (tumor) but minimal at low densities (normal tissues).  NIS expression in MV-
NIS infected cells permits noninvasive monitoring of virus spread by serial gamma 
camera imaging of radioiodine uptake.  In addition, the anti-neoplastic activity of the 
virus can be amplified by administering I-131, a potently ionizing beta emitting isotope 
of radioiodine.  Multiple myeloma is an incurable malignancy of terminally differentiated 
plasma cells that is widely disseminated at diagnosis.  Myeloma plasma cells over-
express CD46 and are therefore highly susceptible to MV-NIS.  Also, systemic virus 
administration is feasible in advanced myeloma since these patients have greatly reduced 
circulating titers of anti-measles antibodies.  MV-NIS demonstrated considerable 
oncolytic potency when administered intravenously to rodents bearing human myeloma 
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 I-131.  We therefore propose to conduct a phase I clinical trial to evaluate the 
safety of MV-NIS administered intravenously to patients with advanced treatment-
refractory multiple myeloma, to determine the maximum tolerated dose by this route, to 
perform pharmacokinetic studies to determine the location of virus-infected cells, the 
time course of viral gene expression, the evolution of the immune response and its impact 
on the virus, and to obtain preliminary evidence for anti-myeloma activity in human 
subjects.  Our overall hypothesis is that MV-NIS administered intravenously to patients 
with advanced multiple myeloma 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 gamma camera imaging of radioiodine uptake after 
MV-NIS therapy to monitor the changing number and location of virus-infected cells.  
 
1.2 
MV-NIS: Description 
 
MV-NIS is a live tissue culture adapted measles virus engineered to express the human 
thyroidal sodium iodide symporter (NIS).  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 ions into the cell.  
Radioiodine uptake by cells expressing NIS provides a basis for in vivo radioiodine 
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 
Edmonston lineage measles virus (MV-tag) and propagates on Vero cells with kinetics 
equivalent to the parental strain. 
 


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1.21 
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 Edmonston lineage measles 
viruses was acquired during tissue culture adaptation [5] and distinguishes them 
from wild-type measles viruses, which enter cells primarily through an 
alternative receptor, SLAM, expressed on activated T cells, B cells and 
monocytes [6].  MV-NIS has dual tropism for both SLAM and CD46.  
 
The cytopathic effect of MV-NIS increases exponentially as the density of CD46 
receptors on target cells increases.  Killing is therefore minimal at the lower 
CD46 receptor densities that typify normal tissues whereas it is dramatic at 
higher CD46 receptor 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. 
 
1.22 
MV-NIS: Radioiodine 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 Tc99m) or 
ablation (with 131I) and for systemic therapy of well-differentiated thyroid 
malignancies [7, 8].  It has recently been shown that radioiodine is efficiently 
trapped by experimental tumors transduced with a NIS gene [9-15].  Non-
invasive assessment of NIS gene expression can then be achieved through -
camera imaging of 123I 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 
[16].  Tumor cell lines and primary tumor cells infected with MV-NIS show 
efficient uptake of radioiodine that can be inhibited by perchlorate, a specific 
inhibitor of NIS.  Moreover, in vivo uptake of radioiodine by MV-NIS-infected 
tumor xenografts is readily detected by 123I -camera imaging.  
 
1.3 
Multiple myeloma: Need for alternative therapies  
 
Multiple myeloma is a disseminated malignancy of antibody-secreting plasma cells [17].  
The neoplastic cells preside predominantly in bone and bone marrow where they secrete 
a monoclonal immunoglobulin and proliferate to form discrete, well-vascularized tumors 
(myelomas) that strongly stimulate osteoclastic bone resorption.  The monoclonal 
immunoglobulin provides a convenient serum or urine marker for disease monitoring, but 
can also cause significant clinical pathology including renal failure, hyperviscosity and 
tissue amyloid deposition.  Other classic disease manifestations are bone pain, 


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hypercalcemia, pathological fractures, anemia and recurrent infections due to profound 
suppression of humoral immunity.   
 
Multiple myeloma is not curable with current therapy and was expected to cause 10,800 
deaths in the USA in 2002 [18].  Median survival is approximately four years and new 
approaches to therapy are urgently required.  The disease responds initially to alkylating 
agents (melphalan, cyclophosphamide) and corticosteroids (prednisolone, 
dexamethasone), but eventually becomes refractory.  High dose (myeloablative) 
melphalan therapy following by autologous stem cell transplantation leads to better 
remissions but does not greatly prolong survival [19-21].  Thalidomide and the 
proteosome inhibitor, PS341, have activity against myeloma but have not yet been shown 
to impact survival [22, 23].  Supportive therapy includes analgesia for pain, regular blood 
transfusions or erythropoietin therapy for anemia, bisphosphonates to inhibit osteoclastic 
bone resorption and antibiotics or intravenous immunoglobulins for infections.   
 
1.4 
Safety of measles vaccine in myeloma patients despite suppression of humoral immunity  
 
Multiple myeloma 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 efficient delivery 
to tumor sites via the bloodstream, which can be inhibited by antiviral antibodies [24]. 
Oncolytic virotherapy is therefore less likely to be effective when there is preexisting 
antiviral immunity.  Multiple myeloma is characterized by profound suppression of 
humoral immune responses with hypogammaglobulinemia, typically affecting IgG, IgA 
and IgM fractions [25-27].  Antibody titers against common vaccine antigens (e.g., 
measles, mumps, rubella, diphtheria and tetanus) are greatly reduced [28, 29], and 
immune responses following vaccination are considerably impaired [27, 30].  We tested 
stored serum samples from patients with heavily pretreated myeloma and age-matched 
controls for anti-measles virus antibody titer and found, in keeping with published 
observations, that sera obtained from myeloma patients often contained very low levels 
of anti-measles antibody.   
 
The measles-mumps-rubella (MMR II) vaccine (Merck) delivers 103 
to 104 
infectious 
units of live attenuated measles virus 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 measles-mumps-rubella vaccine at 24 months post-
transplant. We retrospectively studied multiple myeloma (MM) patients who received 
both their transplant and routine 2 year post-auto SCT vaccination with MMR II at Mayo 
Clinic. Thirty-six patients (M:F – 23:13) who received an autologous stem cell 
transplantation (auto SCT) and also received routine 2 year post-SCT MMR II 
vaccination at Mayo Clinic were identified. MMR II re-vaccination was delivered an 
average of 799 days (range: 539 - 1209) days after SCT. 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 SCT. 
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. No specific toxicities were documented following MMR 
administration. While 5 patients did have a small decrease in monoclonal protein level, 


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averaging only 0.42g/dL (range: 0.1- 1.2) after re-vaccination, only 2 of the 5 patients 
were remote from the influence of treatment effect for relapsed disease at the time. One 
of these 5 patients continues to live relapse free without treatment and with a stable 
monoclonal protein. These data strongly suggests that conventional doses of MMR 
vaccine administered by intramuscular injection are safe, but inadequate for expression of 
oncolytic activity in patients with multiple myeloma.  
 
Although MV-NIS has not previously been administered to humans, there is a vast 
knowledge base concerning the toxic effects of closely related viruses in the human 
population.  Thus wild-type MV causes a well-described illness characterized by fever, 
rash, upper respiratory tract symptoms and transient immunosuppression [32]. 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 Edmonston virus lineage have been used for vaccination, and all of them 
are capable of causing a mild measles-like illness in some variable percentage of 
vaccinees [33-34, 39] It is therefore anticipated that some MV-NIS-treated patients may 
develop a measles-like illness.  However, in the entire history of measles vaccination, no 
case of reversion of vaccine strain to wild-type measles 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 measles viruses cause a measles-like illness in 
patients previously exposed to the virus [41].  
 
1.5 
Multiple myeloma: Susceptibility to MV-NIS 
 
Neoplastic plasma cells from multiple myeloma patients express high levels of CD46 and 
are fully susceptible to infection by MV-NIS.  Myeloma cells over-express CD46 
compared to normal marrow elements and unstimulated peripheral blood lymphocytes.  
CD138+ myeloma cells from 5 patient bone marrow aspirates were infected with MV-
NIS, and radioiodine uptake was measured 48 hours later.  In addition to the classical 
measles virus 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.   
 
Multiple myeloma cells are selectively infected and killed by attenuated measles viruses 
of the Edmonston vaccine lineage.  A recombinant measles virus expressing a fluorescent 
GFP marker protein could efficiently fuse and kill multiple myeloma cells but not non-
transformed cells [31].  
 
Intravenous MV-NIS (or MV-Edm) is a potent oncolytic agent in multiple myeloma 
xenograft models.  Multiple myeloma cells (ARH77, RPMI8226, KAS 6/1, MM1) 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.  
 


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1.51 
Therapy models: Noninvasive imaging of MV-NIS 
Intratumoral spread of MV-NIS could be non-invasively evaluated by serial -
camera imaging in 3 myeloma xenograft models.  SCID mice bearing 
subcutaneous ARH77, KAS 6/1 or MM1 myeloma 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. 
 
1.52 
Therapy models: Radiovirotherapy 
The oncolytic activity of MV-NIS is greatly enhanced by subsequent 
administration of 131I (radiovirotherapy).  To determine whether the oncolytic 
effect of MV-NIS could be enhanced or accelerated by high energy electron 
therapy resulting from intratumoral 131I decay, we examined KAS 6/1 and MM1 
models.  The MM1 model had been previously shown to be resistant to single 
agent MV-NIS therapy.  KAS 6/1 tumor regression was significantly accelerated 
when mice were treated with 131I (37 MBq) administered 6 days after intravenous 
MV-NIS.  Moreover, MM1 xenografts, which were resistant to single agent 
therapy with MV-Edm, MV-NIS or 131I, were shown to regress completely when 
131I was administered 9 days after intravenous MV-NIS. 
 
1.6 
Modulating the Anti-Measles Immune Response 
 
MV-CEA is an oncolytic measles virus expressing a soluble marker peptide (the 
extracellular domain of CEA) which facilitates noninvasive monitoring of viral gene 
expression.  When MV-CEA was administered intraperitoneally to naïve measles-
susceptible (CD46 transgenic IFN receptor knockout) mice, plasma CEA expression 
peaked after 3 days and disappeared by day 8.  However, no plasma CEA was detected in 
mice previously vaccinated with MV-Edmonston and challenged at a later date with the 
same dose of MV-CEA.  We therefore examined the profiles of CEA expression, anti-
measles antibody responses, and susceptibility to second virus challenge in mice that 
received immunosuppressive cyclophosphamide therapy prior to intraperitoneal injection 
of 107 IU of MV-CEA.  Cyclophosphamide treatment (250 mg/kg IP 4 hours before MV-
CEA) prolonged the CEA expression profile from 8 days to 29 days, reduced the anti-
measles antibody titers (measured on day 36) and resulted in significant levels of CEA 
gene expression 3 days post-MV-CEA rechallenge (without additional cyclophosphamide 
day 53).   
 
1.7 
Pre-Clinical Data: MV-NIS toxicity and biodistribution studies 
 
1.71 
Biodistribution in CD46 transgenic, interferon α/β receptor knockout mice 
 
As part of preclinical studies to evaluate MV-NIS, we developed sensitive 
quantitative RT-PCR methodology in order to characterize tissue distribution of 
the virus in non-tumor bearing transgenic IfnarKO 
x CD46 Ge mice that express 
human CD46 with human-like tissue distribution. Groups of male and female 


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mice (10 mice/gender/treatment group) were given I.V. doses of vehicle or MV-
NIS, 105 
TCID50, 107 
TCID50 or 107 
TCID50 + 125 mg/kg cytoxan. 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 I- 123. 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-N 
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 +/- 
cyclophosphamide. Cyclophosphamide 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 
+/- cyclophosphamide on day 91. Of note, 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 + 
cyclophosphamide.  
 
1.72 
Toxicity of MV-NIS in CD46 transgenic, interferon α/β receptor knockout mice 
According to the protocol 144 IfnarKO 
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: 
Measles virus, Edmonston lineage [NSC-731414] for Groups 3, 4, 5 and 6 and 
cyclophosphamide [NDC# 0015-0547-41] for Groups 2 and 6) or the control 
article (MV-NIS vehicle [5% sucrose, 50 mM Tris-HCl, pH 7.4, 2mM MgCl2] 
diluted as per Test Article) via an intravenous injection via the tail vein. 
Cyclophosphamide was at 125mg/kg given 2 days prior (Day -2) to MV-NIS in 
order to modulate the immune response to MV-NIS. Cyclophosphamide 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 by PAI personnel as described in 
the protocol. Protocol-specified tissues were preserved in 10% neutral-buffered 
formalin (NBF) and sent to PAI’s Frederick, MD facility, which conducted the 
remainder of the analysis on those samples. 
 
 


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Dose  
Group 
Day-2  
Day 0  
Day 
2 
 
Day 
5 
 
Day 
22 
 
Day 
91  
 
Total No.  
Mice 
 
Cyclophos-
phamide  
(mg/kg)  
MV-NIS  
(TCID50)  
M  
F  
M  
F  
M  
F  
M  
F  
 
1  
0  
0*  
3  
3  
3  
3  
3  
3  
3  
3  12M/12F  
2  
125  
0*  
3  
3  
3  
3  
3  
3  
3  
3  12M/12F  
3  
0  
10
4 
3  
3  
3  
3  
3  
3  
3  
3  12M/12F  
4  
0  
10
5 
3  
3  
3  
3  
3  
3  
3  
3  12M/12F  
5  
0  
10
6 
3  
3  
3  
3  
3  
3  
3  
3  12M/12F  
6  
125  
10
6 
3  
3  
3  
3  
3  
3  
3  
3  12M/12F  
*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-measles 
antibody titers. The in-life 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 cyclophosphamide. Body weights showed 
no signs of MV-NIS toxicity. Mice from Groups 4 and 5 developed robust anti-
measles virus 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 and effective antibody response.  
 
In Groups 1, 3, 4, and 5, there were no toxicologic 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 
is likely due to the production of anti-measles 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.  
 


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In Groups 2 and 6, there were no toxicologic 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 cyclophosphamide 
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 cyclophosphamide showed changes in the lymphoid 
organs (mandibular and mesenteric lymph nodes, thymus, and spleen), urinary 
bladder, bone marrow, testes and ovaries that were considered to be related to the 
administration of cyclophosphamide at the day 2 sacrifice. The 
cyclophosphamide-related changes showed evidence of recovery in later time 
points.  
 
1.73 
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 I-123 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. Detailed analysis of the data is not yet complete but, by 
naked eye examination of the serial images, the isotope localizes to the thyroid, 
stomach, salivary glands and bladder at all timepoints and the biodistribution 
does not appear to change following MV-NIS administration.  
 
1.74 
Safety study of intravenous MV-NIS in squirrel monkeys  
This study was performed by IIT Research Institute (IITRI) in Chicago, IL 
through the RAID program. 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 cyclophosphamide 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/groups were 
sacrificed on day 29, and the remaining animals were sacrificed on day 91. 


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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. Pending results for 
thyroid hormone levels and viral levels.  
 
Group 
# 
MV-NIS 
(TCID50) 
Cycloph
osphomi
de. 
(mg/kg) 
Monkey
# 
Pre-
Dose* 
d1* 
d2* 
d8* 
d15* 
d29* 
d91* 
 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 
2465000 
2379870 
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.  
Cyclopho. = cyclophosphamide. 
* Data represents Copies of MV N-gene in 1.0 µg RNA extracted from Buccal Cheek Scrapes  
† Dose = 108 or the highest dose available from Mayo Clinic Viral Vector Production Facility 
 
Preliminary Q-RT PCR on cheek swabs is summarized in table above.  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-measles 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. These data would suggest that IV MV-NIS 
circulates, replicates, and clears over time and that replication is enhanced by cyclophosphamide. 
These Q-RT-PCR data also support our choice of time-points for imaging patients—that is days 8-15. 
 
 


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1.8 
MV-NIS Translational Plans 
 
Based on the foregoing observations, we conclude that MV-NIS is a highly 
promising CD46 targeted oncolytic agent that merits clinical testing in patients 
with multiple myeloma. Not only does the virus have an 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.  Furthermore, assuming that 
the expectation of myeloma targeting can be confirmed in this clinical study, it 
will be possible to further boost the potency of MV-NIS by subsequent 
administration of 131I.  Thus, MV-NIS offers the opportunity for rational clinical 
development.   
 
The risks associated with MV-NIS administration to this group of patients are 
considered to be acceptable.  Whereas MV-NIS has not previously been 
administered to humans, there is a vast knowledge base concerning the toxic 
effects of closely related viruses in the human population.  Thus wild-type 
measles virus causes a well-described illness characterized by fever, rash, upper 
respiratory tract symptoms and transient immunosuppression [32].  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 measles 
immunosuppression are a more significant problem.  At the other end of the 
spectrum, live attenuated measles virus vaccines have been used extensively.  In 
the USA alone, more than 550 million doses of measles vaccine have been 
distributed to date.  Several different members of the Edmonston virus lineage 
have been used for measles vaccination, and all of them are capable of causing a 
mild measles-like illness in some variable percentage of vaccinees [33-39].  It is 
therefore anticipated that some MV-NIS-treated patients may develop a measles-
like illness.  However, in the entire history of measles vaccination, no case of 
reversion of vaccine strain to wild-type measles has been documented, and only 6 
deaths have been reported due to uncontrolled spread of the vaccine strain virus 
in severely immune-compromised individuals.  In contrast to their effects in non-
immune subjects, neither wild-type nor attenuated measles viruses cause a 
measles-like illness in patients previously exposed to the virus [40, 41]. 
 
Our longer-term strategy will be to develop and test new versions of MV-NIS 
that have been engineered to enhance or modify their target specificity.  For 
example, we anticipate that whereas the efficacy of the current version of MV-
NIS will be due to its interaction with CD46, the dose limiting toxicity will be a 
measles-like illness due to its interaction with SLAM.  Thus, a recombinant MV-
NIS in which the H protein has been modified to ablate its interaction with 
SLAM may have a better therapeutic ratio than the current version. 
 
1.9 
Post-protocol updates  
1.91  
July 2011 
Improved Good Manufacturing Practice to produce higher titers of MV-NIS 
Due to manufacturing limitations, our clinical studies to date have used a 
maximum dose of 109 TCID50 MV-NIS, only three times higher than the 
minimum effective mouse dose.  Even at this low clinical dose we have shown 
that MV-NIS can traffic via the bloodstream to the tumor, infect the tumor cells, 




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alkylator therapy, and immune modulatory drugs. Patients were also required to 
have negative measles titers both by ELISA and by neutralizing anti-body assay. 
Due to a lack of major responses in the first 11 treated, accrual was stopped, and 
the protocol was modified to include a different cohort of patients. It was felt that 
the safety profile seen to date made it reasonable to test the drug in less heavily 
pre-treated patients. 
 
In the Phase II protocol, the first cohort will be referred to as cohort A and the 
second cohort as cohort B. The eligibility criteria for cohort B includes less 
heavily pretreated patients and the measles titer eligibility was changed to 
include only the ELISA testing. 
 
1.19a 
Hypotheses 
 
The primary hypothesis to be tested in our initial phase I clinical trial is as 
follows:   
 
1. 
MV-NIS administered intravenously to patients with advanced multiple 
myeloma will selectively propagate in myeloma deposits throughout the body 
leading to tumor cell killing and reduction of tumor burden.   
 
 
 
A secondary hypotheses is as follows:  
 
 
2. 
Anti-measles virus antibodies (variable between patients) may sequester 
virus before it reaches the myeloma plasma cells and will thereby interfere with 
tumor cell infection and killing.  Use of the immunosuppressant 
cyclophosphamide will abrogate this immune response. 
 
 
 
An additional hypothesis that will be tested in a future phase I trial is: 
 
 
3. 
131I administered at the appropriate time will synergize with MV-NIS, 
leading to enhanced therapeutic response through destruction of uninfected 
myeloma cells adjacent to the infected cells.   
 
The reason that this hypothesis will not be tested in the initial phase I clinical 
trial is to allow the independent evaluation of MV-NIS toxicity, efficacy and 
kinetics without the additional confounding factor of 131I. 
 
2.0 
Goals 
 
2.1 
Primary 
 
2.11  
Phase I: 
 
 
To determine the maximum tolerated dose (MTD) of MV-NIS when 
administered with or without cyclophosphamide in patients with relapsed 
or refractory multiple myeloma. 
 
 
2.12 
Phase II:  
 


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Cohort A:  To evaluate the confirmed response rate of MV-NIS alone in 
patients with relapsed or refractory multiple myeloma who have 
exhausted all therapeutic options. 
Cohort B:  To evaluate the confirmed response rate of MV-NIS alone in 
patients who are relapsing from VGPR or CR and have not received 
myeloma directed therapy for at least 12 weeks. 
 
2.2 
Secondary 
 
 
2.21 
Phase I: 
 
 
2.211 To determine the safety and toxicity of the intravenous 
administration of an Edmonston vaccine strain measles virus engineered 
to express the thyroidal sodium iodide symporter (MV-NIS) when 
administered with or without cyclophosphamide in patients with relapsed 
or refractory multiple myeloma. 
 
 
 
2.212  To evaluate the confirmed response rate of MV-NIS in patients 
with relapsed or refractory multiple myeloma 
 
 
2.22 
Phase II: 
 
 
2.221 To further evaluate the adverse event profile of MV-NIS in 
patients with relapsed or refractory multiple myeloma. 
 
 
2.222 To evaluate overall survival, failure-free survival and 
progression-free survival 
 
2.3 
Correlative (Both Phase I and Phase II) 
 
 
2.31 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 with or without cyclophosphamide) 
using  99m-Tc  gamma camera imaging. 
 
 
2.32 To assess virus replication, viremia, viral shedding in urine and respiratory 
secretions, and virus persistence after systemic administration of MV-NIS (when 
administered with or without cyclophosphamide). 
 
 
2.33 To monitor humoral responses to the injected virus. 
 
 
2.34 To explore the anti-myeloma efficacy (i.e. clinical response rate, time to 
progression, progression free survival, duration of response) of the virus using 
standard myeloma response criteria as well as immunoglobulin free light chain 
measurements. 
 
 
 


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3.0 
Patient Eligibility 
 
3.1 
Inclusion criteria 
 
 
3.11 
Age  18 years. 
 
 
3.12 
Myeloma relapsing from partial response or better  
3.12a.       Patients relapsing >18 months from transplant if not on   
maintenance, or 
3.12b.       If off maintenance, discontinued at least 6 months ago, or 
3.12c.       If relapsing on maintenance, at least 3 years from transplant, or 
3.12d.       Off prior myeloma therapy at least 6 months ago 
 
 
3.12e. 
Sufficient tumor burden that is assessable for response 
 
 
- Serum M-spike >= 0.5 g/dL, or 
 
 
- If IgA myeloma, IgA > 1000 mg/dL, or 
 
 
- dFLC >10 mg/dL, or  
 
 
- Urine M-spike >=200 mg/24 hours, or 
 
 
- Bone marrow plasmacytosis >= 10%, or 
 
 
- Plasmacytoma >= 2 cm in diameter 
 
 
3.13 
The following laboratory values obtained  14 days prior to study 
registration 
 
ANC 1000/L 
 
PLT 50,000/L 
 
Hemoglobin  8.5 g/dl 
 
AST ≤2 times upper limit of normal 
 
Creatinine < 2 times upper limit of normal 
 
Total bilirubin  1.5 x upper limit of normal  
 
INR  1.4 x ULN at the time of  registration 
 
 
3.14 
Ability to provide informed consent. 
 
 
3.15 
Willingness to return to Mayo Clinic Rochester for follow-up. 
 
 
3.16 
Life expectancy  12 weeks. 
 
 
3.17 
ECOG performance status (PS) 0, 1 or 2. 
 
 
3.18 
Willingness to provide all biological specimens as required by the 
protocol. (See section 14.0) 
 
 
3.19 
Negative serum pregnancy test done ≤ 7 days prior to registration for 
women of childbearing potential only.  
 
 
3.19a 
Measles antibody titer on the BioRad Multiplex assay less than or equal 
to 1.0. 
 
 
 


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3.2 
Exclusion criteria 
 
 
3.21 
Uncontrolled infection. 
 
3.22 
Active tuberculosis. 
 
 
3.23 
Any myeloma directed therapy within 12 weeks of registration including 
plasmapheresis or transfusion 
 
 
3.24 
New York Heart Association classification III or IV, known symptomatic 
coronary artery disease, or symptoms of coronary artery disease on 
systems review  
 
 
3.25 
Active CNS disorder or seizure disorder. 
 
 
3.26 
HIV positive test result. 
 
 
3.27 
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any 
ancillary therapy considered investigational (used for a non-FDA 
approved indication and in the context of a research investigation). 
 
3.28 
Previous exposure to heat inactivated measles virus vaccine (this vaccine 
was given to some individuals between the years of 1963-1967). 
 
3.29a 
Any of the following: 
 Pregnant women or women of reproductive ability who are unwilling 
to use effective contraception 
 Nursing women  
 Men who are unwilling to use a condom (even if they have undergone 
a prior vasectomy) while having intercourse with any woman, while 
taking the drug and for 4 weeks after stopping treatment. 
 
3.29b Evidence of chronic or acute graft versus host disease or on-going 
treatment for graft versus host disease from prior allogenic stem cell 
transplantation 
 
3.29c Exposure to household contacts ≤15 months old or household contact with 
known immunodeficiency. 
 


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4.0 
Test Schedule  
 
 
 
 
 
 
 
 
Active Monitoring Phase 
Observation 
 
 
Pre-treatment 
Post-therapy (relative to MV-NIS administration; all tests  1day) 
Tests and Procedures 
 14 
days 
prior to 
Reg  
Pre-
treat-
ment 
 
 
Day 1 
Day 3 
 
Day 8 
 
Day 15 
 
Day 22, 
Day 29 
 
Week 6l  
 
3 months after 
treatment and 
Q 3 months 
thereafterh 
History and exam, wt, PS 
X 
 
 
 
 
 
 
X 
X 
AE Evaluation 
X 
 
 
X 
X 
X 
X 
X 
X 
WBC, ANC, ALC, Hgb, 
PLT 
X 
 
X,R, k 
X 
X 
X 
X 
X 
X 
aPTT, PT (INR) 
XR 
 
 
XR 
 
XR 
XR 
XR 
XR 
AST, AP, Na, K, TBili, Cr, 
Ca  
X 
 
 
X 
X 
X 
X 
X 
X 
2-M, LDH  
X 
 
 
 
 
 
 
 
 
SPEP, IgA, IgM, IgG; 24 
hr UPEP 
X 
 
 
 
 
 
 
X 
X 
Immunofix of serum & 
urine 
Xa 
 
 
 
 
 
 
Xb 
Xb 
Immunoglobulin FLC 
X 
 
Xk,R 
 
XR 
XR 
XR 
X 
X 
Anti MV IgM and IgG 
Xa,R 
XR 
 
XR 
XR 
 
 
XR 
 
Measles Neutralizing Abm 
 
XR 
 
 
XR 
 
 
XR 
 
HIV by EIAR 
X 
 
 
 
 
 
 
 
 
T&B quant.: CD4, CD8 
 
XR 
 
 
 
XR 
 
XR 
 
ECG 
X 
 
 
 
 
 
 
 
 
BM asp/biopsy  
Xa 
 
 
 
 
 
 
XR 
 
Research Blood/BMi 
 
XR 
 
 
 
 
 
XR 
 
Optional biopsy of affected 
area seen on nuclear 
imaging 
 
 
 
 
XO 
 
 
 
 
Skeletal survey 
Xa 
 
 
 
 
 
 
 
 
Viral shedding: R 
mouth sample collectionc 
and urine collectiond 
 
X 
 
X 
X 
X 
Xf 
Xg 
 
Viremia (PBMC)e, R 
 
X 
Xn 
X 
X 
X 
Xf 
Xg 
Xg 


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Blood for cytokinesR 
 
 
Xk,p,R 
Xp,R 
 
 
 
 
 
Blood for LPA and IFN- 
ELISPOTR 
 
XR 
 
 
X 
XR 
 
XR 
 
SPECT/CTR 
 
See 4.1 
 
 
See 4.1 
See 4.1 
See 4.1 
See 4.1 
 
PET-CTR 
X 
 
 
 
 
 
 
Xq 
 
Pregnancy test R 
Xj 
 
 
 
 
 
 
 
 
See next page for footnotes 
 
a. ≤ 4 weeks prior to registration. 
b. Only required to document complete response. 
c. Patient will gargle with 15mL of Scope mouthwash for 30 seconds and fluid collected in a sterile Falcon tube (50mL). Send to Guggenheim 
1802. 
d. A mid-stream urine sample (15mL) to be collected in a 15mL Falcon conical tube. Send to Guggenheim 1802. 
e. Collect 2.5mL of blood in each of two PAXgene containers. Send to Guggenheim 1802. 
f. These studies will only be performed if there is evidence of continued viral genome presence at day 15. If at day 29, there is 10-fold increase 
in MV-NIS/mcg of RNA, repeat tests will be performed within 2 days to confirm the result. Weekly testing will be done thereafter until 
resolution to baseline. 
g. Only if positive Q-RT-PCR on prior evaluation, check every 3 months by mail-out kit if no negative result at prior measurement. May be done 
by mail-in kit. 
h. Patients will be observed at 3 months after treatment and every 3 months thereafter for a year or until progression—whichever is longer. Visits 
may be +/- 2 weeks.  For those patients who receive alternative myeloma directed therapy, observation will be changed to “limited AE” 
toxicity form without additional scheduled laboratory monitoring.  For those patients who have progressed but not received alternative 
myeloma directed therapy, laboratory tests may be done at home. 
i. 
Blood and bone marrow can be done under IRB number of this trial or under 521-93; max of 450 mL of bone marrow and 50 cc of blood to be 
drawn for research purposes.  
j. 
Necessary in women of childbearing potential ≤ 7 days prior to registration. 
k. Prior to MV-NIS infusion 
l. 
These tests may be done sooner than week 6 if patient progresses and needs to start another treatment for multiple myeloma prior to 6 week 
time point. 
m. If patient requires other active myeloma treatment before week 6, waste serum will be retrieved from one of the clinical labs to run a 
neutralizing antibody test.  
n. Pharmacokinetic samples will be done as follows: blood (5 mL/draw) will be taken at 6 time points: end of infusion, 30 minutes post, 60 
minutes post, 120 minutes post, and 240 minutes post, and 24 hours post.    
o. Biopsy may be done between day 8 and 15 if uptake observed on nuclear scans performed on day 8, if patient agrees to biopsy. 
p. Cytokine samples will be taken as follows: blood (4 mL/draw into a EDTA tube), pre-MV-NIS infusion, 240 minutes post, 24 hours post (day 
+2), and approximately 48 hours post (day +3) 
q. PET-CT will be done as indicated depending on baseline result. If markedly positive PET/CT at baseline, scan will be repeated  
R.   Tests drawn for research purposes only.  
 


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Table 4.1 Nuclear imaging Tablea 
 
SPECT/ CTb,c 
FDG-
PET/CT 
On Study 
 
X 
Any day before MV-NIS 
administration, ~ 1 hour post 
99m-Tc 
X 
 
Day 8 ~1 hour post 99m-Tc 
X 
 
Day 15 ~1 hour post 99m-Tc  
 X 
 
Day 22c ~1 hour post 99m-Tc  
Xd 
 
Day 29 c ~ 1 hour post 99m-Tc   
Xd 
 
Week 6 
 
Xe 
 
a. The scheduling of the nuclear imaging will be as close to the stated time points as possible. 
Flexibility ± 1 day will be allowed. 
b. Up to a total of six 99m-Tc scans will be done on each patient.  
c. The pre-scan and day 8 will cover 80 cm of body length (chest and abdomen); all other scans will 
cover 40-80 cm (chest plus or minus abdomen) depending on regions of interest. 
d. These scans will be elective, based on whether there is continued uptake on prior imaging studies. 
e. PET-CT will be done as indicated depending on baseline result. If marked positive PET/CT at 
baseline, scan will be repeated  
 
5.0 
Grouping Factors:  
 
 
 
5.1 
Stage 1: MV-NIS alone vs. Stage 2: MV-NIS + cyclophosphamide. 
 
5.2 
Phase:  Phase I vs. Phase II 
 
 
 
5.3 
Cohort:  Cohort A (relapsed or refractory multiple myeloma who have exhausted 
all therapeutic options) vs. Cohort B (relapsing from VGPR or CR and have not 
received myeloma directed therapy for at least 12 weeks) 
 
 
 
 
Note:  Cohort A patients were accrued before Addendum 21 and Cohort B 
patients will be accrued after Addendum 21 is implemented.  Eligibility criteria 
were modified with Addendum 21 to reflect this change.  
 
 
 


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6.0 
Registration/Randomization Procedures 
 
 
Phase I  
 
 
 
6.1 
Prior to discussing protocol entry with the patient, call the Registration Office (4-
2753) for dose level and to insure that a place on the protocol is open to the 
patient. 
 
 
6.2 
To register a patient fax (507-284-0885) a completed eligibility checklist to the 
Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through  
 
 
Phase II 
 
6.3 
To register a patient, access the web page at https://mccrc.mayo.edu and enter the 
registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the 
Mayo Clinic Cancer Research Consortium (MCCRC) Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
 
The instructions for the registration/randomization application are available by using 
the Help button.  Prior to initiation of protocol study intervention, this process must be 
completed in its entirety and a MCCRC subject ID number must be available as noted 
in the instructions.  It is the responsibility of the individual and institution registering 
the patient to confirm the process has been successfully completed prior to release of 
the study agent.  Patient registration via the registration/randomization application can 
be confirmed in any of the following ways: 
 
 
Contact the MCCRC Registration Office
.  If the patient was 
fully registered, the MCCRC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
Phase I and II 
 
6.4 
At the time of registration, the registration application will verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
 
The following will also be recorded: 
 
Patient has/has not given permission to store sample(s) for future research of 
multiple myeloma and gene therapy. 
 
Patient has/has not given permission to store bone marrow sample(s) for 
future research to learn, prevent, or treat other health problems. 


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MCCC Addendum 23 
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 
Patient has/has not given Mayo permission to give their sample(s) to outside 
researchers. 
 
Patient has/has not given permission to have optional biopsy. 
 
6.5 
The study coordinator should call the Clinical Research Unit to assure that there 
is bed availability 
 
 
6.6 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary 
 
6.7 
Translational Research: Registration Office will automatically register patients 
separately to the translational component of this study (see Section 14.0).  
 
6.8 
Treatment on this protocol must commence at a Mayo Clinic Rochester under the 
supervision of a medical hematologist/oncologist.  
 
6.9 
Treatment cannot begin prior to registration and must begin 14 days after 
registration 
 
6.9a 
Pretreatment tests must be completed within the guidelines specified on the test 
schedule. 
 
6.9b 
All required baseline symptoms must be documented and graded on the 
Hematology Record. 
 
6.9c 
Study drug availability checked. 
 
7.0 
Protocol Treatment 
 
This study consists of two sequential dose escalation schemes to determine the maximum 
tolerated dose (MTD) of MV-NIS when given with or without cyclophosphamide. These 
will be conducted in two separate stages. First, patients will be accrued to the various 
dose levels (based on the escalation rules below) for MV-NIS alone. Once the MTD is 
determined for MV-NIS alone, then a second stage of dose escalation will occur to 
determine the MTD of MV-NIS when given in combination with 10mg/kg of 
cyclophosphamide.  
 
7.11 
Phase I, Stage 1: Evaluating MV-NIS Alone-Closed to accrual on December 
17, 2009. Reopened on October 13, 2011 for two more dose levels and Phase 
II expansion 
 
 


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7.12 
Treatment Schedule 
 
Agent 
Dose 
Route 
Day 
Prior to Administration of MV-NIS 
99m-Tc 
20mCi (+/- 
10%) 
I.V. 
Any time pre MV-NIS (for baseline 
Tc scan) 
MV-NIS Administration 
MV-NIS 
Assigned by the 
Randomization 
Center 
I.V. 
1 
After MV-NIS Administration 
99m-Tc 
20mCi (+/- 
10%) 
I.V. 
Days 3, 8, and 15 of study  
(2 additional doses may be given 
for imaging based on imaging 
results) 
 
7.121 The virus will be administered by slow intravenous (IV) infusion 1 hour) 
in 250mL of normal saline under close observation in the Clinical 
Research Unit (CRU) or on Hematology in-patient service.  
 
 
7.122 Patients will be closely monitored in the CRU or Hematology in-patient 
service 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 (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, methylprednisone (1mg/kg IV) and epinephrine (1mg 
subcutaneously). Administration of these medications will be tracked. 
 
Therapy for Acute Infusion Reactions 
Agent 
Dose 
Route 
Reaction 
Acetaminophen 
650 mg 
P.O. 
Acute febrile reaction 
Diphenhydramine 
50 mg 
I.V. or P.O. 
Acute febrile reaction 
Meperidine HCl 
hydrochloride 
50 mg 
I.V. 
Rigors 
Methylprednisolone 
1 mg/kg 
I.V. 
Anaphylaxis 
Normal saline 
Prn 
I.V. 
Anaphylaxis 
Epinephrine 
1 mg 
S.C. 
Anaphylaxis 
 
7.123 The in vivo distribution of MV-NIS infected cells and the kinetics of 
virus spread and elimination will be monitored by  99m‐Tc SPECT/CT as 


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described in Table 4.1   whole body gamma camera imaging after oral 
IV99m-T c], and by serial measurements of viral RNA in mononuclear 
cells derived from blood, saliva and urine (Viral N-gene RNA copy 
number/g RNA).  
 
If at day 15 isotope uptake is observed in organs other than the thyroid, 
stomach and salivary glands, further imaging will be performed on day 
22 (and day 29) to document elimination of the virus and virus infected 
cells.   
 
 
7.13 
MV-NIS Dose (Stage 1) 
 
Three patients will initially be treated at each dose level. The dose of each 
subsequent dose level will be determined by the adverse event evaluations.  
NOTE: FOUR DOSE LEVELS OF STAGE 1 COMPLETED IN STAGE 1 
WITHOUT DLT, SO INITIALLY CLOSED AND STAGE 2 BEGUN; 
HOWEVER, DUE TO NEW MANUFACTURING CAPABILITIES, STAGE 1 
RE-OPENED ON October 13, 2011, FOR DOSE LEVELS 5 AND 6. AT THIS 
TIME, STAGE 2 WILL BE IMMEDIATELY SUSPENDED TO COMPLETE 
STAGE 1. STAGE 2 WILL RESUME ONCE THE STAGE 1 MODIFICATION 
AND PHASE II EXPANSION HAVE BEEN COMPLETED. 
 
Dose 
Level 
MV-NIS (TCID50) 
-2 
1x104 
-1 
1x105 
1* 
1x106 
2 
1 x 107 
3 
1 x 108 
4 
1 x 109 
5 
1 x 1010 
6 
1 x 1011 
 
* Starting dose level 
 
 
 


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7.2 
Phase I, Stage 2: Evaluating MV-NIS in Combination with Cyclophosphamide  
 
7.21 
Treatment Schedule 
 
Agent 
Dose 
Route 
Day 
Pre-medication prior to Administration of MV-NIS 
99m-Tc 
20mCi (+/- 
10%) 
I.V. 
Any time pre-MV-NIS (for baseline 
99m-Tc  scan) 
Cyclophosphamide 
10 mg/kg 
I.V. 
2 days prior to MV-NIS 
Administration 
MV-NIS Administration 
MV-NIS 
See table 
7.22 
I.V. 
1 
After MV-NIS Administration 
 99m-Tc 
20mCi (+/- 
10%) 
IV 
Days 3, 8, and 15  
(two additional doses may be given for 
imaging based on imaging results) 
 
7.211 Cyclophosphamide will be administered 2 days prior to infusion of the 
virus. It should be diluted 250 mL of 0.9% sodium chloride and infused 
over 30 minutes. 
 
7.212 The virus will be administered by slow intravenous infusion in 250 mL 
of 0.9% sodium chloride over I hour under close observation in the 
Clinical Research Unit (CRU) or on the Hematology in-patient service.  
 
7.213 The in vivo distribution of MV-NIS and the kinetics of virus spread and 
elimination will be monitored as per section 7.113. 
 
7.22 
MV-NIS Dose escalation (Stage 2) 
 
The starting dose level of MV-NIS in the Stage 2 portion  (MV-NIS combined 
with cyclophosphamide) is the MTD as determined from the first stage 
evaluation of MV-NIS reduced by 2 log (i.e. 100-fold less). For example, if the 
MTD from the first stage evaluation for MV-NIS was 1 x 109, then the starting 
dose level of MV-NIS when given in combination with cyclophosphamide in this 
second stage of the trial will be 1 x 107. 
 
 
Dose Level* 
 
Cyclophosphamide 
(mg/kg) 
MV-NIS (TCID50) 
 
**1 
10 
(MTD/100=107) 
2† 
10 
3 x 107 
3† 
10 
9 x 107  
4† 
10 
1 x 109  
5† 
10 
1 x 1010 
6† 
10 
1 x 1011 


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*Three patients will initially be treated at each dose level.  
**Dose Level 1 equals Stage 1 MTD/100 (If no DLTs were observed at any of 
the dose levels in Stage I, 109 will be used as the MTD since it would be the 
maximum dose delivered in Stage 1) 
† Escalation will not exceed the maximum tolerated dose from Stage I. 
 
7.3 
MV-NIS Dose Escalation Rules (applicable to Phase I,  Stages 1 and 2) 
 
7.31 
If DLT is not seen in any of the 3 patients at a given dose level, then 3 additional 
patients will be treated at the next dose level. Dose escalation will not occur until 
full observation period (6 weeks) has elapsed for the last patient within any given 
dose level cohort. 
 
7.32 
If DLT is seen in 1 of 3 patients treated at a given dose level, 3 additional 
patients will be entered, one by one, at the same dose level. 
 
7.33 
If no additional DLT is observed at that dose level then 3 additional patients will 
be treated at the next dose level. 
 
7.34 
If 2 or more subjects out of 6 experience DLT at any dose level, MTD will have 
been exceeded. 
 
7.35 
If MTD is exceeded at any dose level, the cohort at the next lower dose level will 
be expanded one by one as needed to reach a total of 6 participants. 
 
7.36 
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 Section 7).  In the case that no DLTs are observed in any of the dose 
levels, then the MTD will be the maximum dose delivered.  
 
7.37 
If no DLT is observed at the highest dose level (i.e. 1 x 109 for Stage 1 or 81 x 
107 for Stage 2), dose escalation beyond this dose level will not occur based on 
MV-NIS manufacturing limitations. If the 1 x 109 dose level (for stage 1) is 
reached without dose limiting toxicity, this dose--the maximum feasible dose--
will be used for further study.  
 
7.38 
Stage 1 only: Once MTD or maximum feasible dose is reached in stage 1, 
this cohort will be expanded to treat a total of 37 patients at that level as 
part of a Phase II expansion.  
 
7.4 
Dose De-escalation: Phase I, Stages 1 and 2:  
 
7.41 
In the Phase I, stage 1 evaluation of MV-NIS alone, if two or more patients 
experience DLT at dose level 1, patients will be entered at a lower dose of 1x105 
(see Table in Section 7.12). If two or more patients experience DLT at this dose, 
further patients will be accrued at the dose level of 1x104 TCID50/mL.  
 
7.42 
In the Phase I, stage 2 evaluation of MV-NIS in combination with 
cyclophosphamide, if two or more patients experience DLT at the starting dose 


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level, then the new dose level 1 will be 3 log lower than the MTD for MV-NIS 
alone. Re-escalation will occur according to escalation rules described in 7.3 
except with this one log lower multiplier.  
 
7.5 
Phase II Treatment 
 
7.51 
Treatment Schedule 
 
Agent 
Dose 
Route 
Day 
99m-Tc 
20mCi (+/- 
10%) 
IV 
Any time pre-MV-NIS (for baseline 
99m-Tc scan) 
Pre-medication prior to Administration of MV-NIS 
Acetaminophen 
650 mg 
orally 
30 minutes prior to MV-NIS 
Benadryl 
50 mg 
orally 
30 minutes prior to MV-NIS 
MV-NIS Administration 
MV-NIS 
TCD50 
10(11) 
IV 
1 
After MV-NIS Administration 
 99m-Tc 
20mCi (+/- 
10%) 
IV 
Days 8 and 15  
(two additional doses may be given for 
imaging based on imaging results) 
 
7.52 
To maximize systemic delivery of the MV-NIS, patients will be asked to avoid a 
heavy meal 3-4 hours before treatment. In addition, patients will be kept warm at 
the beginning of the infusion (cover with a warm blanket). The virus will be 
administered by slow intravenous (IV) infusion over 1 hour in 250 mL of 0.9% 
sodium chloride under close observation in the Clinical Research Unit (CRU) or 
on Hematology in-patient service. 
 
 


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7.53 
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 (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, 
methylprednisone (1mg/kg IV) and epinephrine (1mg subcutaneously). 
Administration of these medications will be tracked. 
 
Therapy for Acute Infusion Reactions 
Agent 
Dose 
Route 
Reaction 
Acetaminophen 
650 mg 
P.O. 
Acute febrile reaction 
Diphenhydramine 
50 mg 
I.V. or P.O. 
Acute febrile reaction 
Meperidine HCl 
50 mg 
I.V. 
Rigors 
Methylprednisolone 
1 mg/kg 
I.V. 
Anaphylaxis 
Normal saline 
Prn 
I.V. 
Anaphylaxis or hypotension 
Epinephrine 
1 mg 
S.C. 
Anaphylaxis 
 
7.54 
The in vivo distribution of MV-NIS infected cells and the kinetics of virus spread 
and elimination will be monitored by 99m-Tc SPECT/CT as described in Table 
4.1 and by serial measurements of viral RNA in mononuclear cells derived from 
blood, saliva and urine (Viral N-gene RNA copy number/g RNA).  
 
If at day 15 isotope uptake is observed in organs other than the thyroid, stomach 
and salivary glands, further imaging will be performed on day 22 (and day 29) to 
document elimination of the virus and virus infected cells 
 
7.55 
Phase II stopping rule definitions are described in section 16.521 using DLT  
 
7.6 
Toxicity Observation Period: The first 6 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. The toxicity observation 
period will be waved for the Phase II expansion. 
 
7.7 
Phase I only: If a patient fails to complete the initial course of therapy (i.e. registers,   but 
does not receive therapy or lost to follow-up during first 6 weeks), the patient will be 
regarded as inevaluable 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 Cancer Center 
Clinical Research Administrative Subcommittee (CCCRAS). If more than one participant 
must be replaced at a dose level for reasons other than toxicity, the reasons will be 
reported to the FDA and the trial be voluntarily halted pending comments by the FDA 
review team. 
 


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7.8 
Anticipated toxicity 
 
7.81 Acute febrile reaction to the intravenously administered virus may occur. Ancillary 
support is described in sections 7.113 and 9.2.   
 
7.82 Measles-like illness (coryza, malaise, fever, rash, lymphadenopathy and transient 
suppression of the immune system). 28,29  Patients will be educated about the symptoms of 
measles and asked to report immediately if any of these symptoms develop.  
 
The disease is self-limiting in normal adults but because myeloma patients are 
immunocompromised, treatment will be implemented: 
 
If the symptoms (including temperature > 38.5o C) persist for as long as 6 days, 
or earlier at the treating physician’s discretion.  
 
Earlier treatment is strongly recommended if a typical measles exanthem 
appears.  
 
Treatment will include immunoglobulin (500 mg/kg) and Ribavirin (10 mg/kg/day in 4 
divided doses orally or 20mg/kg/day intravenously) [47, 48]. Administration of these 
medications will be tracked and a participant with persistent measles-like illness will be 
classified as having experienced a DLT (see section 7.8). Additional ancillary support is 
described in section 9.2. 
 
Therapy for Measles Persistence 
Agent 
Dose 
Route 
Reaction 
Intravenous 
immunoglobulin 
500 mg/kg 
I.V. 
Persistent measles-like 
symptoms 
Ribavirin 
10 mg/kg/day 
(in 4 divided 
doses)  
Or 
20 mg/kg/day 
(in 3 divided 
doses) 
P.O. 
 
 
I.V. 
Persistent measles-like 
symptoms  
Or  
Persistent viremia (see 
section 7.8) 
 
7.83 199m-Tc is well tolerated. No acute toxicity is expected. 
 
7.9 
Dose limiting toxicity (DLT) will be defined as follows: 
 
Definitions of Dose Limiting Toxicity (DLT) 
Hematologic 
Neutrophils 
Grade 4 ANC (<500/mm3) 14 days 
Platelets 
Grade 4 PLT (< 25,000/mm3) ≥ 7 days 
All other 
hematologic* 
Grade 3 or greater 
Renal 
Creatinine 
Grade 3 (Serum creatinine > 3x ULN) 
Vascular disorders 
Hypotension 
Grade 4 or greater 
General 
Fever 
Grade 4 (> 40.0 C for > 24 hours) 
Neurologic 
Headache 
Grade 3 lasting more than 6 hours 


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Other non-hematologic* 
 grade 3  
Symptomatic measles infection 
Coryza, malaise, fever, rash, brassy cough; 
conjunctivitis; photophobia;  and 
lymphadenopathy ≥ 6 days  
Viremia (detection of viral RNA by 
RT-PCR in PBL). 
> 10 fold increase in the copy number 
(copies/g RNA) between sequential samples at 
least 3 days apart after day 15.  
*With the exception of lymphopenia, leukopenia, anemia, febrile neutropenia, self-
limited infusion reaction, and nausea, which will not be considered dose limiting 
toxicities. 
 
8.0 
Dosage Modification Based on Adverse Events 
 
8.1 
Given the nature of this study (i.e. a phase I trial and a phase II study with only one dose 
of drug administered), there are no dose modifications in this study.   
 
9.0 
Ancillary Therapy 
 
9.1 
Patients should receive full supportive care during the study including blood products, 
antibiotics and treatment of concurrent medical conditions and other newly diagnosed 
diseases.  
 
9.2 
Patients will be closely monitored as an in-patient during infusion of the virus acute 
febrile reaction to the intravenously administered virus. For phase II, patients will be pre-
medicated with acetaminophen. 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. 
 
9.3 
Patients will be educated about the symptoms of measles (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 measles (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 24 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 the face 


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and body, a feature that is such a distinct characteristic of measles 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 myeloma patients are 
immunocompromised, treatment will be implemented if the symptoms (including 
temperature > 38.5o C) persist for as long as 6 days, and earlier at the treating physician’s 
discretion. Earlier treatment is strongly recommended if a typical measles exanthem 
appears. Treatment will include intravenous gammaglobulin (500 mg/kg) and Ribavirin 
(10 mg/kg/day in 4 divided doses orally or 20mg/kg/day intravenously) [47, 48]. 
Administration of these medications will be tracked and a participant with persistent 
measles-like illness will be classified as having experienced a DLT (see section 7.7) 
9.4 
Patients who demonstrate persistent viremia or viral shedding (10-fold increase in MV-
NIS genome/mcg RNA at 4 weeks) that is confirmed on 2 consecutive samples after day 
15 will also be treated with measles immunoglobulin and Ribavirin. 
 
9.5 
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 and all Mayo Clinic staff have measles virus immunity documented upon 
commencement of employment, we will require 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 measles virus (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 measles virus, transmission of has 
not been documented. However, since other patients on the Mayo Clinic grounds may be 
severely immunosuppressed, we will require that MV-NIS treated patients wear a mask 
when outside of their hospital room on Mayo Clinic grounds while they are shedding 
virus (tested by RT-qPCR). 
 
If a patient is found to be shedding the virus in urine or throat gargle specimens(s), family 
members (or close personal contacts) who don’t have documentation of immunity, will 
be offered testing to assess anti-measles virus immunity by Enzyme Immunoassay for the 
presence of MV-NIS. Measles vaccination will be offered to seronegative individuals, as 
per standard clinical practice.  
 
9.6 
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. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring  
 
10.1 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
v3.0 for adverse event monitoring and reporting.  The CTC v3.0 can be downloaded from 
the CTEP home page (http://ctep.info.nih.gov/CTC3/ctc ind term.htm).  All appropriate 
treatment areas should have access to a copy of the CTCAE v3.0. 
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE.  Next, 


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determine whether the event is expected or unexpected (refer to Section 15.0 
and/or product literature) and if the adverse event is related to the medical 
treatment or procedure (see Section 10.13).  With this information, determine 
whether an adverse event should be reported as an expedited report (see Section 
10.2) or as part of the routinely reported clinical data. 
 
Expedited adverse event 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 in Section 10.2.  All expedited 
adverse event reports should also be submitted to the local Institutional Review 
Board (IRB).   
 
10.12 Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the investigational agent(s). 
Probable - The adverse event is likely related to the investigational agent(s). 
Possible - The adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s) 
 
10.13 Expected vs. Unexpected 
 
The determination of whether an AE is expected is based on agent-specific 
adverse event information provided in Section 15.0 of the protocol.  
 
Unexpected AEs are those not listed in the agent-specific adverse event 
information provided in Section 15.0 of the protocol. 
 
10.14 When a study includes both investigational and commercial agents, the following 
apply: 
 
When an investigational agent(s) is used in combination with a commercial 
agent(s) the combination is considered investigational. Expedited reporting 
of adverse events follows the guidelines for investigational agents.  
 


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10.2 
Expedited Adverse Event Reporting Requirements  
 
 
Grade 4 or 51 
Unexpected  
with  
Attribution of Possible, 
Probable, or Definite 
Other Grade 4 or 5 
or  
Any hospitalization 
during treatment6 
Secondary 
AML/MDS2, 4 
Submit written report within 5 working 
days3, 5 
X 
 
 
Submit Grade 4 or 5 Non-AER Reportable 
Events/Hospitalization Form within 5 
working days.4 
 
  
 
Submit Serious Adverse Event Reporting 
Form for Human Gene Transfer Clinical 
Studies 5, 6 
X 
 
 
1. Includes all deaths within 30 days of the last dose of investigational agent regardless of attribution or 
any death attributed to the agent(s) (possible, probable, or definite) regardless of timeframe.  
2. Reporting for this AE required during or after treatment. 
3. Use Adverse Event Expedited Report – Single Agent or Multiple Agents report form.  Submit to the 
Cancer Center SAE Coordinator for further processing (see footnote 7)  
4. Submit the report by fax 
to the MCCC SAE Coordinator. If Adverse Event 
Expedited Report – Single Agent or Multiple Agents report form was completed, this form does not 
need to be completed. 
5. Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies, along with the 
UPIRTSO cover sheet, by fax
to the MCCC Regulatory Affairs 
Unit (RAU) Risk Information Specialist who will determine and complete IRB 
reporting. The RAU will submit to the MCCC SAE Coordinator and the MCCC IND Coordinator to 
determine if FDA submission is needed. 
6. This reporting is in addition to all other reporting.  Submit form to the Office of Recombinant 
DNA Activities, NIH, MSC 7010, 600 Executive Boulevard, Suite 302, Bethesda MD 20892-
7010; Phone 
.  Submit copies of the report to the Cancer Center PDC for IRB 
reporting and to the Cancer Center SAE Coordinator for further processing (see footnote 7).   
 
10.3 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per (CTCAE) v3.0 grading unless otherwise stated in the table 
below: 
 
 
X 


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Table 10.3a  
 
Category 
Adverse 
event/Symptoms 
Baseline 
Each Evaluation 
BLOOD/BONE MARROW 
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 
Nausea 
X 
X 
ENDOCRINE 
Thyroid function , low 
(hypothyroidism 
X 
X 
 
Table 10.3b 
 
Upon receiving alternative myeloma directed therapy, only limited adverse events as indicated 
below will be monitored until 1 year after MV-NIS therapy 
 
Category 
Adverse event/Symptoms 
Observation 
CONSTITUTIONAL 
Fever 
X 
RESPIRATORY 
Cough 
X 
INFECTION 
Upper airway NOS 
X 
 
Febrile neutropenia 
X 
 
10.31 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic as applicable) 
the following AEs experienced by a patient and not specified in Section 10.3: 
 
10.311 Grade 2 AEs deemed possibly, probably or definitely related to the study 
treatment or procedure.  
 
10.312 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure.  
 
10.313 
Grade 5 AEs (Death) 
 
10.3131 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or procedure. 
 
10.3132 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 


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be submitted as a grade 5 AE, with a CTCAE type and attribution 
assigned.  
 
10.32 Refer to the instructions in the forms packet (or electronic data entry screens as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0).  
 
 
11.0 
Treatment Evaluation 
 
11.1 
Terms and definitions 
 
 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.   
 M-proteins migrating in the -region (usually IgA M-proteins)  
 Cases in which the M-spike is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
 Cases in which there are multiple peaks of same monoclonal protein 
(aggregates or dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted.  However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-spike values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are defined 
as having monoclonal lambda FLC and those with ratios >1.65 as having a 
monoclonal kappa FLC.  The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC type.  
 
 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), Minimal Response (MR), stable disease (SD), progressive disease 
(PD) and relapse from CR (RFCR).  
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will applied at the time of the first measurement 
at which the quantitative aspect of the response category has been satisfied without 


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the confirmation step having been satisfied. The designation “u” will precede the 
standard abbreviations, and will include usCR, uCR, uVGPR, uPR, uMR, uPD.  
 
Measurable disease: Patients who have a measurable serum or urine M-protein.  
 
 
Serum M-protein ≥1 g/dl  
 
Urine M-protein ≥ 200 mg/24 h 
 
Serum FLC assay: Involved FLC level ≥  10 mg/dl provided serum FLC ratio is 
abnormal 
 
Bone marrow plasma cells ≥ 30% 
 
The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory or non-secretory disease and should be used 
in assessing response only if the baseline serum and/or urine M proteins are not 
“measurable” as above, and the baseline level of the involved FLC is ”measurable.” 
When using this assay, it is important to note that the FLC levels vary considerably with 
changes in renal function and in patients with renal insufficiency, the levels of both the 
kappa and lambda may remain elevated, but the ratio normalizes with achievement of 
CR. Thus both the level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response. Patients included on the study on the basis of FLC  alone (i.e. no 
measurable serum/urine) should be the only ones who are evaluated using FLC 
response criteria. The others should follow usual criteria and ignore FLC results. 
 
 
Evaluable disease: Patients who do not have a “measurable” serum M-spike, serum 
free light chain, or urine M-spike. 
 
 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-spike or urine M-spike, but has had a detectable monoclonal 
protein in his/her serum and/or urine and/or measurable serum free light chain.  
 
 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable monoclonal protein in his/her serum and/or urine. 
 
11.2 
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.   
 
Table 11.2 
Tests  Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP  24 hr 
UPEP2  
Ig 
FLC 
BM Bx 
Serum M-spike ≥1 g/dl, and urine M-spike≥ 200 
mg/24 hrs 
X 
X 
 
 
Serum M-spike ≥ 1 g/dl, but urine M-spike < 200 
mg/24 hrs 
X 
 
 
 
Serum M-spike<1 g/dl, and urine M-spike≥ 200 
mg/24 hrs 
 
X 
 
 


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Serum M-spike < 1 g/dl, urine M-spike < 200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum M-spike < 1 g/dl, urine M-spike < 200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X3 
1 Immunofixation studies of both serum and urine are required to document CR 
regardless of registration values, and in addition FLC measurement and bone marrow 
immunophenotyping is required to document sCR. 
 
2 For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category 
 
 3 Bone marrow biopsyresults do not need to be confirmed (i.e. repeated after documented 
response). 
 
11.3 
Confirmed response  
 
In order to be classified as a hematologic response, confirmation of serum monoclonal 
protein, serum immunoglobulin free light chain (when primary determinant of response) 
and urine monoclonal protein (when primary determinant of response) results must be 
made by verification on two consecutive determinations.   
 
Bone marrow aspirate and biopsy are only required to document or confirm CR 
or sCR, except for patients with evaluable disease only, where a bone marrow is 
required to document all response categories including progression. However, a 
second confirmatory bone marrow is not required to confirm response. 
 
Radiographic studies are not required to satisfy these response requirements, 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 11.2 
 
11.4 
Bone progression  
 
Caution must be exercised to avoid rating progression or relapse on the basis of variation 
of radiologic technique alone.  Compression fracture does not exclude continued response 
and may not indicate progression.  When progression is based on skeletal disease alone, it 
should be discussed with the study chair before removing the patient from the study.  
 
11.5 
Response and Progression 
 
Criteria for response and progression are listed in Table 11.2. Progressive disease for all 
patients as defined in Table 11.2. Although the definition for “relapse from CR (or sCR) 
is listed, this will be documented as a response category in ONLY those protocols 
evaluating disease free survival.  
 
 


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Table 11.5 
CATEGORY 
RESPONSE CRITERIA a 
Stringent complete 
response (sCR)   
 
 
CR as defined below plus all of the following 
 
Normal serum FLC ratio  
 
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence b 
Complete response 
(CR) 
 
Negative immunofixation of the serum and urine  
 
< 5% plasma cells in bone marrow  
 
Disappearance of any soft tissue plasmacytomas  
 
If at on study, the only measurable non-bone marrow parameter was  FLC, 
normalization of FLC ratio 
Very good partial 
response (VGPR)e 
 
 
PR as defined below plus all of the following: 
 
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
 
If at on study, serum measurable, ≥ 90% or greater reduction in serum M-
component  plus urine M-component <100 mg per 24 h  
 
If at on study, the only measurable non-bone marrow parameter was  FLC, ≥ 
90% or greater reduction in the difference between involved and uninvolved 
free light chain levels 
Partial Response 
(PR) 
 
One of the following: 
 If at on study, serum and urine measurable, a ≥ 50% reduction of serum 
M-protein and reduction in 24-h urinary M-protein by ≥ 90% or to 
<200 mg per 24 h  
 If at on study, only serum measurable (but urine not), a ≥ 50% reduction 
of serum M-protein  
 If at on study, urine measurable (but serum not), a reduction in 24-h 
urinary M-protein by ≥ 90% or to <200 mg per 24 h  
 If at on study, only the only measurable non-bone marrow parameter was  
FLC, a ≥ 50% decrease in the difference between involved and uninvolved 
FLC levels   
 If at on study, the bone marrow was only measurable parameter, ≥ 50% 
reduction in bone marrow plasma cells is required in place of M-protein, 
provided baseline percentage was ≥ 30% 
 
In addition to the above criteria, if  a plasmacytoma present at baseline, ≥ 
50% reduction in the size of soft tissue plasmacytomas is also required 
Minor Response 
(MR) 
 
≥25% but < 49% reduction of serum M-protein and reduction in 24h urine M-
protein by 50-89%, which still exceeds 200 mg per 24 h 
 
In addition to the above criteria, if  a plasmacytoma present at baseline, 25-
49% reduction in the size of soft tissue plasmacytomas is also required 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease 
Progressive disease 
(PD) 
Any one or more of the following:  
 
Increase of 25% from lowest confirmed response in: 
 Serum M-component (absolute increase must be ≥ 0.5 g/dl)c  
 Serum M-component increase ≥ 1 g/dl, if lowest M component was ≥ 5 
g/dl 


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 Urine M-component (absolute increase must be ≥ 200 mg/24 h) c 
 If at on study, only the only measurable non-bone marrow parameter was  
FLC, the difference between involved and uninvolved FLC levels 
(absolute increase must be >10 mg/dl) c  
 Bone marrow plasma cell percentage (absolute % must be ≥10%)c 
Or any one or more of the following felt related to the underlying clonal plasma cell 
proliferative disorder 
 Development of new soft tissue plasmacytomas or bone lesions 
 Hypercalcemia (≥11.5 mg/dl) 
 Decrease in hemoglobin of ≥2 g/dl 
 Serum creatinine level ≥2 mg/dl 
Relapse from CR 
or sCR d 
 
Patient who has achieved confirmed CR who has any one or more of the following: 
 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
 
Development of ≥ 5% plasma cells in the bone marrow f 
 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic 
bone lesion, or hypercalcemia) 
a All response categories require two consecutive assessments made at anytime before the 
institution of any new therapy; complete and PR, MR and SD categories also require no known 
evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be confirmed. Each category, except for stable disease, will have a working 
subcategory of “unconfirmed” [prefix ‘u”] to designate first time point at which response 
category MAY have been achieved if confirmed. 
b Presence/absence of clonal cells is based upon the k/  ratio. An abnormal k/  ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is k/  of >4:1 or <1;2.  
c  Positive immunofixation alone in a patient previously classified as CR will not be considered 
progression. 
d This category will ONLY be used on a protocol specific basis, i.e. only those protocols looking 
at disease free survival. 
e This response category is not available for those patients being followed by bone marrow only. 
f Relapse from CR has the 5% cutoff versus 10% for other categories of relapse. 
11.6 
Criteria for engraftment (for hematopoietic stem cell transplant studies only) 
 
Engraftment is defined as: 
• 
The first day of three consecutive days on which the absolute neutrophil 
count (ANC) >500/mm3 
  
• 
The first of three consecutive days with an untransfused platelet count 
>20,000/mm3. 


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12.0 
Descriptive Factors: 
 
12.1 
Number of prior treatments and what type 
 
12.2 
Disease status: Primary responsive, primary refractory, chemosensitive relapse, 
chemoresistent relapse, untested relapse. 
 
12.3 
Prior stem cell transplant:  Yes vs. no 
 
12.4 
Date of last therapy 
 
12.5 
Date of myeloma diagnosis and Durie Salmon Stage at diagnosis.  
 
12.6 
At diagnosis was serum M-spike ≥1 g/dL: Yes vs. no.   
 
12.7 
At diagnosis was urine M-spike ≥ 200 mg/24 hours: Yes vs. no. 
 
12.8 
Durie Salmon Stage at entry  
 
12.9 
Measles IgG and IgM titers at entry 
 
12.9a 
Pre-treatment disease measurements: serum M-spike ≥1 g/dL; urine M-spike ≥ 200 
mg/24 hours; immunoglobulin free light chain ≥ 10 mg/dL; bone marrow ≥ 30% plasma 
cells. 
 


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13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
 
13.1 
The investigator may discontinue individual patients from the study at any time for the 
following reasons: a) if the patient develops adverse events that in the judgment of the 
investigator preclude further exposure to the study agent; b) if a patient develops an 
intercurrent illness that is not consistent with the protocol requirements, that patient may 
be withdrawn from the study; c) if the patient is not compliant with the study plan. 
 
13.2 
Phase I only: Indications for replacing a patient include: a) If a patient fails to complete 
the initial course of therapy (defined as 1 cycle of drug administration and 6 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 7.6). If more than one 
participant must be replaced at a dose level for reasons other than toxicity, the reasons 
will be reported to the FDA and the trial be voluntarily halted pending comments by the 
FDA review team. 
 
13.3 
Patients who have disease progression, refuse further observation, or go on to receive 
alternate therapy will be monitored  by Q-RT-PCR for N-gene according to test schedule 
until Q-RT-PCR becomes negative. This can be done through mail-in kits.    
 
13.4 
Patients who discontinue treatment due to unacceptable toxicity as defined in Section 7 
will be actively monitored in Observation and will follow the test schedule per Section 
4.0 until progression and until Q-RT-PCR for N-gene becomes negative. This will be 
done according to test schedule and can be accomplished through mail-in kits.     
 
13.5 
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.  On-study material is to be submitted.  No further follow-up information is 
necessary.  
 
13.6 
For the purposes of this study, patients will be evaluated for clinical response at 6 weeks 
and 12 weeks and every 3 months thereafter while on observation. Blood, urine, bone 
marrow and skeletal radiography will be performed as outlined in Section 4.0. 
 


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14.0 
Pharmacologic/Ancillary studies (Mandatory) and Optional Biopsy 
 
14.1 
Assessment of viremia and viral shedding. Mononuclear cells will be isolated from blood, 
throat washings and urine from all study patients on days 3, 8, 15. Additional samples on 
days 22 and 29 might be collected (depending on the viral RNA profile) and all will be 
tested for a) viral replication (quantitative RT-PCR to determine virus RNA copy number 
and co-culture on Vero cells for virus isolation). Testing will be performed in Dr S.J. 
Russell’s laboratory (Guggenheim 1802) under the supervision of Dr Dispenzieri.  
 
If a patient is found to be shedding the virus in urine or throat gargle specimens(s), family 
members (or close personal contacts) who don’t have documentation of immunity, will 
be offered testing to assess anti-measles virus immunity by Enzyme Immunoassay for the 
presence of MV-NIS. Measles vaccination will be offered to seronegative individuals, as 
per standard clinical practice.  
 
14.2 
Assessment of immune competence will be performed by evaluation of immunoglobulin 
levels, CD4 and CD8 counts  
 
14.3 
Assessment of the peripheral immune response to viral administration. MV specific 
immunity will be evaluated at baseline and on day 42 by (a) measuring anti MV specific 
antibodies (IgG) and (b) by performing lymphocyte proliferation assays, and IFN-g 
ELISPOT assays on peripheral blood. These latter tests will also be performed on day 8 
and day 15; and (c) cytokine levels around the time of MV-NIS administration.   
 
14.4 
Appraisal of baseline bone marrow CD46 and SLAM expression by flow cytometry. 
 
14.5 
Assessment of baseline bone marrow’s infectivity ex vivo. 
 
14.6 
Assessment of day 42 bone marrow syncytia formation and levels of measles virus N 
mRNA within bone marrow cells. 
 
14.7 
Evaluation of MV-NIS biodistribution using SPECT/CT.  Table 4.1. 
 
14.8 
Pharmacokinetic studies will be done during Stage 2 and Stage 1 patients at dose levels 5 
and 6 of trial on all patients as well as all Phase II patients 
 
14.9 
Optional biopsy of area of interest will be performed by Dr. Stephanie Carlson (or 
colleagues) to biopsy “area of interest” if uptake seen on SPECT scan day 8 to confirm 
presence of virus in lesion.  The biopsy of the lesion will be done per usual image-guided 
techniques using CT-guidance (see Section 17). 
 


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Summary of Research blood and bone marrow 
 
Sample 
Tube (volume); 
#tubes 
Timing 
Destination 
Total trial 
APTT 
Citrate (5 mL) 
5x 
Routine coagulation lab 
 
25 mL 
FLC 
Red top (1 mL) 
6x 
Routine immunology lab 
 
6 mL 
Anti MV IgM & IgG 
Red top (0.5 mL) 
2x  
Routine serology lab  
1 mL 
Measles neutralizing Ab 
Red top (2 mL) 
2x 
Guggenheim 
 
4 mL 
Cytokines 
EDTA (4 mL) 
4x 
Guggenheim 
 
16 mL 
T & B quantitation (CD4 & 
CD8) 
EDTA (5 mL) 
3x  
Routine cell kinetics lab 
 
15 mL 
PBMC for viremia 
PAXgene x2 (2.5 mL 
per tube) 
10 to 15 x 
(baseline, PK x 6; day 
8, 15, 42, and possibly 
days 22 and 29, and 
month 3, 6, and 12) 
Guggenheim 
 
50-75mL 
Blood for LPA and IFN- 
ELISPOT 
CPT tube  (10 mL x 4) 
4x 
Guggenheim 
 
160 mL 
Bone marrow aspirate & 
biopsy 
40 mL (IRB 521-93) 
2x entire study 
Guggenheim 
 
80 mL 
Mouth rinse 
 
4 to 6 x/ cycle 1 and 
once per cycle 
thereafter 
Guggenheim 
 
 
Mid-stream urine 
400 mLin sterile 50 
mL Falcon tube 
4 to 6 x/ cycle 1 and 
once per cycle 
thereafter 
Guggenheim 
 
 
Optional biopsy of lesion* 
 
 
Guggenheim 
 
 
 
 Cores of the tissue (either bone or soft tissue depending on the lesion and if it is associated with a soft tissue mass or not) will 
be acquired using a biopsy needle (ranging in size from 12-guage to 20-guage depending again on lesion site, consistency, and 
size).  As per usual practice a core and smears will be sent to cytology and pathology for analysis and confirmation of the 
malignancy (charge to grant, not to patient).  One core of tissue (and an associated cytology smear) will go to Dr. Stephanie 
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15.0 
Drug Information 
 
15.1 
MV-NIS (recombinant Edmonston measles virus carrying the human NIS gene) 
 
15.11 Background:  MV-NIS is an attenuated measles virus, engineered to express the 
human thyroidal sodium-iodide symporter (NIS).  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 human 
malignancies.  Multiple myeloma cells are selectively infected and killed by 
attenuated measles viruses of the Edmonston vaccine lineage  
 
15.12 Formulation: MV-NIS infusions yield doses ranging from 1 x 104, 1 x 105, 1 x 
106, 1 x 107, 1 x 108, 1 x 109, to 1 x 1011 TCID50.  See Section 1.91 for a more 
complete description of the production and purification process 
 
15.13 Administration: The virus will be administered by slow intravenous (IV) infusion 
(1 hour) in 250ml of normal saline under close observation in the Clinical 
Research Unit (CRU) or on the Hematology in-patient service.  (See Appendix I) 
 
15.14 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 measles virus and 
we anticipate that the most common toxicities will be similar to those 
experienced after the administration of the measles vaccine [44]. The main 
reaction associated with measles vaccination is a mild measles-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 measles like illness has been described only in measles-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  
 
Optic neuritis  
 
Ataxia  


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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. 43 If 
symptoms suggestive of persistent measles or either pneumonitis or encephalitis 
develop, the patients will be treated aggressively with anti-measles virus immune 
globulin and ribavirin and all the supportive care necessary as the situation might 
dictate.42 
 
15.15 Risks to caretakers and other Mayo Clinic Patients 
Viral transmission between patient and his/her contacts is thought to be unlikely, 
unless the patient develops florid measles infection. The vaccine strain of the 
measles virus (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 measles virus, there has been 
only 1 case of symptomatic measles virus presumptively transmitted from a 
vaccinated individual (Rota et al J. Clin Microbiology 2005). However, since 
other patients on the Mayo Clinic grounds may be severely immunosuppressed, 
we will require that MV-NIS treated patients wear a mask when outside of their 
hospital room on Mayo Clinic grounds while they are shedding virus (tested by 
RT-qPCR).  
 
15.2 
Radioactive technetium –99m-Tc  
 
15.21 Generic or Common Drug Name (others such as Brand, Alpha-numeric): Sodium 
Pertechnetate Tc 99m, Mo-99/Tc-99m generator, TechneLite® (Technetium Tc 
99m Generator), Ultra-TechneKow™ DTE Generator.  
 
15.22 Background: Mechanism of action, drug family. 
 
The pertechnetate ion distributes in the body similarly to the iodide ion but is not 
organified when trapped in the thyroid gland. Pertechnetate concentrates in the 
thyroid gland, salivary glands, stomach and choroid plexus. After intravenous 
administration it gradually equilibrates with the extracellular space. A fraction is 
promptly excreted via the kidneys. 
 
15.23 Formulation: How supplied, available strengths, excipients. 
 
Supplied in a Mo-99/Tc-99m generator which contains the amount of 
molybdenum Mo-99 at the date and time of calibration stated on the label. 
 
The sterile, non-pyrogenic solution used to elute the generator column 
contains 0.9% sodium chloride. The eluant does not contain an 
antimicrobial agent. 
 
The generator should not be used after the expiration date stated on the label. The 
expiration time of the Sodium Pertechnetate Tc 99m solution is not later than 12 
hours after time of elution. If the eluate is used to reconstitute a kit, the 
radiolabeled kit should not be used after 12 hours from the time of generator 
elution or after the expiration time stated on the labeling for the prepared drug, 
whichever is earlier. (BUD assignment for prepared drug is based on 
radiopharmaceutical package insert or internal validated SOPs) 


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15.24 Preparation and storage: admixture instructions, light sensitivity, 
temperature for storage, product specific information. 
 
Store generator and Sodium Pertechnetate Tc 99m solution at controlled 
room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room 
Temperature], and such generator system should be eluted in an ISO Class 
8 or cleaner air environment to permit special handling, shielding, and air 
flow requirements [see USP <797> “Radiopharmaceuticals as CSPs”]. 
 
15.25 Administration:  Intravenous rates, details for oral administration.  
 
Sodium Pertechnetate Tc 99m is usually administered by intravascular injection 
but can be given orally.. 
The suggested dose range employed for various diagnostic indications in the 
average ADULT PATIENT (70kg) is: 
 
Vesico-ureteral Imaging 18.5 to 37MBq (0.5 to 1mCi) 
Brain Imaging 370 to 740MBq (10 to 20mCi) 
Thyroid Gland Imaging 37 to 370MBq (1 to 10mCi) 
Salivary Gland Imaging 37 to 185MBq (1 to 5mCi) 
Placenta Localization 37 to 111 MBq (1 to 3mCi) 
Blood Pool Imaging 370 to 1110MBq (10 to 30mCi) 
Nasolacrimal Drainage System Max. 3.7MBq (100μCi) 
 
The patient dose should be measured by a suitable radioactivity calibration 
system immediately prior to administration of the dose.  
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. The 
solution to be administered as the patient dose should be clear and contain no 
particulate matter.  
 
15.26 Pharmacokinetic information: 
 
a)  Absorption –  
 
b)  Distribution –  
 
c)  Metabolism –  
 
d)  Excretion –  
 
After intravascular administration Sodium Pertechnetate Tc 99m  remains in the 
circulatory system for sufficient time to permit blood pool, organ perfusion, and 
major vessel studies. It gradually equilibrates with the extracellular space. A 
fraction is promptly excreted via the kidneys. 
 
15.27 Potential Drug Interactions:   
 
None 
 
15.28 Known potential toxicities:   
 




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cycle phase nonspecific agent. Cyclophosphamide also possesses potent 
immunosuppressive activity. Cyclophosphamide is a prodrug that must be 
metabolized to active metabolites in the liver. 
 
15.32 Formulation: Commercially available for oral administration as:  
Tablets: 25 mg, 50 mg  
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature preferably below 25ºC (77ºF). This product will withstand 
brief exposure to temperatures up to 30ºC (86ºF), but should be protected 
from temperatures above 30ºC (86ºF). Dispense in a tight container as 
defined in the USP/NF. Refer to labeling on the bottle for expiration date 
of the commercial tablets. 
 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. Tablets are not scored and should not be cut or crushed. To 
minimize the risk of bladder irritation, do not administer tablets at bedtime. 
 
15.35 Pharmacokinetic information: 
Distribution: Vd: 0.48-0.71 L/kg; crosses placenta; crosses into CSF (not 
in high enough concentrations to treat meningeal leukemia) 
Protein binding: 10% to 60% 
Bioavailability: >75% 
Time to peak, serum: Oral: ~1 hour 
Metabolism: Hepatic to active metabolites acrolein, 4-aldophosphamide, 
4-hydroperoxycyclophosphamide, and nor-nitrogen mustard 
Half-life elimination: 3-12 hours 
Excretion: Urine (<30% as unchanged drug, 85% to 90% as metabolites) 
 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of  CYP2A6 (minor), 2B6 (major), 
2C9 (minor), 2C19 (minor), 3A4 (major); Inhibits CYP3A4 (weak); 
Induces CYP2B6 (weak), 2C8 (weak), 2C9 (weak)  
Increased Effect/Toxicity: Allopurinol may cause an increase in bone 
marrow depression and may result in significant elevations of 
cyclophosphamide cytotoxic metabolites. CYP2B6 and CYP3A4 inducers 
may increase the levels/effects of acrolein (the active metabolite of 
cyclophosphamide); see package insert for example inducers. Etanercept 
may enhance the adverse effects of cyclophosphamide. Cyclophosphamide 
reduces serum pseudocholinesterase concentrations and may prolong the 
neuromuscular blocking activity of succinylcholine and mivacurium. 
Decreased Effect: Cyclophosphamide may decrease the absorption of 
digoxin tablets. CYP2B6 and CYP3A4 inhibitors may decrease the 
levels/effects of acrolein (the active metabolite of cyclophosphamide); see 
package insert for example inhibitors. 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors.  
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  


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Common known potential toxicities, > 10%:   
Dermatologic: Alopecia but hair will usually regrow although it may be a 
different color and/or texture. Hair loss usually begins 3-6 weeks after the 
start of therapy. 
Endocrine & metabolic: Fertility: May cause sterility; interferes with 
oogenesis and spermatogenesis; may be irreversible in some patients; 
gonadal suppression (amenorrhea) 
Gastrointestinal: Nausea and vomiting, usually beginning 6-10 hours after 
administration; anorexia, diarrhea, mucositis, and stomatitis are also seen 
Hematologic: Thrombocytopenia and anemia are less common than 
leukopenia 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Facial flushing 
Central nervous system: Headache 
Dermatologic: Skin rash 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Cyclophosphamide may potentiate the cardiac toxicity of anthracyclines. 
Other adverse reactions include anaphylactic reactions, darkening of 
skin/fingernails, dizziness, hemorrhagic colitis, hemorrhagic ureteritis, 
hepatotoxicity, hyperuricemia, hypokalemia, jaundice, malaise, 
neutrophilic eccrine hidradenitis, radiation recall, renal tubular necrosis, 
secondary malignancy (e.g., bladder carcinoma), SAIDH, Stevens-Johnson 
syndrome, toxic epidermal necrolysis, weakness. 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines: 
 
15.391 Myelosuppression is common. Monitor CBC including platelets. Instruct 
patient on signs/symptoms of infection and to inform health care team of 
any unusual bruising, or signs of bleeding. 
 
15.392 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 three hours to 
facilitate keeping the bladder clear of drug. 
 
15.393 Instruct patient to report any urinary urgency, frequency, dysuria, or 
hematuria. Administer mesna with high dose cytoxan to prevent 
hemorrhagic cystitis.  It may be necessary to catheterize and provide 
constant bladder irrigation. 
 
15.394 Advise patient in possible strong metallic taste associated with Cytoxan 
and suggest hard candy with a strong flavor (cinnamon, peppermint) to 
alleviate it. 
 


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15.395 Administer antiemetics as necessary to minimize nausea and vomiting, 
which usually occurs 6-8 hours after administration. 
 
 
15.396 Report and record any complaint of lightheadedness, facial “heat 
sensation,” diaphoresis during administration. 
 
15.397 Use of an ice cap may be helpful in preventing or limiting alopecia. 
 
15.398 Corticosteroids, phenothiazine, imipramine, vitamin A succinylcholine, 
digoxin, thiazide diuretics, warfarin and allopurinol may inhibit Cytoxan 
metabolism and modify its’ effect.  They may also increase bone marrow 
suppression. 
 
15.399a Advise female patients of possible menstrual changes or amenorrhea. 
 
15.399b Patients on anticoagulant therapy should have INR levels 
carefully monitored as cytoxan increases their effect. 
 
15.399c Monitor electrolytes and for signs/symptoms of SIADH and 
tumor lysis syndrome. 
 
15.399d Monitor digoxin levels closely as cytoxan may decrease these levels. 
 
15.399e Cytoxan may potentiate doxorubicin-induced cardiomyopathy. Instruct 
patient to report any chest pain. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Overview: This is a Phase I/II study designed to  evaluate the toxicity and efficacy of 
MV-NIS.  The phase I portion will determine in a sequential manner the MTD of MV-
NIS when administered with or without cyclophosphamide. This will be done in two 
stages (MV-NIS alone and then MV-NIS with cyclophosphamide), where each 
evaluation will use the standard ‘cohort of three’ design used in phase I clinical trials.  
Toxicity and pharmacokinetics (viral spread, expression and elimination) of MV-NIS in 
the treatment of multiple myeloma will be evaluated in each of the stages.  Once the 
MTD has been determined in Stage 1, the phase II portion will assess the efficacy of MV-
NIS alone in 2 cohorts (Cohort A: relapsed or refractory multiple myeloma who have 
exhausted all therapeutic options and Cohort B:  relapsing from VGPR or CR and have 
not received myeloma directed therapy for at least 12 weeks).  The same one-stage design 
with an interim analysis will be used to evaluate efficacy in each cohort independently.  
 
16.11 Sample Size, Accrual and Study Duration for Phase I: The first stage of this study 
(MV-NIS alone) may involve as few as 9 patients (DLTs in at least 2 patients observed in 
first three patients at the starting dose level and 6 at dose level -1 if deemed MTD) and as 
many as 24 patients (6 each at dose levels 1 through 4).  
 
ADDENDUM 10: The number of patients needed for Stage 1, is recalculated based on 
the knowledge that only 12 patients were required for dose levels 1-4 since not DLT 
observed; Re-opening Stage 1 for dose levels 5 and 6 (new manufacturing capabilities) 


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could require 6-12 patients depending on whether dose-limiting toxicity is seen at this 
level. 
 
The second stage of the Phase I  study (MV-NIS with 1 dose of cyclophosphamide) may 
involve as few as 3 patients (DLTs in at least 2 of the first 3 patients at the starting dose 
level and decision not to de-escalate) and as many as 30 (6 per dose level).  
 
ADDENDUM 10: The number of patients needed for Stage 2, is recalculated based on 
the knowledge that for Stage 2, dose levels 1 and 2 required only 6 patients since no DLT 
observed at these levels. With the revised dose-escalation scheme of 10-fold rather than 
3-fold increases per dose level, there would be a total of six Stage 2 dose levels, for a 
minimum and maximum number of patients on Stage 2 of 18 and 30, respectively, 
assuming Stage 1 maximum tolerated dose is equivalent to maximum feasible dose. If 
not, the Stage 2 patient numbers would drop to a minimum of 12 and a maximum of 18 
patients. 
 
At trial inception, the overall the minimum number of patients to be enrolled was 12 and 
the maximum number of patients was 54.  After Amendment 10, the revised estimates of 
overall minimum and maximum are 30 and 54. For Stages 1 and 2, the accrual rate for 
this study is expected to be about 3 patients per month. Assuming each patient cohort will 
require approximately 5 weeks to follow for dose-limiting toxicity after the last patient 
has been accrued (see Section 7.5), each cohort of 3 patients in Stage 1 or 2 will require 
about 2 months for accrual, treatment, and observation to determine incidence of DLTs 
and whether or not dose escalation can proceed.  
 
Therefore, the accrual period for Phase I is expected to be at most 72 months, taking into 
account the time needed to assess toxicity in each cohort.  
 
ADDENDUM 17:  As of June 16, 2014, 32 patients had been accrued to Phase I. With 
the interesting responses seen in Stage I, dose level 6, Stage II (escalation with addition 
of cyclophosphamide) was suspended to move to a Phase II single agent MV-NIS trial.  
A minimum of 12 and a maximum of 37 evaluable patients will be accrued in phase II. 
We anticipate accruing 4 additional patients to account for ineligibility, cancellation, 
major treatment violation, or other reasons.  Therefore, we expect to accrue a maximum 
of 41 additional patients for 73 patients overall.   The expectation is to start accruing 
patients in August 2014 at a rate of 4 per month, with an anticipated accrual time of 10 
months for the Phase II trial. The phase II analysis can begin after the last patient accrued 
has been followed for 3 months 
 
ADDENDUM 21:  As of March 2015, 44 patients have been accrued to this study (32 
phase I and 12 phase II cohort A).  Due to lack of major responses seen in phase II cohort 
A, accrual to cohort A will be suspended.  Cohort B will be added to evaluate the efficacy 
of this regimen in less heavily pretreated patients.  A minimum of 12 and a maximum of 
37 additional evaluable patients will be accrued to cohort B in phase II. We anticipate 
accruing 4 additional patients to account for ineligibility, cancellation, major treatment 
violation, or other reasons.  Therefore, we expect to accrue a maximum of 41 additional 
patients in cohort B for 85 patients overall.   The expectation is to start accruing patients 
at a rate of 2 patients per month once Addendum 21 is implemented, with an anticipated 
accrual time of 20 months for cohort B of the Phase II trial. The phase II analysis can 
begin after the last patient accrued has been followed for 3 months 
 


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16.12 General Statistical Considerations: The trial is designed to provide data about 
pharmacokinetics (biodistribution, targeting, viral gene expression and viral 
elimination), safety and biological activity of MV-NIS in patients with myeloma. 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 data 
will be used both in exploratory and hypothesis generating fashions to examine factors 
related to toxicity and pharmacology. 
 
16.2 
Phase I Portion 
 
16.21 Primary outcome analyses: 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 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. MTD determination: See Section 7.0 
 
16.22 Secondary endpoints: The following secondary endpoints will be evaluated for 
each stage independently. In addition, differences in dose levels with and without 
cyclophosphamide may also be explored where appropriate.  
 
16.221 The number and severity of toxicity incidents will indicate the level of     
myeloma. For each of the stages, non-hematologic toxicities will be evaluated via 
the CTCAE v. 3 standard toxicity grading. Hematologic toxicity measures such 
as anemia, neutropenia and thrombocytopenia will be assessed using continuous 
variables as the outcome measures (nadir and percent change from baseline 
values) as well as categorization via CTCAE v. 3 standard toxicity grading. 
Frequency distributions and other descriptive measures will form the basis of the 
analysis of these variables 
 
16.222 Clinical Response: The number of clinical responses may provide useful 
preliminary data on the efficacy of this treatment regimen in this patient 
population. A clinical response in this setting will be defined as noted in Section 
11.0. The number of responses (CR, VGPR, PR, or MR) will be summarized by 
simple descriptive summary statistics across all patients in each group as well as 
by dose level.  
 
16.223 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 and time until hematologic nadirs 
(WBC, ANC, platelets). 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 
logrank 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.  
 
 


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16.23 Correlative Analyses 
16.231 Data will be collected for a number of laboratory correlative variables as 
discussed before (e.g. viral replication and shedding). 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 gamma 
camera imaging of MV-NIS following 123I consumption (or after revised 
protocol 99m-Tc administration) will be used to determine the bio-
distribution and kinetics of virus spread and NIS gene expression in vivo 
and correlate it with tumor distribution. We will also estimate the 
radiation dose that could be delivered to the bone marrow as well as 
critical organs such as the liver, lungs and kidneys if I-131 were to be 
administered using MIRDOSE 3 program. 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. 
 
16.3 
Phase II Portion (to be evaluated in each cohort independently) 
 
16.31 Statistical Design: 
 
16.311 Decision Rule:  The largest success proportion where the proposed 
treatment regimen would be considered ineffective in this population is 
5%, representing a response by chance alone. The smallest success 
proportion that would warrant subsequent studies with the proposed 
regimen in this patient population is 20%. The following one-stage 
design with an interim analysis is based on a Simon optimal design 
and uses 12 or 37 patients to test the null hypothesis that the true success 
proportion in a given patient population is at most 5%. 
 
16.3111 Interim Analysis:  Enter 12 patients into the study. If no 
successes are observed in the first 12 evaluable patients, we 
will consider this regimen ineffective in this patient population 
and terminate this study. Otherwise, if the number of successes 
is at least 1, we will continue accrual. 
 
16.3112 Final Decision Rule:  Enter an additional 25 patients into the 
study. If 3 or fewer successes are observed in the first 37 
evaluable patients, we will consider this regimen ineffective in 
this patient population. If 4 or more successes are observed in 
the first 37 evaluable patients, we may recommend further 
testing of this regimen in subsequent studies in this population. 
 
16.3113 Over Accrual: If more than the target number of patients are 
accrued, the additional patients will not be used to evaluate the 
stopping rule or used in any decision making process.  


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Analyses involving over accrued patients are discussed in 
Section 16.413. 
 
16.3114 NOTE: We will not suspend accrual at the interim analysis to 
allow the first 12 patients to become evaluable, unless undue 
toxicity is observed. Given the limited overall sample size and 
the inclusion of an adverse events stopping rule, we feel it is 
ethical to not halt accrual for the interim analysis. However, if 
accrual is extremely rapid, we may temporarily suspend 
accrual in order to obtain safety data on these patients before 
re-opening accrual to further patients. 
 
16.312 Power and Significance Level:  Assuming that the number of successes 
is binomially distributed, the significance level is .10, i.e. there is a 10% 
chance of finding the drug to be effective when it truly is not.  The 
probability of declaring that this regimen warrants further study (i.e. 
statistical power) and the probability of stopping after the interim 
analysis under various success proportions can be tabulated as a function 
of the true success proportion as shown in the following table. 
 
If the true success proportion is... 
0.05 
0.10 
0.15 
0.20 
0.25 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.10 
0.45 
0.75 
0.90 
0.96 
And the probability of stopping 
after the interim analysis is… 
0.54 
0.28 
0.14 
0.07 
0.03 
 
16.313 Other considerations:  Adverse events, quality/duration of response, and 
patterns of treatment failure observed in this study, as well as scientific 
discoveries or changes in standard care will be taken into account in any 
decision to terminate the study 
 
16.4 
Analysis Plan for Phase II Portion (to be evaluated in each cohort independently) 
 
16.41 
Primary Outcome Analyses: 
 
16.411 Definition:  The primary endpoint in the phase II portion of this trial is 
the proportion of confirmed response.  A confirmed response is defined 
as a PR or better noted as the objective status on two consecutive 
evaluations.  Confirmed response will be evaluated using all cycles.  All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for confirmed response. 
 
16.412 Estimation:  The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients Ninety-
five percent confidence intervals for the true success proportion will be 
calculated according to the method of Duffy and Santner. 
 
16.413 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 


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in any decision making processes; however, they will be included in final 
endpoint estimates and confidence intervals. 
 
16.42 
Secondary Outcome Analyses 
 
16.421 Overall survival is defined as the time from registration to death due to 
any cause.  The distribution of survival time will be estimated using the 
method of Kaplan-Meier. 
 
16.422 Time to progression is defined as the time from registration to the earliest 
date with documentation of disease progression   If a patient dies without 
a documentation of disease progression,  the patient will be considered to 
have had tumor progression at the time of their death unless there is 
sufficient documented evidence to conclude no progression occurred 
prior to death.  The distribution of time to progression will be estimated 
using the method of Kaplan-Meier.(Kaplan and Meier 1958)  The 
progression-free rate at 1 year and 2 years will be assessed. 
 
16.423 Failure-free survival is defined as the time from registration to the 
earliest of progressive disease, alternative treatment for myeloma, or 
death due to any cause.  The distribution of failure-free survival will be 
estimated using the method of Kaplan-Meier. 
 
16.424 Adverse Events:  All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s).  The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns.  
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
16.43 Correlative Analyses  
 
16.431 Data will be collected for a number of laboratory correlative 
variables as discussed before (e.g. viral replication and shedding). 
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 
gamma camera imaging of MV-NIS following 99m-Tc infusion will be 
used to determine the biodistribution and kinetics of virus spread and 
NIS gene expression in vivo and correlate it with tumor distribution. We 
will also estimate the radiation dose that could be delivered to the bone 
marrow as well as critical organs such as the liver, lungs and kidneys if I-
131 were to be administered using MIRDOSE 3 program. 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. 
 
 


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16.5 
Data & Safety Monitoring: 
 
16.51 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. 
This study will be monitored according to the MCCC Data Safety Monitoring 
Plan that is currently in place, and if necessary will report to the MCCC Data 
Safety Monitoring Board. 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 (QT-PCR monitoring). 
 
16.52 The principle investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
 
16.521 Adverse Event Stopping Rules (to be evaluated in each cohort 
independently in the phase II portion):   The stopping rules specified 
below are based on the knowledge available at study development.  We 
note that the Adverse Event Stopping Rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the 
conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under 
investigation.  The study team may choose to suspend accrual because of 
unexpected adverse event profiles that have not crossed the specified rule 
below.   
 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as  “possible,” “probable,” or 
“definite”) that satisfy one of the following: 
 
· if 5 or more patients in the first 15 treated patients experience a grade 4 
or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
· if after the first 15 patients have been treated, 33% of all patients 
experience a grade 4 or higher non-hematologic adverse event at least 
possibly related to treatment. 
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.6 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
along with other required information for this study will be reported on 


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ClinicalTrials.gov. For purposes of timing of the Results Reporting, the initial estimated 
completion date for the Primary Endpoint of this study is  approximately 15 months after 
the implementation of Addendum 21. The definition of “Primary Endpoint Completion 
Date” (PECD) for this study is at the time the last patient registered has been followed for 
at least 3 months (and allowing 2 months for data entry). 
 
16.7 
Subset Analyses for Women and Minorities: 
 
16.71 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. 
 
16.72 Since women typically comprise 45% of this patient population, the number of 
women enrolled in this trial is expected to be at most approximately 38 
depending on the number of patients needed to establish the MTD. 
 
16.73 
In prior Mayo Clinic studies in this disease, approximate 3% of all patients were 
classified as ethnic minorities.  Therefore, it is likely that only 1 or 2 patients 
classified as ethnic minorities will be enrolled in this trial.  
 
16.74 
Expected sizes of ethnicity and race by gender subsets are shown in the following 
table: 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
0 
0 
0 
Not Hispanic or Latino 
38 
47 
0 
85 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all 
subjects* 
38 
47 
0 
85 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
2 
2 
0 
4 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
0 
White 
36 
45 
0 
81 
More than one race 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
Racial Category: Total of all subjects 
38 
47 
0 
85 
 


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Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, 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. 
 
17.0 
Pathology Considerations:  
17.1 
Optional biopsy of area of interest will be performed by Dr. Stephanie Carlson (or 
colleagues) to biopsy “area of interest” if uptake seen on SPECT scan day 8 to confirm 
presence of virus in lesion.  The biopsy of the lesion will be done per usual image-guided 
techniques using CT-guidance 
 


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18.0 
Records and Data Entry Procedures 
 
Forms 
Active-Monitoring Phase 
(Compliance with Test Schedule) 
At Each Occurrence 
Initial 
Material 
 
Follow-up material 
≤2 weeks 
after 
registration 
At each 
evaluation 
At end of  
treatment 
Observation: 
3 months after 
treatment and Q 3 
months 
thereafter1,7 
At 
PROG  Death 
ADR/AER 
New 
Primary 
Grade 4 or 5 Non-
AER Reportable 
Events/ 
Hospitalization 
 
On-Study Form 
X 
 
 
 
 
 
 
 
 
Baseline Adverse Events Form 
X 
 
 
 
 
 
 
 
 
Other Laboratory Form 
 
X 
X 
 
 
 
 
 
 
Measurement Form 
X 
X 
X 
X5 
 
 
 
 
 
Evaluation/Treatment  
 
Form 
 
X 
X 
 
 
 
 
 
 
Nadir/Adverse Event 
 
Form 
 
X 
X 
X 
 
 
 
 
 
End of Active 
Treatment/Cancel 
Notification  Form 
X3 
 
X 
 
 
 
 
 
 
Bone marrow biopsy report  
X 
X7 
X7 
X7 
 
 
 
 
 
SPEP, UPEP, FLC, 
Immunofixation reports 
X 
X8 
X8 
X8 
 
 
 
 
 
Skeletal Survey 
X 
 
 
X7 
 
 
 
 
 
Event-Monitoring Form 
 
 
 
 
X 
X 
 
X 
 
Therapy for Acute Infusion  
Reaction Form 
 
X4 
 
 
 
 
 
 
 
Evaluation/Observation Form 
 
X2 
 
X2 
 
 
 
 
 
PK Specimen Submission 
Form 
 
X6 
 
 
 
 
 
 
 
Cytokine Samples Submission 
Form 
 
X9 
 
 
 
 
 
 
 
Concurrent Treatment Log 
X 
X 
X 
 
 
 
 
 
 
ADR/AER (See Section 10.0) 
 
 
 
 
 
 
X 
 
 
Secondary AML/MDS Report 
Form (See Section 10.0) 
 
 
 
 
 
 
X 
 
 
Grade 4 or 5 Non-AER 
Reportable 
Events/Hospitalization Form 
(See Section 10.0) 
 
 
 
 
 
 
 
 
X 
 
Footnotes on the following page. 


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1. If a patient is still alive 1 year after completing therapy, no further follow-up is required. 
2. Complete at each evaluation during Observation (see Section 4.0). 
3. Submit this form only if withdrawal/refusal prior to beginning protocol therapy. 
4. See section 7.113. 
5. Only to be done until patient progression. 
6.  Specimens collected as per Sections 4.0 and 14.07. Upon receiving alternative myeloma directed therapy, only limited to adverse events as indicated in 
Table 3b will be monitored until 1 year after MV-NIS therapy 
7.  Only when required by the test schedule (see section 4.0) 
8.  Submission of these reports is only required for documentation of CR (including sCR) or progression. For documentation of CR, submit all of these reports 
at the first confirmation of CR. For documentation at first signs of progression, submit reports to the QAS for MC038C. 
9. Specimens collected pre-MV-IS infusion, 240 minutes post, 24 hours post (day +2), and approximately 48 hours post (day +3) as per Section 4.0.


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19.0 
Budget  
19.1 
Costs charged to patient: Routine clinical care.  
19.2 
Patients enrolled in the study will not be billed for room and board or nursing charges 
while in the CRU or Hematology in-patient service. However, participants may be billed 
for ancillary expenses such as any oral medications prescribed at the time of discharge. 
 
19.3 
Tests that will be research funded: All nuclear imaging costs (nuclear medicine 
personnel, FDG-PET/CT, and SPECT /CT imaging will be charged to either 
All other research costs (, 
Cyclophosphamide, follow up bone marrow biopsy, tests pertaining viral status and 
shedding, tests of immune function, thyroid hormone measurements, and serial 
immunoglobulin free light chain levels.) will be charged to 
 
. According to CMS guidelines, baseline, FDG-PET/CT will be covered 
by Medicare for patients who are on Medicare. Subsequent FDG-PET will be charged to 
the grant. 
19.4 
Cost of MV-NIS production will be charged to 
 and 
 


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20.0 
References 
 
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Immunol, 1999. 36(13-14): p. 929-39. 
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Liszewski, M.K., T.W. Post, and J.P. Atkinson, Membrane cofactor protein (MCP or CD46): 
newest member of the regulators of complement activation gene cluster. Annu Rev Immunol, 
1991. 9: p. 431-55. 
3. 
Seya, T., et al., Distribution of C3-step regulatory proteins of the complement system, CD35 
(CR1), CD46 (MCP), and CD55 (DAF), in hematological malignancies. Leuk Lymphoma, 1994. 
12(5-6): p. 395-400. 
4. 
Dorig, R.E., et al., The human CD46 molecule is a receptor for measles virus (Edmonston strain). 
Cell, 1993. 75(2): p. 295-305. 
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Nielsen, L., et al., Adaptation of wild-type measles virus to CD46 receptor usage. Arch Virol, 
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Tatsuo, H., et al., SLAM (CDw150) is a cellular receptor for measles virus. Nature, 2000. 
406(6798): p. 893-7. 
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Bushnell, D.L., et al., Complications, sequela and dosimetry of iodine-131 therapy for thyroid 
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Sisson, J.C. and J.E. Carey, Thyroid carcinoma with high levels of function: treatment with 
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Boland, A., et al., Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into 
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Carlin, S., et al., Experimental targeted radioiodide therapy following transfection of the sodium 
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Mandell, R.B., L.Z. Mandell, and C.J. Link, Jr., Radioisotope concentrator gene therapy using 
the sodium/iodide symporter gene. Cancer Res, 1999. 59(3): p. 661-8. 
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Nakamoto, Y., et al., Establishment and characterization of a breast cancer cell line expressing 
Na+/I- symporters for radioiodide concentrator gene therapy. J Nucl Med, 2000. 41(11): p. 
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Smit, J.W., et al., Expression of the human sodium/iodide symporter (hNIS) in xenotransplanted 
human thyroid carcinoma. Exp Clin Endocrinol Diabetes, 2001. 109(1): p. 52-5. 
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Spitzweg, C., et al., Treatment of prostate cancer by radioiodine therapy after tissue- specific 
expression of the sodium iodide symporter. Cancer Res, 2000. 60(22): p. 6526-30. 
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Spitzweg, C., et al., In vivo sodium iodide symporter gene therapy of prostate cancer. Gene Ther, 
2001. 8(20): p. 1524-31. 
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Thierens, H.M., et al., Dosimetry from organ to cellular dimensions. Comput Med Imaging 
Graph, 2001. 25(2): p. 187-93. 
17. 
Kyle, R.A., Multiple myeloma: an odyssey of discovery. Br J Haematol, 2000. 111(4): p. 1035-44. 
18. 
Anonymous, Cancer Statistics. Cancer Journal Clin, 2002. 52: p. 23-47. 
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Attal, M. and J.L. Harousseau, Randomized trial experience of the Intergroupe Francophone du 
Myelome. Semin Hematol, 2001. 38(3): p. 226-230. 
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Bjorkstrand, B., European Group for Blood and Marrow Transplantation Registry studies in 
multiple myeloma. Semin Hematol, 2001. 38(3): p. 219-225. 
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Fassas, A. and G. Tricot, Results of high-dose treatment with autologous stem cell support in 
patients with multiple myeloma. Semin Hematol, 2001. 38(3): p. 231-242. 
22. 
Kyle, R.A. and S.V. Rajkumar, Therapeutic application of thalidomide in multiple myeloma. 
Semin Oncol, 2001. 28(6): p. 583-587. 
23. 
Richardson, P.G., et al., A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J 
Med, 2003. 348(26): p. 2609-17. 


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24. 
Russell, S.J., Replicating vectors for cancer therapy: a question of strategy. Semin Cancer Biol, 
1994. 5(6): p. 437-43. 
25. 
Chapel, H.M., et al., 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(8905): p. 1059-63. 
26. 
Jacobson, D.R. and S. Zolla-Pazner, Immunosuppression and infection in multiple myeloma. 
Semin Oncol, 1986. 13(3): p. 282-90. 
27. 
Petersen, J., et al., B lymphocyte function in multiple myeloma: analysis of T cell- and monocyte-
dependent antibody production. Eur J Haematol, 1989. 42(2): p. 193-201. 
28. 
Bjerrum, O.W. and B. Mansa, Antibodies to common viruses in sera from patients with multiple 
myeloma. Acta Pathol Microbiol Immunol Scand [B], 1982. 90(6): p. 397-401. 
29. 
Heath, R.B., G.H. Fairley, and J.S. Malpas, Production of antibodies against viruses in leukemia 
and related diseases. British Journal of Haematology, 1964. 10: p. 365-370. 
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Landesman, S.H. and G. Schiffman, Assessment of the antibody response to pneumococcal 
vaccine in high- risk populations. Rev Infect Dis, 1981. 3 Suppl: p. S184-97. 
31. 
Peng, K.W., et al., Systemic therapy of myeloma xenografts by an attenuated measles virus. 
Blood, 2001. 98(7): p. 2002-7. 
32. 
Griffin, D., Measles Virus, in Field's Virology, D. Griffin, et al., Editors. 2001, Lippincott 
Williams & Wilkins: Philadelphia. p. 1401. 
33. 
Katz, S.L., et al., Studies on an attenuated measles-virus vaccine. N Engl J Med, 1960. 263(4): p. 
180-4. 
34. 
Katz, S.L., Immunization of children with live attenuated measles vaccines: five years of 
experience. Arch Ges Virusforsch, 1960. 16: p. 222-30. 
35. 
Schwarz, A.J.F., et al., Experimental vaccination against measles. Jama, 1960. 173(8): p. 81-92. 
36. 
Anonymous, Update: vaccine side effects, adverse reactions, contraindications, and precautions 
recommendations of the Advisory Committee on Immunization Practices (ACIP), in MMWR Morb 
Mortal Weekly Report. 1996. p. 1-35. 
37. 
Collard, P., et al., Vaccination against measles: Part II. Clinical trial in Nigerian children. Br 
Med J, 1961. 1246-50. 
38. 
Aldous, I.R., et al., Vaccination against measles: Part III.  Clinical trial in British children. Br 
Med J, 1961. 11: p. 1250-53. 
39. 
Hilleman, M.R., et al., Development and evaluation of the Moraten measles virus vaccine. Jama, 
1968. 206(3): p. 587-90. 
40. 
Norby, E., The paradigms of measles vaccinology, in Measles Virus, V.T. Meulen and M.A. 
Billeter, Editors. 1995, Springer-Verlag: Heidelburgh. p. 167-80. 
41. 
Hilleman, M.R., Current overview of the pathogenesis and prophylaxis of measles with focus on 
practical implications. Vaccine, 2001. 20(5-6): p. 651-65. 
42. 
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 47, RR-8. (1998). 
43. 
Kaplan, L.J., Daum, R.S., Smaron, M. & McCarthy, C.A. Severe measles in 
immunocompromised patients. JAMA 276, 1237 – 40. (1992). 
44. 
Duclos, P. & Ward, B.J. Measles vaccines. A review of adverse events. Drug Safety 6, 435 – 54. 
(1998). 
45. 
Dingli, D., et al. Image-guided radiovirotherapy for multiple myeloma using a recombinant 
measles virus expressing the thyroidal sodium iodide symporter. Blood (in press). 
46. 
Jacobson, D.R. & Zolla-Pazner, S. Immunosuppression and infection in multiple myeloma. Semin 
Oncol 13, 282-90. (1986). 
47. 
Barnard DL. Inhibitors of measles virus. Antivir Chem Chemother. 2004;15:111-119. 


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48. 
Forni A, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical 
characteristics and therapy with intravenous ribavirin. Clinical Infectious Diseases. 
1994;19:454-462. 
49. 
Duffy, D. and Santner, T., Confidence intervals for a binomial parameter based on 
multistage tests. Biometrics, 1987. 43: p. 81-93 
 
 


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Appendix I 
GUIDELINES FOR MV-NIS ADMINISTRATION AND DAY 1 AND 2 
PHARMACOKINETICS BY NURSING STAFF 
Synopsis: Patients have been asked to take part in this study because they have evidence 
of recurrent or refractory MM that has progressed through established treatments.  We are 
trying to find new treatments that may be more effective at treating MM.  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 extra gene added for a protein called NIS inserted into it.  NIS is 
normally found in the thyroid gland and helps the body concentrate iodine.  Having this 
additional gene will make it possible to track where this virus goes in the body 
1.0 
Drug Information 
 
MV-NIS is a live, tissue culture adapted measles virus 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 Edmonston lineage measles virus 
(MV-tag). 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 myeloma. 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.  
 
1.1 
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 -80C. The virus will be thawed and 
mixed with normal saline prior to administration according to good practice guidelines for any 
Biohazard Level 2 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.  
 
 


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1.2 
Administration: 
 
1.2.1 General precautions 
 Pregnant, breastfeeding, and/or immunosuppressed healthcare workers 
must not enter the room (place a sign on door) 
 Contact Isolation 
 Hazardous Medication Precautions 
 Protective Environment Precautions 
 Patient to wear mask (N95) when out of patient room post MV‐NIS 
infusion 
o Patient education point: since other patients on the Mayo Clinic 
grounds may be severely immunosuppressed, we will require that 
you wear a mask when you are outside of your hospital room on 
Mayo Clinic grounds.  The results of these tests will determine how 
long you should wear a mask when in public. 
 
1.2.2 Patient preparation 
 Patient to avoid heavy meal 3‐4 hours prior to MV‐NIS infusion 
 Patient to be NPO for 30 minutes prior to CRU nurse collecting 
mouthwash sample (see below) 
 Saline Lock X2 (one in each arm) if no central line access 
 Notify Pharmacy 1 hour before you are ready for the drug 
 Have emergency red box at nursing station during infusion 
 Cover patient with warm blanket(s) pre and during infusion 
 Continuous Pulse Oximetry during treatment and for 24 hours after 
treatment 
 Cooling Blanket prn fever >39.0 post infusion 
 
1.2. 3 Preparation for infusion and pharmacokinetic studies  
 Do not start MV‐NIS infusion until mobile CRU (clinical research unit) 
mobile staff has drawn baseline bloodwork and taken urine and 
mouthwash samples. They will come at 0800 the day of treatment to 
collect these samples.  If questions call 6‐2302 and ask for mobile CRU 
nurse. 
o Mouthwash sample: Pt must be NPO for 30 minutes prior to 
collecting this sample 
o Please verify the Scope mouthwash is ordered and sent from 
pharmacy the evening before so ready for the CRU mobile nurse 
visit day of treatment 
o If pt needs to void just prior to mobile CRU nurse arrives, save 
urine in hat or urinal (need 100cc or more) 
 Notify Hematology Research Nurse 127‐16808 with infusion 
start/estimated stop time (this is needed to coordinate for the post 
infusion lab samples). Hematology Research Nurse will come draw the 


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post infusion PK lab samples (end of infusion, 30 min post, 60 min post, 
120 min post, 240 min post and 24 hours post infusion) 
 
1.2. 4  MV‐NIS Infusion 
 
 The MV-NIS product will be administered by slow intravenous infusion in 
250mL of   0.9% sodium chloride under close observation in the Clinical 
Research Unit (CRU) or at Rochester Methodist Hospital.  
 Prior to administration of MV‐NIS, two chemotherapy prepared RNs will 
verify the drug and dose against the orders and the CDM, and the identity of 
the patient to receive the drug. 
 RN will remain in room with the patient during the one hour infusion. 
Continue to monitor them closely. 
 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 
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. 
 If acute febrile or allergic reaction occurs or if the patient develops rigors, 
contact the primary service and treat per orders. 
 If symptoms suggestive of anaphylaxis such as dyspnea, itching, dizziness or 
symptomatic hypotension occur, stop the infusion, call the primary service 
and treat per orders. 
o Upon completion of medication administration flush tubing by the following 
procedure: 
1. Attach your flush bag to the secondary medication tubing set‐up, 
prime tubing and turn clamp off. 
2. Attach secondary IV set to the main IV tubing at the first port directly 
below the drip chamber. 
3. When the MV‐NIS gets just below the air check valve and above the 
first port, lower the MV‐NIS bag on the hook found in the secondary 
medication set‐up and continue running at the same rate of infusion, 
change the volume to be infused to 15 and continue running until 
the pump reads 0.  This will be the end of the infusion. 
4. While wearing PPE, cover IV site with 4x4 and disconnect the infusion 
from the saline lock.  Dispose of bags and tubing in red bag. Flush 
saline lock with 10cc NS (and other flushes required for type of line 
prn). 
 
1.3 
Post infusion support, monitoring and pharmacokinetics (PK) 
 
 
 
1.3.1 Vital signs 
During and post‐infusion, the schedule of vital sign monitoring will change 
from “Baseline on admission and then every 8 hours until infusion of MV‐


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NIS” to schedule shown below. Vitals may be done by Hematology Research 
staff, LPN or non‐chemotherapy nurse. May be preferred for Hematology 
Research Staff to do the time points that coincide with PK blood draws (Post‐
infusion time points: 30 minutes, 1 hour, 2 hours, and 4 hours) 
 Every 15 minutes during infusion 
 End of Infusion 
 30 minutes post end of infusion (research nurse may perform) 
 1 hour post end of infusion (research nurse may perform) 
 2 hours post end of infusion (research nurse may perform) 
 4 hours post endo of infusion (research nurse may perform) 
 Every 2 hours while awake, then every 4 hours 
 
 
1.32 
Pharmacokinetics and cytokine measurements 
The Hematology research staff will be responsible for these blood draws 
 End of Infusion (PK only) 
 30 minutes post end of infusion (PK only) 
 1 hour post end of infusion (PK only) 
 2 hours post end of infusion (PK only) 
 4 hours post end of infusion  (PK + cytokine) 
 24 hours post end of infusion (PK + cytokine)  
 48 hours post infusion (cytokine only) 
 
1.33 
Other post‐infusion support 
 IV Fluids (see orders) to start 2 hours after completion of MV-NIS infusion 
 Fever typically begins about 2 hours after infusion: support with 
acetaminophen, meperidine, and cooling blanket as needed 
 Nausea is not unusual so anti‐emetics will be available 
 
1.4 
Other precautions:  
 
In the hospital setting, utensils (e.g., bedpans, urinals) are cleaned with an institutionally 
approved detergent and rinsed twice following each use.  
 
In the inpatient setting, 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. 
 
 
All spills should be reported. 


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 
Cytotoxic Spill kits (MC115455) are available from Central Service at Rochester Methodist 
Hospital (RMH) or by paging the General Par Stock pager (127-05232) at Saint Marys 
Hospital (SMH). In the outpatient setting spill kits are obtained from the MIC Warehouse 
through the Lawson ordering system. A spill kit should be obtained and available on a patient 
care unit/area prior to a patient receiving spillable (non-solid) cytotoxic medications.  
 
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. 
1.5 
Known potential toxicities of MV-NIS: 
 
MV-NIS was rescued from a derivative of the Edmonston B vaccine strain of measles virus and 
we anticipate that the most common toxicities will be similar to those experienced after the 
administration of the measles vaccine. The most common side-effects seen with high doses of 
MV-NIS have been high fever that lasts for a couple to several days, nausea and headache. These 
tend to be most severe within a couple of hours after completing infusion. Thus patients might 
experience moderate fever up to 39.4C fever and rash (minimal) within the first 5 to 12 days 
after virus injection. However it should be noted that this vaccine related measles like illness has 
been described only in measles-naïve subjects. 
 
Not uncommon reactions: 
 
Moderate to high fever(with rigors)  lasting 1 – 2 days, starting within a week or two of 
vaccination 
 
Nausea and vomiting 
 
Headache 
 
Cough and rhinitis 
 
Arthralgias 
 
Thrombocytopenia 
 
Lymphopenia 
 
Anemia 
 
A rash, lasting 1 – 2 days 
 
Unexpected and rare reactions associated with the vaccine: 
 
Allergic reactions including anaphylaxis 
 
Reactions at the injection site such as a wheal, flare or urticaria 
 
Diarrhea 
 
Erythema multiforme 
 
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 measles infection. The vaccine strain of the measles virus (of which MV-NIS is a 


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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 measles virus, there has been only 1 
case of symptomatic measles virus presumptively transmitted from a vaccinated individual (Rota et al 
J. Clin Microbiology 2005). However, since other patients on the Mayo Clinic grounds may be 
severely immunosuppressed, we will require that MV-NIS treated patients wear a mask when outside 
of their hospital room on Mayo Clinic grounds while they are shedding virus (tested by RT-qPCR). 
 
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 measles or either pneumonitis or 
encephalitis develop, the patients will be treated aggressively with anti-measles virus immune 
globulin and ribavirin and all the supportive care necessary as the situation might dictate. 


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Appendix II 
APPENDIX II: Pre-Screening Process, Script, and Minimal Risk HIPPA Consent for Patients 
Who Initiated Contact Regarding Protocol Participation for inclusion/exclusion of MC038C, “A 
Phase I/II Trial of Systemic Administration of (Edmonston Strain) of Measles Virus, Genetically 
Engineered to Express NIS, with or without Cyclophosphamide in Patients with Recurrent or 
Refractory Multiple Myeloma”  
 
AIMS, PURPOSE, OR OBJECTIVES:  
 
To provide better service to patients by allowing a level of pre-screening prior to their 
investment in traveling to Rochester, MN to be screened for trial participation. This will be 
accomplished by contacting them, running through a checklist of eligibility criteria, and sending 
them a blood kit which can be completed locally and returned to the trial team. Patients have 
already contacted the study team expressing interest in the trial, so they have made first contact. 
 
REASONING:  
The reason is that there are more patients interested in the trial than there are doses of drug. We 
are going through the list on a first contact, first serve basis to exclude those subjects who will 
not be eligible and save them unnecessary financial costs.  
 
The logistics of the pre-screening process are as follows: 
 
1. The list of patients who have made contact have been collated and organized by date of 
contact. 
2. Subjects who have expressed interest will be contacted by phone in the order in the 
spreadsheet. The telephone script (Appendix II-1) and oral consent (Appendix II-2) will 
be used to run through the eligibility check list. 
3. If patients appear to be eligible based on the check list, we will instruct them that they 
will be receiving a kit for a mail-in blood test to check for measles virus anti-body titers 
along with a HIPAA Authorization to Use and Disclose Protected Health Information 
Form. The blood can be drawn at the time of a routine blood test. The kit will come with 
a self-paid mailing label. Cover letter is contained in Appendix II-3 and HIPPA form is 
Appendix II-4).  
4. Patients will be informed of the results of their measles titers. If titers are positive, the 
patients will be told that they are not eligible for the trial, but that they are welcome to 
come to Mayo at any time for a consultation and/or participation in other clinical trials. If 
negative, the patients will be told that they are a potential candidate and offered an 
appointment. We will keep track of doses of drug, availability of beds at CRU and on 
Hematology in-patient service.  
5. If there are more eligible patients than there are slots in the trial, we will call and/or mail 
these patients informing them of the trial status without running through the checklist and 
without sending them the blood kit. We will ask them that if there is further expansion to 
the trial whether they would like to be contacted again at that time. 
 


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Mayo Clinic: Office for Human Research Protection 
Telephone Script 
 
 
APPENDIX II-1: Pre-Screening Process, Script, and Minimal Risk HIPPA Consent for Patients Who 
Initiated Contact Regarding Protocol Participation for inclusion/exclusion of MC038C, “A Phase I/II 
Trial of Systemic Administration of (Edmonston Strain) of Measles Virus, Genetically Engineered to 
Express NIS, with or without Cyclophosphamide in Patients with Recurrent or Refractory Multiple 
Myeloma”  
 
 
Introduction: 
Hello, this is ________________ calling from the Mayo Clinic in Rochester, Minnesota (if out of 
state).  May I please speak to _____________? 
***If the participant is there continue with the script. 
***If the participant is not there, ask when it would be a good time to speak with     
______________? 
 
Describe the Reason for the Call: 
(Example of phone call to potential participant) 
I am calling you because in May/June 2014 you expressed interest in our Phase II clinical MV-
NIS trial for patients with relapsed refractory myeloma. As we shared with you previously, the 
clinical trial will re-open in August/September 2014. There was tremendous interest in this 
treatment trial with more than 1000 inquiries. Since the Phase 2 trial will have a maximum of 37 
slots available, we have generated a list of patients and are making contact to see if these 
individuals still have interest in participating in this trial.  
 
Are you still interested? 
 
Please understand that your current or future medical care at the Mayo Clinic will not be 
jeopardized if you choose not to participate. 
If no: Thank them for their time and stop the recruitment process. 
If yes: Since you are still interested in enrolling on the measles (MV-NIS) for myeloma clinical 
trial, we would like to make things as convenient for you as possible. As the case for all clinical 
trials, there are ‘eligibility ‘criteria, which means that there are certain requirements about you 
and your medical condition that are necessary to make you a candidate. To save you time and 
travel, I would like to run through several of these criteria with you.  
 
If we find that you are ineligible, you are still welcome to make an appointment to be seen at the 
Mayo Clinic to receive care/recommendations about your multiple myeloma and/or participate in 
another clinical trial.  


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If the screening questions would suggest that you are eligible, the next step would be to 
determine if you have existing immunity to the measles virus. Our studies show that if you have 
existing antibodies to measles (as measured by a blood test), it is almost a guarantee that the 
MV-NIS will not provide you with any benefit, so the absence of measles titers is an eligibility 
criterion.  
 
For your convenience, we can send you a blood test kit that you can bring to your local 
laboratory to draw and mail back to us. If the test shows that there are no antibodies, then you 
will likely be eligible for the trial. If the test is show antibodies to measles, then you would not 
be a candidate for the trial. Once again, you are still welcome to make an appointment to be seen 
by one of our myeloma specialists; however, if the only reason that you would consider coming 
to the Mayo Clinic in Rochester at this time would be to participate on this particular trial, then 
we will have saved you the trip. 
There is no payment for your travel expenses. The standard of care myeloma therapy will not be 
covered by the trial, but all of the extra blood work and scans related to the trial will be free of 
charge. There are several days of testing followed by admission to our clinical research unit for a 
day and a night during which time you would get the therapy and be monitored for side-effects. 
Additional blood work and scans are done 2, 7, 14 and 42 days after treatment in all patients. 
Some patients also require testing 21 and 28 days after treatment.  
There is no guarantee that this treatment will help your myeloma, but we are hopeful that it will. 
Are you interested in hearing more and going through the checklist to see if you may be eligible?  
If no: Thank them for their time and stop the recruitment process. 
If yes: I would like to receive your formal permission to ask you questions and to potentially 
offer you the opportunity to have a blood test kit sent to you for further testing to see if you are 
potentially eligible. 
Go to ORAL CONSENT SCRIPT (Appendix II-2).   
Once consented, start the check list 
 
Inclusion 
criteria 
  
 
3.11 
Are you older than 18 years? 
 
3.12 
Is your myeloma progressing now? 
 
 
Was your last response called a “very good partial response” 
or better? That would also include a complete response (CR) 
or stringent complete response? 
 
 
Has it been 12 weeks or more since your last myeloma 
therapy (drugs like pamidronate (Aredia) or zolendronic acid 
(Zometa) are allowed? 
 
 
Do you have measurable disease as defined as: 
- Serum M-spike >= 0.5 g/dL, or 
- If  IgA myeloma, IgA > 1000 mg/dL, or 
- dFLC >10 mg/dL, or  
 


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- Urine M-spike >=200 mg/24 hours, or 
- Bone marrow plasmacytosis >= 10%, or 
- Extramedullary plasmacytoma >= 2 cm in diameter 
3.13 
The following laboratory values obtained  14 days prior to 
study registration 
 
 
 ANC 1000/L 
 
 
 PLT 50,000/L 
 
 
 Hemoglobin  8.5 g/dl 
 
 
 AST ≤2 times upper limit of normal 
 
 
 Creatinine < 2 times upper limit of normal 
 
 
 Total bilirubin  1.5 x upper limit of normal  
 
 
 INR  1.4 x ULN at the time of  registration 
 
3.15 
Are you willing to return to Mayo Clinic Rochester for follow‐
up? For the study, you will need to be here for treatment and 
testing days 1, 3, 8, 15 (possibly 22 and 29) and day 42 (6 
weeks after treatment)? 
 
3.17 
Are you up and about for at least 50% of the day? 
 
3.18 
Are you willing to provide all blood and bone marrow 
specimens as required by the protocol? 
 
 
 
 
Exclusion 
criteria 
 
Answers 
should all be 
“no” 
3.21 
Do you have an uncontrolled infection? 
 
3.22 
Do you have active tuberculosis? 
 
3.23 
Have you been off therapy for at least 12 weeks? 
 
3.24 
Do you have symptomatic heart disease? 
 
3.25 
Do you have active brain problem or seizure disorder? 
 
3.26 
Have you been told that you have tested positive for HIV (the 
AIDS virus)? 
 
3.28 
 
Were you immunized with the heat inactivated measles virus 
vaccine (this vaccine was given to some individuals between 
the years of 1963‐1967)? 
 
3.29 
 
[If appropriate] Are you pregnant? 
 
 
[If appropriate] Are you nursing? 
 
 
Will you be willing to use contraception for at least 4 weeks if 
you are having intercourse?   
 
 
Have you had a prior allogeneic hematopoietic stem cell 
transplant and have active GVHD? 
 
 
Do you have household contacts ≤15 months of age or a 
household contact with known immunodeficiency? 
 
 


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If they are not eligible: Thank them for their time and stop the recruitment process. 
If yes: We will send you a mail-in kit. You should receive it within a week and then you should 
hear from us within 1-2 weeks after we receive the blood test. 
------------------------------------------------------------------------------------------------------------ 
Closing 
Thank you for participating in our research study.  Please understand that your answers will 
remain confidential.  If you have any additional questions, please call 
 
.   
 


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Mayo Clinic: Office for Human Research Protection 
Oral Consent Script 
 
 
Protocol Title: Minimal risk, first pass screening consent for MV-NIS trial eligibility: survey and 
blood test 
 
IRB #: 06-005263 
Principal Investigator: Angela Dispenzieri 
 
You are being asked to answer questions in order to screen you for eligibility for the MV-NIS 
(measles for myeloma) Phase II clinical trial. If the answers to the questions suggest that you 
may be eligible for the clinical trial, we will invite you to have a blood test done at home to see if 
you have antibodies to the measles virus. If you do have immunity to the measles virus, there 
would not be any potential advantage for you to participate on the treatment trial. 
 
If you agree to participate you will be asked to answer about 30 questions. You will not receive 
any payment for your participation. 
 
The risks associated with the first pass screening portion of this research study are time burden 
and discomfort during interviews. Using sensitive questions during the oral consent process is 
common and can often lead to discomfort. You could also experience some discomfort during 
the blood draw. Otherwise, there are no known physical risks to you from taking part in the 
screening portion of this research study. 
 
The benefits which may reasonably be expected to result from this screening are possible 
eligibility for the MV-NIS (measles) for myeloma trial. 
 
Please understand your participation is voluntary and you have the right to withdraw your 
consent or discontinue participation at any time without penalty.  Specifically, your current or 
future medical care at the Mayo Clinic will not be jeopardized if you choose not to participate.  
 
If you have any questions about this research study you can contact me at 
 
  If you have any concerns, complaints, or general questions about research or your 
rights as a participant, please contact the Mayo Institutional Review Board (IRB) to speak to 
someone independent of the research team at 
    


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Mayo Clinic: Office for Human Research Protection 
Contact Letter Template 
 
 
 
(Date} 
 
{ Name} 
{Street Address} 
{City, State  Zip} 
RE:     { first name} { last name} 
MC#:  {mc #} 
 
 
Protocol Title: Minimum Risk Screening Process for Patients Who Initiated Contact Regarding 
Protocol Participation for inclusion/exclusion of MC038C, “A Phase I/II Trial of Systemic 
Administration of (Edmonston Strain) of Measles Virus, Genetically Engineered to Express NIS, 
with or without Cyclophosphamide in Patients with Recurrent or Refractory Multiple Myeloma 
 
IRB #: 06-005263   
Principal Investigator: Dr. Dispenzieri  
 
Dear {Mr., Ms, or Mrs.}  
 
You are being asked to participate in a pre-screening research study for the Phase I/II measles 
trial for patients with myeloma. You previously contacted the Mayo Clinic stating that you 
would like information or were interested in participating in the MC038C trial. This pre-
screening process is being done to find out if you do/do not qualify for potential participation in 
the measles for myeloma Phase I/II trial without you having to physically travel to Mayo Clinic 
and incur unnecessary financial costs.  
 
Please understand your participation is voluntary and you have the right to withdraw your 
consent or discontinue participation at any time without penalty.  Specifically, your current or 
future medical care at the Mayo Clinic will not be jeopardized if you choose not to participate.  
 
If you agree to participate, you will be asked to sign the enclosed authorization form and have 10 
cc (2 teaspoons) of blood drawn (kit enclosed) from a vein in your arm during your next routine 
clinical lab work up at your local treating medical facility. This lab kit will be mailed back to us 
by that facility for processing. This process can take up to two weeks. You will be notified of the 
results by either phone or mail.  
 
If you do qualify, you will be invited for an appointment for further medical evaluations and 
formal trial screening for the measles for myeloma Phase I/II trial. There is no guarantee that you 
will still meet the qualifications at that time.  
 
All information related to your multiple myeloma disease including current treatments, labs, past 
vaccines) obtained from you during this pre-screening process from the research team will be 
kept confidential. If you do not qualify or if you chose later not to participate, all information 
obtained from you up to that point will be destroyed immediately by the research team. 




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MC#:  {mc #} 
 
 
 
  I am enclosing the HIPAA Authorization to Use and Disclose Protected Health 
Information form only.  Please call me. 
 
 
Your name: _____________  
Telephone number: (___)___-_____  
Today’s date: __/__/__ 
 
Best time to call: 
 Morning   
 Afternoon   
 Evening     
Best day(s) to call:______________ 
 
  I am not willing to participate in this research study. 
 


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