Phase I/II Trial of Intraperitoneal Administration of Adipose Tissue Derived Mesenchymal Stem Cells Infected With a NIS-Expressing Derivative Manufactured From a Genetically Engineered Strain of Measles Virus in Patients With Recurrent Ovarian Cancer
Phase: PHASE1
Conditions: Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Mucinous Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Malignant Ovarian Brenner Tumor, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mucinous Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Adenocarcinoma, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Primary Peritoneal Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: Mayo Clinic

MC1266 
Protocol Version Date: 22Mar2024 
Mayo Clinic Cancer Center 
MC1266 Phase I/II Trial of Intraperitoneal Administration of adipose tissue derived mesenchymal 
stem cells infected with a NIS-Expressing Derivative Manufactured from a Genetically Engineered 
Strain of Measles Virus in Patients with Recurrent Ovarian Cancer 
 
 
Study Chair: 
 
 
 
Study Co-Chairs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statisticians:  
 
 
† Study contributor(s) not responsible for patient care 
 
Drug Availability 
Supplied Investigational Agent(s):  MV-NIS (NIS-Measles Virus – Edmonston Strain (IND #15317), 
MV-NIS/MSC (Mesenchymal Stem Cell (MSC) infected with NIS-Measles Virus – Edmonston 
Strain) 
 
Purchased with study funds: Liothyronine (Cytomel®, T3) 
 
Document History 
Effective Date 
 
 
Activation 
3/31/2014 
MCCC Addendum 10 
(Consent Changes Only) 
October 8, 2019 
MCCC Addendum 1 
September 11, 2014 
MCCC Addendum 11 
November 2, 2020 
MCCC Addendum 2 
December 31, 2014 
MCCC Addendum 12 
pending 
MCCC Addendum 3 
February 10, 2015 
 
 
MCCC Addendum 4 
August 18, 2015 
 
 
MCCC Addendum 5 
June 23, 2016 
 
 
MCCC Addendum 6 
October 12, 2017 
 
 
MCCC Addendum 7 
April 13, 2018 
 
 
MCCC Addendum 8 
September 6, 2018 
 
 
MCCC Addendum 9 
March 26, 2019 
 
 
 

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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
  
Study coordinators (Forms completion and 
submission) 
 
 
  
Protocol document, consent form, 
regulatory issues 
 
 
 
 
Serious Adverse Events  
  
*No waivers of eligibility per NCI  
 

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Table of Contents 
MC1266 Phase I/II Trial of Intraperitoneal Administration of adipose tissue derived 
mesenchymal stem cells infected with a NIS-Expressing Derivative Manufactured from a 
Genetically Engineered Strain of Measles Virus in Patients with Recurrent Ovarian Cancer ....... 1 
Protocol Resources.......................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
Schema MV-NIS ............................................................................................................................. 4 
1.0 
Background ...................................................................................................................... 5 
2.0 
Goals............................................................................................................................... 11 
3.0 
Patient Eligibility ............................................................................................................ 12 
4.0 
Test Schedule ................................................................................................................. 14 
5.0 
Grouping Factors: ........................................................................................................... 17 
6.0 
Registration/Randomization Procedures ........................................................................ 17 
7.0 
Protocol Treatment ......................................................................................................... 19 
8.0 
Dosage Modification Based on Adverse Events ............................................................ 24 
9.0 
Ancillary Treatment ....................................................................................................... 25 
10.0 Adverse Event (AE) Reporting and Monitoring ............................................................ 27 
11.0 Treatment Evaluation ..................................................................................................... 30 
12.0 Descriptive Factors ......................................................................................................... 33 
13.0 Treatment/Follow–up Decision at Evaluation of Patient ............................................... 33 
14.0 Pharmacologic/Correlative ............................................................................................. 35 
15.0 Drug Information ............................................................................................................ 38 
16.0 Statistical Considerations and Methodology .................................................................. 43 
17.0 Pathology Considerations: .............................................................................................. 49 
18.0 Records and Data Collection Procedures ....................................................................... 50 
19.0 Budget Considerations ................................................................................................... 51 
20.0 References ...................................................................................................................... 52 
 

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Schema MV-NIS 
 
Registration (See Section 6.0) 
↓ 
Peritoneal Catheter Placement 
Fat Collection 
↓ 
NIS-Measles Virus (Edmonston Strain MV-NIS)  
Intraperitoneal administration (IP) Cycle 1, Day 1 
 
↓ 
 
 
Mesenchymal stem 
 
PROG  
cell infected with 
 
Unacceptable Toxicity 
Patient Refusal 
Alternate Treatment 
MV-NIS 
MV-NIS/MSC 
Cycle 2-6 Day 1* 
CR/PR/Stable Disease 
Continue Treatment 
 up to 6 cycles 
↓ 
 
↓ 
Observation per Section 4.0 
 
Observation per Section 4.0 
↓ 
 
↓ 
Event monitoring per Section 18.1 
 
Event monitoring per Section 18.1 
 
 
 
*Patient will proceed to Cycle 2 
treatment only if acceptable 
tolerance and lack of progression 
following Cycle 1 
 
 
Cycle Length = 28 days 
 
 
 
 
 
Mayo Drug Names/Abbreviations 
 
 
Generic name: 
None - NIS-Measles Virus (Edmonston Strain) 
Synonym: 
 
Brand Name(s): 
 
Mayo abbreviation: 
MV-NIS 
Generic name: 
None-Mesenchymal stem cell infected with NIS-Measles Virus (Edmonston Strain)  
Synonym: 
 
Brand Name(s): 
 
Mayo abbreviation: 
MV-NIS/MSC 
Generic name: 
Liothyronine sodium  
Synonym: 
 
Brand Name(s): 
Cytomel® 
Mayo abbreviation: 
T3 

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1.0 
Background 
1.1 
Ovarian cancer 
Ovarian cancer is the second most common malignancy of the female genital tract in the 
United States, with an estimated 14,000 deaths in 2013[1]. Because there is no effective 
screening method for ovarian cancer, more than 70% of cases are diagnosed after the 
tumor has already spread beyond the ovaries. Seventy to 80% of patients continue to 
present with advanced disease, and despite the high response rate that can be obtained 
with a platinum/taxane based regimen, the majority of these patients will relapse. The 
available salvage therapy for relapsed disease consists mostly of chemotherapy or 
biologic agents such as bevacizumab and it is not curative. It can lead to responses in the 
minority of patients and most patients will subsequently progress in a few to several 
months. There is an urgent need for innovative approaches for the treatment of advanced 
disease. 
1.2 
Measles virus as a cancer therapy 
The idea of using measles virus strains as anticancer therapy has emerged from the 
observation that natural measles infection can result in an antitumor effect.  For example, 
natural infection with measles virus has been shown to lead to regression in patients with 
Hodgkin’s disease and non-Hodgkin’s lymphoma [2,3].  
Measles virus is a negative strand, RNA virus, whose genome includes six protein 
products [4].  Three of these proteins participate in the formation of the viral envelope; 
the H-protein is the surface glycoprotein which mediates measles virus attachment to its 
receptors, the CD46 molecule [5], the SLAM receptor (the latter being predominantly 
present on activated B and T cells) and the epithelial receptor nectin-4 [6].  The F-protein 
is responsible for cell after viral attachment has taken place.  During natural infection 
with the measles virus, the virus replicates in susceptible tissues causing a very 
characteristic cytopathic effect, with development of multinucleated giant cells 
(syncytia).  Cells infected by measles virus express F and H-proteins on their membranes 
and therefore become highly fusogenic.  These cells can cause fusion not only with other 
infected cells but also with uninfected neighboring cells.  Although wild type measles 
virus can lead to a potentially serious infectious disease, attenuated strains (vaccine 
strains) of measles virus have an excellent safety record and have resulted in significant 
decreases in measles incidence and mortality worldwide [7]. 
In preclinical studies, we showed that intratumoral or intravenous injection of a measles 
virus strain, derived from the Edmonston vaccine lineage, can cause growth inhibition or 
total regression for a variety of established tumors and xenografts [8].   
Systemic use of an attenuated strain of measles virus as an anticancer agent can be 
potentially hampered by high levels of protecting anti-measles virus antibodies, which are 
present in more than 90% of the Western population as a result of immunization or 
natural infection [9]. Ovarian cancer, however, provides us with a unique opportunity to 
exploit the antitumor potential of the vaccine strain of measles virus.  In 85% of patients, 
ovarian cancer remains confined within the peritoneal cavity, providing an optimal 
setting for viral delivery and direct virus-tumor interaction.   
MV strains have demonstrated potent antitumor activity against human epithelial ovarian 
cancer cells in vitro and in vivo. Most importantly, the virus was selectively oncolytic for 
ovarian tumor cells but caused minimal cytopathic damage on normal ovarian surface 
epithelium and normal mesothelium.  This selectivity was in part mediated through 

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overexpression of the measles virus receptor CD46 in ovarian cancer cells in contrast to 
low levels of expression in mesothelial cells and normal ovarian surface epithelial cells.  
When an MV derivative producing the human carcinoembryonic antigen (MV-CEA) was 
injected directly into established subcutaneous SKOV3ip.1 human epithelial ovarian 
xenografts in athymic mice, the virus induced complete regression of 80% of the tumors. 
Survival of mice bearing intraperitoneal tumors was significantly enhanced by virus 
therapy. The median survival of mice in the treated group was more than 80 days 
compared to 30 days for the control group.  By day 48 post implantation of cells, all mice 
in the control group had developed ascites and had to be euthanized. Similar data were 
subsequently obtained with MV-NIS [10]. Toxicology and biodistribution studies in 
measles virus infection susceptible Infarko CD46 Ge mice have demonstrated the safety of 
the approach [11].  
1.3 
Clinical experience with MV derivatives in ovarian cancer treatment:  
A phase I trial of intraperineal administration of MV-CEA has been completed. 21 
patients were treated with MV-CEA IP every four weeks for up to six cycles at ten 
different dose levels from 103 to 109 TCID50. We observed no dose-limiting toxicity, 
treatment induced immunosuppression, development of anti-CEA antibodies, increase in 
anti-CEA antibody titers or viral shedding in urine or saliva. Dose dependent CEA 
elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of 
patient tumor specimens revealed overexpression of measles virus receptor CD46 in 
13/15 patients. Best objective response was dose-dependent disease stabilization in 14/21 
patients with a median duration of 92.5 days (range 54 to 277 days). Five patients had 
significant decrease in CA-125 levels. Median survival of patients on study was 12.5 
months, (range 1.3 to 38.4 months) comparing favorably to an expected median survival 
of 6 months in this patient population. MV-NIS is an MV-Edmonston derivative, 
identical to MV-CEA except that it encodes the sodium iodine symporter (NIS) gene 
instead of the CEA gene [12].  MV-NIS is at least as efficacious as MV-CEA in 
orthotopic ovarian cancer models [10] and it allows use of radioactive iodine isotopes for 
imaging [10] and treatment purposes [12].  A phase I trial with phase II dose expansion 
of MV-NIS in patients with recurrent ovarian cancer has been completed. Six patients 
have been treated at the dose expansion part of the study and 10 patients at the dose 
expansion cohort. No dose-limiting toxicity has been observed.  Median overall survival 
was a very promising 26.6 months (range 1.8-33.9+ months) despite the fact that patients 
were heavily pretreated. MV-NIS has the advantage that can be easily produced in higher 
titer and an FDA-approved protocol has been developed for this purpose and employed in 
subsequent studies.  
1.4 
Rationale for use of cells as viral delivery vehicles:  
One of the potential limitations following intraperitoneal administration of the measles 
virus pertains to the presence of neutralizing antibodies in the peritoneal cavity [13]. 
Furthermore, when the virus is diluted in normal saline, which is its current delivery 
vehicle, it is expected that within 4 to 6 hours the viral containing solution will have been 
absorbed systemically; the latter suggests that viral delivery through an approach 
allowing longer contact with the target tumor sites, could increase infectivity and further 
improve antitumor efficacy.  
1.5 
Adipose tissue derived mesenchymal stem cells (MSC) can be successfully infected 
by MV and allow the virus to resist immune serum neutralization [13]. 
To determine the susceptibility of MSC to MV infection, MSC were infected with MV-
RFP at MOI (0.01, 0.1, 1.0 or 4.0). There was a corresponding increase in the numbers of 

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infected cells with increase in MOI. To enable quantitation of the percentage of infected 
cells by flow cytometry, MSC were maintained in media containing a fusion inhibitory 
peptide (+FIP) that prevents intercellular fusion (syncytia formation). At MOI of 1.0 and 
4.0, 20% and 60% of cells were expressing RFP by 48h post infection, respectively. 
Viability of MSC post infection by MV-GFP (MOI 1.0) was determined by trypan blue 
exclusion assay. In the presence of FIP, there was no significant difference in numbers of 
viable cells in the infected culture over time. The numbers of viable cells decreased by 
96h if the infected MSC were allowed to fuse with neighboring cells in the absence of 
FIP. The amount of viral progeny produced by infected MSC (cell-associated virus) or 
conditioned media (released virus) was determined by TCID50 titrations. Infected MSC 
were able to propagate the virus, but to a smaller extent, compared to Vero producer 
cells. The majority of measles virus progeny was cell-associated, requiring freeze/thaw 
cycles to release the viruses. 
Intercellular fusion is more resistant to neutralizing anti-MV antibodies than cell-free 
virus: the anti-MV IgG titers in different lots of human AB pooled sera were determined 
using an enzyme immunoassay. An individual with a titer of more than 20 EU/mL is 
measles immune. Full plaque reduction neutralization (PRN) assays using 250 TCID50 
MV-GFP were also performed to determine the corresponding virus neutralization titers 
of the sera. Pooled AB serum lot K61552 (277 EU/mL, PRN=256) and lot C80553 (300 
EU/ml, PRN=256) were used in all subsequent experiments. 
Vero cells were infected with MV-GFP (103 TCID50) in the absence or presence of 
increasing concentrations of measles immune serum. The numbers of infectious centers 
(syncytia) in the Vero monolayer were counted at 48h post infection and represented as a 
percentage of syncytia count in the absence of anti-MV antibodies. `Naked’ MV-GFP 
was neutralized by measles immune sera; no syncytium was detected at the highest 
concentration of human serum used (1:4 dilution, 69 EU/mL). It was not until at 1:128 
serum dilution (2 EU/mL) that 40% of infectious centers was recovered in the Vero 
monolayer. 
To determine if MSC could deliver MV to target cells in the presence of anti-MV 
antibodies, MSC were preinfected with MV-GFP at MOI 1.0 and the next day, MSC 
were overlaid on Vero cells (1 MSC: 100 Vero cells) in the presence of increasing 
concentrations of measles immune serum. MSC associated viruses were more resistant to 
the neutralizing effects of anti-MV antibodies. At 1:4 serum dilution (69 EU/mL), 40% of 
infectious centers was present and at 1:16 dilution, the numbers of infectious centers were 
comparable to the control in which no serum was added. Hence, infected MSC were able 
to fuse with Vero cells and delivered MV infection to the target cells in an environment 
with a high amount of anti-MV antibodies.  
1.6 
Infected MSC localize to ovarian cancer metastases after intraperitoneal 
administration and result in significant antitumor efficacy [13]. 
Athymic mice were implanted intraperitoneally with SKOV3ip.1 human ovarian cancer 
cells and 7 days later, mice were injected IP with MV-Luc infected MSC and imaged 
non-invasively for Fluc gene expression. Firefly luciferase signals were seen both in 
tumor-free and tumor-bearing mice given MV-Luc infected MSC at day 1 post MSC 
delivery. In the non-tumor bearing mice the MV-Luc infected cells were seen at the 
injection site and at the omental region by Day 3, the luciferase signals had decreased 
significantly and were undetectable by day 7 after death of the virus infected MSC cells. 
In contrast, bioluminescent signals remained high and continued to increase over time in 
tumor-bearing mice given MV-Luc infected MSC. It is evident that in tumor-bearing 

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mice, the infected MSC were able to transfer MV-Luc infection to the peritoneal tumors. 
The infected tumors continued to propagate the virus, resulting in increase of Fluc 
bioluminescent signal even after death of the infected MSC. As expected, naked MV-Luc 
was highly efficient at infecting tumors in these measles naïve mice. 
To determine if MSCs co-localized with the tumor nodules, another cohort of mice 
bearing intraperitoneal SKOV3ip.1, OVCAR5 or A2780 human ovarian tumors were 
injected IP with CellTracker Red CMTPX dye labeled MSC (MV infected or uninfected). 
Tumors were harvested and examined directly under a fluorescence microscope 24h later. 
Abundant red fluorescent MSC were found at the omental tumor nodules and on smaller 
peritoneal tumor nodules that have seeded on the mesenteric linings or intestines. There 
was no apparent difference in the biodistribution of uninfected and infected MSC; both 
types of MSC were able to traffick to and localize on the tumors. Gross examination of 
the peritoneal cavity indicated that peritoneal tumor nodules in all 3 models of ovarian 
cancer were covered with red fluorescent MSC. In the OVCAR5 model in which there 
was significant coverage of the peritoneum wall by a cake of tumor cells, abundant MSC 
were found on the tumor cake. In contrast, the tumor free peritoneal wall next to this 
tumor cake had minimal numbers of MSC. When given IP into control athymic mice with 
no tumor, MSC accumulated predominantly on the omentum. Cryosections of the 
peritoneal tumors were examined using confocal microscopy to determine the extent of 
MSC infiltration into the tumor parenchyma. At 4h and 24h post cell infusion, red 
fluorescent MSC were seen lining the surface of the tumor nodules and in the tumor 
parenchyma. 
Antitumor efficacy in the presence of neutralizing antibodies 
Athymic mice were implanted with SKOV3ip.1-Gluc tumor cells and 8 days later, mice 
received saline or equal numbers (1×106) of `naked’ cell free MV-Luc or MV-Luc 
infected MSC. Mice were imaged non-invasively using bioluminescent imaging for Gluc 
expression with colenterazine substrate (tumor burden) and the next day, for Fluc 
expression using D-luciferin substrate (viral gene expression). Imaging was performed 
one day apart to ensure that all Gluc bioluminescent signals had disappeared prior to Fluc 
imaging. We observed a good correlation between the location and intensity of Gluc and 
Fluc signals indicating robust infection of the tumors by cell-free and MSC-associated 
virus in measles naïve animals. In measles immune animals, the MV-Luc infected MSC 
were able to transfer the infection to ovarian tumors, resulting in increase in Fluc signal. 
In contrast, `naked’ MV-Luc was neutralized by the anti-measles antibodies and the 
peritoneal tumors were not infected. Hence, delivery of MV is superior when MSC are 
used as virus carriers in measles immune animals. The increase in Fluc signal in the 
tumors at day 7 was not due to presence of infected MSC. A significant portion of virus 
infected MSC died by day 3 post IP delivery into mice resulting in complete loss of 
bioluminescent signals. 
To investigate the antitumor activity of the various treatments, athymic mice were 
implanted IP with 2 × 106 SKOV3ip.1-Gluc tumor cells and 8 days later, mice were 
passively immunized by IP administration of measles immune human serum (50 EU) or 
given saline. Three hours later, mice were given equal numbers (1×105) of cell-free MV-
NIS or MV-infected MSC IP. The MV/MSC had been loaded with MV-NIS by 
incubation with virus at MOI 4.0 for 2 hours (approximately 60% infection) and washed 
once in PBS. In the measles immune groups, MV-NIS and MV/MSC were subsequently 
incubated in vitro with measles immune serum (50 EU) for 30 min at 37°C prior to 
injection into the animals to ensure neutralization of any surface bound virus. Thus, each 
measles immune mouse received a total of 100 EU of anti-MV IgG Ab. 

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The Kaplan Meier survival curves of the mice were plotted. The median survival for 
saline control was 31 days (n=5 mice), uninfected MSC was 31 days (n=5 mice), MV 
(−Ab) was 64 days (n=12 mice), MV (+Ab) was 31 days (n=12 mice), MV/MSC (−Ab) 
was 62 days (n=10 mice) and MV/MSC (+Ab) was 66 days (n=11 mice). All mice in the 
saline, uninfected MSC, and MV (+Ab) groups (22 out of 22) were euthanized because 
they developed bloody ascites (3–4.5 mL), with extensive dissemination of ovarian 
tumors in the peritoneal cavity, perigastric area and on the peritoneal side of the 
diaphragm. In contrast, only a few of the mice in the MV (−Ab) or MV/MSC groups (+ 
Ab and – Ab) developed ascites (6 out of 33). Several of the mice appeared jaundiced and 
were euthanized (12 out of 33). Examination at necropsy indicated tumor 
obstruction/constriction around the gall bladder or bile duct. The rest of the animals were 
euthanized due to weight loss of more than 20%, or development of an ulcerated 
subcutaneous tumor at the injection site towards the end of the study. 
The survival curves of the respective treatment groups were compared against the saline 
control and the p values were determined. Uninfected MSC did not have any antitumor 
activity against human ovarian cancer, survival of these mice was not significantly 
different from the saline treated group (p=0.92). As expected, MV-NIS (−Ab) 
significantly extended the survival of mice compared to saline control (p<0.0001). 
However, the antitumor activity of MV-NIS was negated in passively immunized mice. 
Thus, there was a significant difference in survival outcome using `naked’ MV-NIS in 
measles naïve mice versus measles immune mice (p<0.0001). In contrast to therapy using 
cell-free virus, treatment of passively immunized mice with MV-infected MSC 
significantly extended the survival of mice (p<0.0001), doubling the median survival 
from 31 days (MV-NIS +Ab) to 66 days for MV/MSC +Ab. Furthermore, there was no 
significant difference in therapy using MV/MSC in measles naïve or measles immune 
animals (p=0.93). The presence of pre-existing antimeasles antibodies did not diminish 
the delivery and transfer of MV from infected MSC. We did not observe a significant 
difference in survival of measles naïve mice treated with MSC-associated MV compared 
to cell-free virus (p=0.67). 
Cryosections of omental tumors harvested at necropsy were immunostained with an 
antibody specific for the measles nucleocapsid (MV-N) protein and CD68, a macrophage 
marker. MV-N positive areas were found in MV-NIS (−Ab), MV/MSC (−Ab) and 
MV/MSC (+Ab) tumors but not in MV-NIS (+Ab) tumors. Staining for CD68+ 
macrophages indicated abundant infiltration of phagocytic macrophages into the MV 
infected tumors, either surrounding or in necrotic areas or co-localizing with the MV-N 
positive areas. It is likely that the macrophages are phagocytic in nature, as suggested by 
the abundance of CD68 staining in the necrotic areas of the tumors. There were also areas 
of MV-N staining with no corresponding CD68 staining. 
The study was subsequently extended to include evaluation of the ability of infected 
MSC to seek other human ovarian cancer cell lines, specifically A2780 and OVCAR5. 
Intraperitoneally implanted MSC successfully demonstrated their ability to home to and 
localize to these tumors and subsequently transfer the virus to the tumor cells [Mader and 
Peng, unpublished data]. 
1.7 
Successful MSC generation from the adipose tissue of ovarian cancer patients: 
Following IRB approval, adipose tissue was obtained in the form of fat biopsies from 
three recurrent ovarian cancer patients and six newly diagnosed patients. MSCs were 
successfully isolated and expanded. Importantly, all lots of patient-derived MSCs could 
be infected with MV with a range of 6-90% infectivity. These patient-derived infected 

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MSCs were administered to mice with peritoneal involvement by ovarian cancer. The 
MSC successfully homed to undelivered virus to this human ovarian cancer tumors as 
demonstrated via fluorescent xenogene imaging.  
1.8 
Pilot assessment of MSC tumorigenicity 
Three groups of athymic mice were administered (1) SKOV3ip.1 human ovarian cancer 
cells, (2) SKOV3ip.1 cells in conjunction with MSC (1:1 ratio). MSC did not enhance or 
suppress tumor growth.  
Our data collectively demonstrate that MSC can be successfully isolated from ovarian 
cancer of the adipose tissue cancer patients expanded in vitro and infected with MV 
strains with a high infectivity. Infected MSC can home into peritoneal ovarian tumors, 
thus supporting the concept of improving viral delivery in patients with recurrent ovarian 
cancer in whom the virus is administered intraperitoneally. 
These data collectively support that adipose tissue derived MSCs can effectively deliver 
MV to ovarian cancer metastasis and increase treatment efficacy at the presence of 
neutralizing antibodies. 
 
 
 

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2.0 
Goals 
2.1 
Phase I 
To determine the maximally tolerated dose (MTD) of intraperitoneal administration of an 
Edmonston’s strain measles virus genetically engineered to produce NIS (MV-NIS) in 
patients with recurrent ovarian cancer, delivered by adipose tissue derived mesenchymal 
stem cells (MSC). 
2.2 
Phase II:   
2.21  
Primary:  
To assess the 12-month overall survival of patients treated with this regimen 
2.22  
Secondary: 
2.221 To assess the tolerability of this regimen 
2.222 To assess the 4-month progression free survival of patients treated with 
this regimen 
2.223 To assess the response rate, progression-free survival, and overall 
survival of patients treated with this regimen 
2.23 
Translational: 
2.231 To assess the time course of viral gene expression and virus elimination 
and biodistribution of virally infected cells at various time points after 
infection with MV-NIS versus MSC delivered MV-NIS using 
SPECT/CT imaging. 
2.232 To assess viremia, viral replication, and measles virus 
shedding/persistence following intraperitoneal administration. 
2.233 To assess humoral and cellular immune response to the injected virus. 
2.234 To assess in a preliminary fashion the development of antitumor immune 
response. 
 
 

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3.0 
Patient Eligibility 
3.1 
Inclusion criteria 
3.11 
Age ≥18 years. 
3.12 
Must have: 
• 
Recurrent or progressive ovarian cancer, primary peritoneal cancer or 
fallopian tube cancer after prior treatment with platinum and taxanes 
• 
Histologic confirmation of the original primary tumor 
• 
Prior bilateral oophorectomy 
3.13 
The following histologic epithelial cell types are eligible:  
Serous adenocarcinoma, endometroid adenocarcinoma, mucinous 
adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed 
epithelial carcinoma, transitional cell carcinoma, malignant Brenner’s Tumor, or 
adenocarcinoma NOS.  
3.14 
ECOG performance status (PS) of 0, 1, or 2. 
3.15 
The following laboratory values obtained ≤7 days prior to registration: 
• 
ANC ≥1500/µL 
• 
PLT ≥100,000/µL 
• 
Total bilirubin ≤ upper normal limit 
• 
AST ≤2 x ULN  
• 
Creatinine ≤1.5 x ULN 
• 
Hgb ≥9.0 g/dL 
3.16 
Normal cardiac function as defined by a normal ejection fraction by MUGA or 
echocardiogram. 
3.17 
Provide informed written consent. 
3.18 
Willing to return to Mayo Clinic Rochester for follow-up. 
3.19a 
Life expectancy ≥12 weeks. 
3.19b Willing to provide all biologic specimens as required by the protocol. 
3.19c 
Measurable disease by exam or CT scan, or for patients with CA-125 elevation or 
with microscopic residual but without measurable disease on imaging, 
willingness to undergo laparoscopy for evaluation of treatment effect if no 
radiographic progression after 6 treatment cycles. 
3.19d CD4 count ≥200/µL or ≥15% of peripheral blood lymphocytes 
3.2 
Exclusion criteria 
3.21 
Epithelial tumors of low malignant potential, stromal tumors, and germ cell 
tumors of the ovary. 
3.22 
Known standard therapy for the patient’s disease that is potentially curative or 
definitely capable of extending life expectancy.  Subjects will be excluded if this 
is their first relapse and they have recurred >6 months from completion of 
primary (adjuvant) chemotherapy. 
3.23 
Active infection ≤5 days prior to registration. 
3.24 
History of tuberculosis or history of PPD positivity. 

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3.25 
History of other malignancy ≤5 years prior to registration except for non-
melanoma skin cancer, carcinoma in situ of the cervix, and DCIS. 
3.26 
Any of the following prior therapies: 
• 
Chemotherapy ≤3 weeks prior to registration 
• 
Immunotherapy ≤4 weeks prior to registration 
• 
Biologic therapy ≤4 weeks prior to registration 
• 
Extensive abdominal surgery if it includes enterotomy(ies) ≤3 weeks prior to 
registration. This criterion does not apply to placement of the peritoneal port-
a-cath or lysis of adhesions at the time of registration. 
• 
Any viral or gene therapy prior to registration. 
• 
Radiation therapy to the abdomen or pelvis. 
3.27 
New York Heart Association Classification III or IV, known symptomatic 
coronary artery disease, or symptoms of coronary artery disease on systems 
review, or known cardiac arrhythmias (atrial fibrillation or SVT). 
3.28 
Other cardiac or pulmonary disease that, at the investigator’s discretion, can 
impair treatment safety. 
3.29a 
Requiring blood product support. 
3.29b CNS metastases or seizure disorder. 
3.29c 
HIV-positive test result or history of other immunodeficiency. 
3.29d History of organ transplantation. 
3.29e 
History of chronic hepatitis B or C. 
3.29f 
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary 
therapy considered investigational (utilized for a non-FDA-approved indication 
and in the context of a research investigation). 
3.29g Intra-abdominal disease >8 cm in diameter at the time of registration, intrahepatic 
disease, or disease beyond the abdominal cavity. Patients with intra-abdominal 
lymph node involvement are eligible based on biodistribution data indicating 
viral dissemination to lymph nodes following intraperitoneal administration [14]. 
3.29h Treatment with oral/systemic corticosteroids, with the exception of topical or 
inhaled steroids. 
3.29i 
Exposure to household contacts ≤15 months old or household contact with 
known immunodeficiency. 
3.29j 
Allergy to measles vaccine or history of severe reaction to prior measles 
vaccination. 
3.29k Allergy to iodine. This does not include reactions to intravenous contrast 
materials. 
3.29l 
Any other pathology or condition where the principal investigator may deem to 
negatively impact treatment safety. 
 

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4.0 
Test Schedule 
4.1 
Schedule of assessments 
 
Pre-Treatment 
Active Treatment 
Observation1 
Tests and Procedures 
≤7 days 
prior to 
registration 
At 
peritoneal 
catheter 
placement* 
Post 
catheter 
placement 
visit*2,3 
Cycle 1 
Day 1  
prior to 
treatment* 
Cycles 
1-6, 
Day 1 
Cycle 1 
and 2, 
Day 3 
Cycle 1 
and 2, 
Day 8 
Cycle 1 
and 2, 
Day 15 
Cycles 3-6, 
Day 3; 
Cycles 1-6, 
Day 23 
Cycles 2-6, 
Day 1 prior 
to treatment;  
and  
End of 
treatment 
q 3 months 
until 
progression 
or alternate 
treatment 
3 months, 6 
months, and 
12 months 
after 
progression 
or alternate 
treatment 
window 
 
 
 
 
 
±1 day 
±1 day 
±1 day 
±72 hours 
±3 days 
 
 
History and exam, wt, height4, PS, vital signs, 
assessment of  toxicity5 
X 
 
X 
 
X6 
 
 
 
 
X 
X 
X 
Gyn Consult for Port Placement 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment 
 
 
X7 
 
 
 
 
 
 
X 
X 
 
Hematology group (WBC, ANC, Lymphocyte 
count, Hgb, PLT) 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
INR, APTT 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Chemistry group  (AST, AP, Na, K, Creat, bili) 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Urine analysis including sediment 
X 
 
X 
 
 
 
 
 
 
 
 
 
Chest x-ray 
X 
 
X 
 
 
 
 
 
 
 
 
 
Echo/ or MUGA  
X8 
 
 
 
 
 
 
 
 
 
 
 
HIV blood test 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor Measurement / Evaluation of indicator 
lesion (CT, MRI, etc.)9 
X 
 
X10 
 
 
 
 
 
 
X 
X 
X 
ECG 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
SPECT CT R,11 
 
 
X 
 
 
X 
X 
X12 
 
X13 
 
 
CA125 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
1 Follow instructions in Section 13 for Observation; then Section 18 for Event Monitoring 
2 Laboratory evaluation and imaging do not need to be repeated if the patient has a peritoneal port PRIOR to enrollment/registration if done ≤14 days before C1D1 
3 ≤7 days prior to treatment unless otherwise noted 
4 Height only needed at baseline 
5 Additional assessment of toxicity will be performed as described in Section 8.0. 
6 Weight and PS only 
7 ≤2 weeks prior to treatment 
8 To be performed ≤42 days prior to registration 
9 For patients with measurable disease. Must be ≤21 days so we have enough time for scans  (CT to be performed with contrast) and prior to all subsequent cycles (without contrast if SPECT is to be 
performed; otherwise with contrast). Pre-registration and post-port placement CTs to be reviewed and compared with subsequent CTs. Post-port placement CT will be used as the baseline scan for 
response purposes. See Section 11.0 for Response Evaluation Criteria in Solid Tumors (RECIST). NOTE: Same modality CT or MRI should be used throughout the trial. 
10 Post-port placement CT will be used as the baseline scan for response purposes. 
11 See Table 4.1. 
12 See Table 4.1. Scans at Cycle 1, Day 15, Day 28, and Cycle 2, Day 15 are optional.  
13 See Table 4.1. Scans on Cycles 3-6 are optional only needed if prior scans are positive. 

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Pre-Treatment 
Active Treatment 
Observation1 
Tests and Procedures 
≤7 days 
prior to 
registration 
At 
peritoneal 
catheter 
placement* 
Post 
catheter 
placement 
visit*2,3 
Cycle 1 
Day 1  
prior to 
treatment* 
Cycles 
1-6, 
Day 1 
Cycle 1 
and 2, 
Day 3 
Cycle 1 
and 2, 
Day 8 
Cycle 1 
and 2, 
Day 15 
Cycles 3-6, 
Day 3; 
Cycles 1-6, 
Day 23 
Cycles 2-6, 
Day 1 prior 
to treatment;  
and  
End of 
treatment 
q 3 months 
until 
progression 
or alternate 
treatment 
3 months, 6 
months, and 
12 months 
after 
progression 
or alternate 
treatment 
window 
 
 
 
 
 
±1 day 
±1 day 
±1 day 
±72 hours 
±3 days 
 
 
Assessment of immune competenceR,, 
Immunoglobulins, CD4 & CD8 counts, 
complement levels (clinical test) 
X14 
 
 
 
 
 
 
 
 
X15 
 
 
Measles virus immunityR 
 Serum anti-measles IgG (clinical test) 
X 
 
 
 
 
 
 
 
 
X16 
 
 
 Ascites anti-measles IgGR** 
 
 
 
X* 
 
 
X17 
 
 
X18 
 
 
 IFN-γ, IL-10 measles ELISPOTR** 
 
 
 
X* 
 
 
 
 
 
X19 
 
 
Assessment of viral sheddingR** 
 
 
 
X* 
 
X 
X 
 
X 
 
 
 
Assessment of Viremia (PMBC)R** 
 
 
 
X* 
 
X 
X 
X 
X 
 
 
 
Peritoneal aspiratesR** 
 
X* 
 
 
 
X 
X 
 
 
X20 
 
 
Tumor biopsy, Tumor and benign tissueR,21 
 
X* 
 
 
 
 
 
 
 
 
 
 
Fat aspirate R 
 
X* 
 
 
 
 
 
 
 
 
 
 
Assessment of immune response against tumor 
 
 
 
X* 
 
 
 
 
 
X22 
 
 
Cytokine multiplex assays 
 
 
 
X* 
 
 
 
 
 
X23 
 
 
Study Drug Administration 
 
 
 
 
X24 
 
 
 
 
 
 
 
Concomitant Medications25 
 
X* 
 
X 
X 
 
 
 
 
X 
 
 
* 
To be performed after registration but prior to study agent being given on Cycle 1, Day 1. 
** 
See Section 14.0 for details. 
R 
Research funded 
 
14 To be performed ≤42 days prior to registration 
15 Prior to Cycle 2 and Cycle 3 
16 Not done at end of treatment 
17 Day 8 of Cycle 1 only 
18 Cycle 3 Day 1 only 
19 Not done at end of treatment 
20 Not done Cycle 2 Day 1; Not done at end of treatment 
21 Can be done anytime up to one month prior to registration. Not necessary if adequate prior biopsy material exists. Only fat grossly free of tumor will be collected. See Section 17.0 for details. 
22 Not done at end of treatment 
23 Not done at end of treatment 
24 Cycle 1 is MV-NIS and Cycle 2-6 are MV-NIS/MSC 
25 To be completed per tables in Section 18.0 

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4.2 
Nuclear imaging Tables 
Table 4.21 
Cycle 1a,c 
TIMEPOINT 
 SPECT/CT 
Pre-treatment 
 
X 
Day 3 
 
X 
Day 8 
 
X 
Day 15 (optional-see footnote) 
 
Xb 
Day 28 (optional-see footnote)  
Xb 
 
Table 4.22 
Cycle 2 and optional Cycle 3a,c 
TIMEPOINT 
 SPECT/CT 
Pre-treatment 
 
Day 3 
 
X 
Day 8 
 
X 
Day 15 (optional-see footnote) 
 
Xb 
Day 28 (optional-see footnote)  
Xb 
 
a. The scheduling of the nuclear imaging will be as close to the stated time points as possible. 
Flexibility of ±1 day will be allowed. 
b. These scans will be elective, based on whether there is continued uptake on prior imaging studies. 
c. Imaging with SPECT CT will be performed in cycles 1 (MV-NIS alone) and 2 (MSC delivered 
MV-NIS). Imaging to be performed in Cycle 3, only if positive imaging is obtained in Cycle 2-
these tests in Cycle 3 will continue as long as the prior scan is positive up to a maximum of 15 
total. In this case, SPECT/CT imaging in Cycle 3 will be timed to correspond to SPECT/CT in 
Cycles 1and 2. 
 

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5.0 
Grouping Factors: 
5.1 
Phase I vs Phase II 
5.2 
Dose level: -1 vs 0 vs 1 (Phase I only) 
5.3 
Disease: Measurable vs non-measurable  
6.0 
Registration/Randomization Procedures 
6.1 
Phase I 
6.11 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
for dose level and to ensure that a place on the protocol is 
open to the patient.  
6.12 
To register a patient, fax 
 a completed eligibility checklist to the Mayo 
Clinic Cancer (MCCC) Registration Office between 8 a.m. and 4:30 p.m. central 
time, Monday through Friday. 
6.2 
Phase II 
6.12 
Registration Procedures 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The registration 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 MCCC 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 on 
the MCCC web page 
and detail the process 
for completing and confirming patient registration. Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions. It is the responsibility of 
the individual registering the patient to confirm the process has been successfully 
completed prior to release of the study agent. Patient registration via the 
registration application can be confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
If the patient was fully 
registered, the MCCC 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.” 
6.3 
 Phase I and II 
6.31 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19d, 14.0, and 
17.0). 
6.32 
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 

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MCCC Addendum 12 
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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. 
6.33 
At the time of registration, Registration Office personnel will verify the 
following: 
• 
IRB approval 
• 
patient eligibility  
• 
existence of a signed consent form  
• 
existence of a signed authorization for use and disclosure of protected health 
information. 
In addition, the following will be recorded: 
• 
Patient has/has not given permission to store samples for future research of 
cancer 
• 
Patient has/has not given permission to store samples for future research to 
learn about, prevent or treat other health problems 
• 
Patient has/has not has given Mayo permission to give their samples to 
outside researchers 
6.34 
Treatment on this protocol must be administered at Mayo Clinic Rochester under 
the supervision of a medical or gynecologic oncologist. 
6.35 
Treatment cannot begin prior to registration and must begin ≤42 days after 
registration. 
6.36 
Pretreatment tests must be completed within the guidelines specified on the test 
schedule. 
6.37 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
6.38 
Following patient registration, the clinical research associate (CRA) will notify 
 for coordination of collection and delivery of 
specimens for laboratory correlative studies. 
6.39 
Patients will be admitted to the CRTU (Clinical Research and Trials Unit) on the 
evening prior to each cycle of therapy. The clinical research associate (CRA) 
should inquire with the CRTU on bed availability prior to registering the patient. 
 
 
 

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7.0 
Protocol Treatment 
Note: For patients who have surgery for intraperitoneal port placement, a waiting period 
of 4 weeks (±2 weeks) will commence prior to receipt of Cytomel®. 
7.1 
Treatment schedule – Phase I 
Agent 
Dose 
Route 
Day 
Pre-medication prior to administration of MV-NIS Cycles 1 & 2. Given prior to Cycle 3 if 
the Cycle 2 SPECT/CT is positive. 
Liothyronine 
sodium 
(Cytomel®) 
0.025 mg 
1 tablet three times 
a day 
Day –7 through day of last SPECT/CT 
scan 
 
Cycle 1 
Agent 
Dose 
Route 
Day 
MV-NIS1 
109 TCID50 
IP 
Day 1 
1MV-NIS will be diluted in 500 mL of 0.9% Sodium Chloride and administered over 30 
minutes 
 
Cycles 2-61 
Agent 
Dose 
Route 
Day 
Re-Rx 
MV-NIS 
infected 
MSC(MV-
NIS/MSC)2 
Assigned by the 
Registration Office 
IP 
Day 1 
Every 28 days for 
up to 5 cycles 
1Patient will proceed to Cycle 2 treatment, only if acceptable tolerance and lack of progression 
following Cycle 1 
2MV-NIS/MSC will be diluted in 500 mL of Lactated Ringers and administered over 30 minutes 
 
After MV-NIS Administration 
Agent 
Dose 
Route 
Day 
123I 
5 mCi 
Oral 
Day 3 and 8 of study 
(2 additional doses may be 
given for imaging based on 
imaging results) 
 
 
 
 

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7.11 
Upon consent and prior to Cycle 1, patients will undergo fat aspiration at the time 
of catheter placement. The surgeon placing the catheter will be performing the 
procedure. Once it is collected, it will be placed in Sterile Buffered Saline and 
transported to the Human Cellular Therapy Laboratory for manufacturing and 
freezing. If patients have already had catheter placement, fat aspiration can be 
conducted in the Clinical Research Trials Unit (CRTU). 
7.12 
Patients will receive liothyronine sodium (Cytomel®) to prevent thyroid uptake 
when repeated imaging doses of 123I are administered. 
7.13  
The virus will be administered through intraperitoneal port-a-cath that will be 
surgically placed at the time of study entry. If ascites is present, it will be drained 
through the port-a-cath prior to administration of MV-NIS. The patient will 
receive infusion of the assigned dose of MV-NIS diluted in 500 mL of 0.9% 
Sodium Chloride over 30 minutes in Cycle 1. The assigned dose of MV-NIS 
infected MSC will be diluted in 500 mL of Lactated Ringer’s and administered 
over 30 minutes (Cycles 2-6). Treatment will be administered at the Clinical 
Research and Trials Unit (CRTU).  
7.14 
The in vivo distribution of MV-NIS infected cells and the kinetics of virus spread 
and elimination will be monitored by SPECT/CT imaging after oral 123I 
administration (2 hours after 5 mCi).  
SPECT/CT imaging will be performed on Days 3 and 8 after MV-NIS 
administration. In addition patients may be imaged on Days 15 and 28 if previous 
imaging is positive for continued uptake. 
These scans will be elective, based on whether there is continued uptake on prior 
imaging studies. Imaging at the same schedule will be performed in Cycle 2. 
Imaging by SPECT/CT to be performed in Cycle 3, only if positive imaging is 
obtained in Cycle 2. In this case, SPECT/CT imaging in Cycle 3 will be timed to 
correspond to SPECT/CT in Cycle 2. 
7.15   The first and second cycle will be administered in the inpatient setting. Patients 
will be admitted the evening prior to administration and dismissed 24 hours after 
administration of the agent. For subsequent cycles, the agent will be administered 
in the outpatient CRU and the patients will be observed in the facility for three 
hours after administration of the agent. A saline lock for IV access, if necessary, 
will be placed prior to viral administration. 
 
7.2 
Phase I Dose Escalation: 
Level 
Dose infected cells 
(MV-NIS/MSC) 
-1 
106 
0* 
107 
1 
108 
*Starting dose. 
7.21 
Patients will be observed for a minimum of 4 weeks after the third patient at each 
cohort has received treatment on Cycle 2, before new patients are treated. The 
study will temporarily close. Resolution of viremia is required prior to dose 
escalation being allowed.  Doses will not be escalated in any individual patient.   
 

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7.22 
For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse 
event attributed (definitely, probably, or possibly) to the MV-NIS infected MSC 
study treatment and meeting the following criteria: 
 
Toxicity 
Definition 
Hematologic 
≥Grade 3 per NCI Common Terminology Criteria for 
Adverse Events v4.0 except grade 3 ANC lasting <72 hours. 
Investigations 
Creatinine increased ≥2 times baseline 
Other nonhematologic 
≥Grade 3 per NCI Common Terminology Criteria for 
Adverse Events v4.0* 
Viremia** 
Lasting for ≥6 weeks from last viral administration 
Allergic reaction 
The Grade 2 allergic reactions: asymptomatic bronchospasm 
and/or urticaria; and ≥Grade 3 allergic reactions 
* 
Grade 3 nausea, vomiting, or diarrhea, while receiving the maximum supportive care 
regimen described in the protocol, will be considered dose-limiting. Alopecia will not 
be considered dose limiting. 
** Viremia is defined as detection of any titer of virus by RT-PCR in patient’s PBMCs. 
Detection limit for this assay is 1000 genome copies/mcg RNA. 
 
7.23 
Accrual for this study will cease permanently if:  
a) 2 or more patients experience DLT at a particular dose level during the phase I 
component or 
b) any patient experiences a Grade 5 treatment-related toxicity. 
 
7.24 
Dose de-escalation: 
Dose de-escalation MV-NIS: If dose-limiting toxicity is seen at dose level 0, 
patients will be entered at a dose level of 106 infected MSC. 
 
7.25 
If a patient on the phase I component fails to complete the initial course of MSC 
therapy (defined as drug administration on Cycle 2 plus four weeks of 
observation) for reasons other than toxicity, the patient will be regarded as 
treatment intolerant and an additional patient will be treated at the current dose 
level; however, all toxicity information will be utilized in the analysis.  For these 
instances, a specific notation will be made for review by the Scientific Progress 
Review Committee (SPRC). 
 
7.26 
The MTD of the phase I component of the trial will be used as the dose for the 
phase II component of the trial (See Section 16.0). 
 
 
 

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7.3 
Treatment schedule – Phase II 
7.31 
Premedication 
Agent 
Dose 
Route 
Day 
Pre-medication Prior to Administration of MV-NIS cycles 1 & 2.  Given prior to cycle 3 
if the cycle 2 SPECT/CT is positive. 
Liothyronine 
sodium 
(Cytomel®)* 
0.025 mg 
1 tablet three times 
a day 
Day –7 through day of last 
SPECT/CT scan 
*For a patient who is receiving thyroid replacement (ex. levothyroxine), discuss the case with 
Endocrinology prior to administering Cytomel®. It may be appropriate to reduce or omit 
Cytomel® for patients receiving thyroid replacement to avoid thyrotoxicosis. 
 
7.32 
Cycle 1 
Cycle 1 
Agent 
Dose 
Route 
Day 
MV-NIS 
109 TCID50 
IP 
Day 1 
 
7.33 
Cycles 2-6 
Cycles 21-6 
Agent2 
Dose 
Route 
Day 
Re-Rx 
MV-NIS 
/MSC 
108 MV-NIS/MSC 
IP 
Day 1 
Every 28 days for 
up to 5 cycles 
1Patient will proceed to Cycle 2 treatment, only if acceptable tolerance(i.e. not meeting criteria 
for treatment discontinuation as per section 8.0) and lack of progression following Cycle 1. Given 
the difference between MV-infected MSC (cycle 2) versus naked MV treatment (cycle 1), if 
progressive disease at the end of cycle 1, patient may still proceed with cycle 2 treatment at the 
discretion of the treating physician, if the progression is asymptomatic. 
2If MSC not available (e.g., due to manufacturing issues) patient may receive MV-NIS alone at 
same dose as Cycle 1. 
7.34 
Prior to Scans 
After MV-NIS Administration 
Agent 
Dose 
Route 
Day 
123I 
5 mCi 
Oral 
Day 3 and 8 of 
study (2 additional 
doses may be 
given for imaging 
based on imaging 
results) 
 
 
 

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7.35 
Liothyronine sodium (Cytomel®) 
Patients will receive Liothyronine sodium (Cytomel®) to prevent thyroid uptake 
when repeated imaging doses of 123I are administered. 
NOTE; For a patient who is receiving thyroid replacement (ex. levothyroxine), 
discuss the case with Endocrinology prior to administering Cytomel®. It may be 
appropriate to reduce or omit Cytomel® for patients receiving thyroid 
replacement to avoid thyrotoxicosis. 
7.36 
Virus administration 
The virus will be administered through intraperitoneal port-a-cath that will be 
surgically placed at the time of study entry. If ascites is present, it will be drained 
through the port-a-cath prior to administration of MV-NIS. The patient will 
receive infusion of the assigned dose of MV-NIS diluted in 500 ml of NS over 30 
minutes.  The assigned dose of MV-NIS /MSC will be diluted in 500 ml of 
Lactated Ringer’s and administered over 30 minutes (Cycles 2-6). Treatment will 
be administered at the Clinical Research Unit (CRU).  
7.37 
Monitoring by SPECT/CT 
The in vivo distribution of MV-NIS infected cells and the kinetics of virus spread 
and elimination will be monitored by SPECT/CT imaging after oral 123I  
administration (2 hour after 5 mCi).  
SPECT/CT imaging will be performed on Days 3 and 8 after MV-NIS 
administration. In addition patients may be imaged on Days 15 and 28. These 
scans will be elective, based on whether there is continued uptake on prior 
imaging studies. Imaging at the same schedule will be performed in Cycle 2. 
Imaging by SPECT/CT to be performed in Cycle 3, only if positive imaging is 
obtained in Cycle 2. In this case, SPECT/CT imaging in Cycle 3 will be timed to 
correspond to SPECT/CT in Cycle 2. 
7.38 
Administration Setting 
The first and second cycle will be administered in the inpatient setting.  Patients 
will be admitted the evening prior to administration and dismissed 24 hours after 
administration of the agent.  For subsequent cycles, the agent will be 
administered in the outpatient CRU and the patients will be observed in the 
facility for three hours after administration of the agent. A saline lock for IV 
access, if necessary, will be placed prior to viral administration. 
 
 
 

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8.0 
Dosage Modification Based on Adverse Events 
Strictly follow the modifications in this table until individual treatment tolerance can be 
ascertained.  If multiple adverse events are seen, administer dose based on greatest reduction 
required for any single adverse event observed.  Dose modifications apply to the treatment given 
in the preceding cycle and are based on adverse events observed since the prior dose. 
 
ALERT: ADR reporting may be required for some adverse events. See Section 10. 
 Use Common Terminology Criteria for Adverse Events (CTCAE) v4.0  
unless otherwise specified  
CTCAE 
CATEGORY 
ADVERSE EVENT 
AGENT(S) 
DOSE MODIFICATIONS 
BASED ON INTERVAL ADVERSE EVENT 
Investigations 
Grade 3 Platelet 
count decreased  
MV-NIS/  
↓ by one dose level.** 
Grade 3 Neutrophil 
count decreased 
Grade 4 Platelet 
count decreased  
Discontinue treatment and follow up per 
Section 18 
Grade 4 Neutrophil 
count decreased 
All other non-
hematologic 
categories* 
Grade 3 
Nonhematologic 
↓ by one dose level.** 
Grade 4 
Nonhematologic 
Discontinue treatment and follow up per 
Section 18. 
AT SCHEDULED RETREATMENT (e.g. Day 1 of subsequent cycle) 
Investigations 
Grade 3 Platelet 
count decreased  
MV-NIS/ 
MSC 
↓ by one dose level.** 
Grade 3 Neutrophil 
count decreased 
Grade 4 Platelet 
count decreased 
Discontinue treatment and follow up per 
Section 18. 
Grade 4 Neutrophil 
count decreased 
All other non-
hematologic 
categories* 
Grade 3 
Nonhematologic 
Wait until ≤Grade 1  
then retreat per interim toxicity. 
If no resolution within 2 weeks (Week 6), 
discontinue treatment and follow-up per 
Section 18.0  
Grade 4 
Nonhematologic 
Discontinue treatment and follow-up per 
Section 18.0 

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CTCAE 
CATEGORY 
ADVERSE EVENT 
AGENT(S) 
DOSE MODIFICATIONS 
Other specific 
event 
Viremia 
If no resolution within 2 weeks (Week 6), 
discontinue treatment and follow-up per 
Section 18.0 
*Dose modification for nausea and vomiting will be implemented only if they persist despite 
optimal antiemetic treatment. 
** If patient is at lowest level, discontinue therapy and proceed to observation 
 
9.0 
Ancillary Treatment 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, anti-emetics received from the first administration of study 
drugs until 30 days after the final dose are to be recorded in the medical record. 
 
9.2 
Antiemetics and antidiarrheals 
Prophylactic administration of antiemetics or antidiarrheals prior to the first cycle of 
treatment will not be allowed; however, prophylaxis is allowed prior to subsequent cycles 
should a patient develop nausea/vomiting associated with the first treatment cycle. 
• 
Dexamethasone as antiemetic is not allowed. 
Acceptable treatment options for nausea include ondansetron 4 mg PO every 8 hours as 
needed, if still nauseated in one hour may give an additional 4 mg. 
Acceptable treatment options for vomiting include:  First prochlorperazine 10 mg every 6 
hours as needed (if unable to take orally) give 10 mg IV every 6 hours as needed.  Second 
(if still vomiting 30 to 60 minutes status post prochlorperazine) lorazepam 0.5 mg PO 
every 4 hours as needed.  If unable to take oral medications, may administer IV. 
Acceptable treatment options for diarrhea include: First suggest loperamide 4 mg after 
first diarrheal bowel movement and 2 mg after each subsequent one up to 16 mg a day.  If 
diarrhea is not controlled with loperamide, may try atropine sulfate/diphenoxylate 
hydrochloride (Lomotil®) 2 tablets every 6 hours as needed or 10 mL every 6 hours as 
needed. 
Acceptable treatment options for fever include acetaminophen 500-1000 mg every 6 
hours as needed up to 4 grams a day.  If fever is not controlled with acetaminophen or the 
patient has a contraindication to acetaminophen, may give ibuprofen 400 mg every 6 
hours as needed (first) or naproxen 250-500 mg twice daily (second). 
9.3 
Diagnosis of measles 
Diagnosis of measles in this trial is based on the CDC definition of clinical measles and 
includes: 
• 
a generalized rash lasting ≥3 days, and 

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MCCC Addendum 12 
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• 
temperature ≥38.3°C (≥101°F), and 
• 
cough, coryza, and conjunctivitis. 
9.4 
Support if patient is diagnosed with measles 
Should a patient develop measles, treatment with immune globulin will be administered 
at a dose of 400 mg/kg/day for 3-5 days.  Aerosolized ribavirin (6 g/day) can also be 
considered at the discretion of the treating physician for patients not responding to 
immune globulin.  Patients who develop measles will be removed from the trial and 
followed up to 15 years for evidence of persistent toxicity. 
9.5 
Coenrollment in other trials or studies 
Patients participating in Mayo Clinic Cancer Center Phase I Program clinical trials are 
not to be considered for enrollment in any other study involving a pharmacologic agent 
(drugs, biologics, immunotherapy approaches, gene therapy) whether for symptom 
control or therapeutic intent. 
 

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MCCC Addendum 12 
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10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
  
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 version 4.0. 
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.5).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
10.2  
Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific 
consent form. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.0 of the protocol and the study specific consent form. 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
10.3 
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 agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  

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10.4  
Expedited Reporting Requirements for IND/IDE Agents 
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting 
Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization  
≥24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form: 

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or investigational agents or 
commercial/investigational agents on the same arm.  
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
 10.5 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
System Organ Class 
(SOC) 
Adverse 
events/Symptoms 
Baseline 
Each evaluation 
General disorders 
and administration  
Fever 
X 
X 
site conditions 
Chills 
X 
X 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo-papular 
X 
X 
Gastrointestinal  
Diarrhea  
 
X 
disorders 
# of stools 
X 
 
 
Flatulence 
X 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Abdominal pain 
X 
X 
Respiratory, thoracic 
and mediastinal 
disorders 
Dyspnea (shortness of 
breath) 
X 
X 
 
10.51 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 10.6: 
10.511 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.512 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.513 Grade 5 AEs (Deaths) 
10.5131 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.5132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
 

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11.0 
Treatment Evaluation 
For the purposes of this study, patients should be re-evaluated every 4 weeks. In addition to a 
baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. Modified Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria will be used. NOTE: Per Section 7.3, if progressive disease at the end of 
Cycle 1, patient may still proceed with Cycle 2 treatment at the discretion of the treating 
physician, if the progression is asymptomatic. 
11.1 
Definitions 
11.11 Measurable disease: the presence of at least one measurable lesion.  
11.12 Measurable lesions: lesions that can be accurately measured in at least one 
dimension with longest diameter >20 mm. With spiral CT scan, lesion must be  
>10 mm in at least one dimension. 
11.13 Non-measurable lesions: all other lesions, including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm with spiral CT) and 
other non-measurable lesions. These include: ascites; abdominal masses that are 
not confirmed and followed by imaging techniques; and cystic lesions. 
11.2 
Response Criteria 
11.21 Evaluation of target lesions 
A maximum of 3 measurable lesions should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repetitive measurements (either by imaging techniques or clinically).  A sum of 
the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  The baseline sum LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the 
disease. 
 
Complete Response (CR): Disappearance of all target lesions and normalization 
of CA125 if elevated at baseline. 
 
Partial Response (PR): 
At least 30% decrease in the sum of the longest 
diameter (LD) of target lesion taking as reference the 
baseline sum LD 
 
Progression (PD): 
As least a 20% increase in the sum of LD of target 
lesions taking as reference the smallest sum LD 
recorded since the treatment started or the 
appearance of one or more new lesions 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as 
references the smallest sum LD 
 
 
 

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11.22 Evaluation of non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as “present” or “absent.” 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor maker level 
 
Non-Complete 
Response: (non-CR): 
Persistence of one or more non-target lesions or/and 
maintenance of tumor marker level above the normal 
limits 
 
Progression (PD): 
Appearance of one or more new lesions. 
Unequivocal progression of existing non-target 
lesions. Although a clear progression of “non-target” 
lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail, 
and the progression status should be confirmed at a 
later time by the review panel (or study chair) 
 
Note: 
• 
If tumor markers are measured and are initially above the upper normal limit, 
they must normalize for a patient to be considered in complete clinical 
response.   
• 
Cytology and histology. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
These techniques can be used to differentiate between PR and CR in rare 
cases (for example, residual lesions in tumor types such as germ cell tumors, 
where known residual benign tumors can remain).  
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
11.23 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient’s best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
 

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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Notes: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
Note: 
Tumor lesions in a previously irradiated area are not optimally considered 
measurable disease. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
• 
Conventional CT and MRI should be performed with cuts of 10mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to the chest, abdomen, and pelvis.  
11.4 
Confirmatory measurement/Duration of response 
11.41 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed 4 weeks after the criteria 
for response are first met.  In the case of SD, follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum interval of 6 
weeks. 
11.42 Duration of overall response 
The duration of overall response is measured from the time measurement criteria 
are met for CR/PR (whichever is first recorded) until the first date that recurrent 
or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). 

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The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease 
is objectively documented. 
11.43 Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded 
since the treatment started.  
11.5 
Evaluation criteria for patients enrolled in the study based on a positive second look or 
after secondary debulking but without measurable disease 
Patients will be monitored radiographically for reappearance or increasing parameters of 
disease.  Use of only the CA-125 tumor marker will not be taken as an indicator of 
progression.  Patients who have not progressed after 6 cycles of treatment will have a 
laparoscopy performed for evaluation of treatment efficacy. 
 
12.0 
Descriptive Factors 
12.1 
Ascites present: Yes vs. no. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
No PD and no intolerable toxicity 
Patients who have not had PD at time of their reassessment and have not experienced 
intolerable toxicity will be allowed to continue protocol treatment until PD or for a 
maximum of 6 cycles. 
13.2 
Stable disease 
Patients who experience regression or stable disease will be allowed to continue 
treatment for up to 6 cycles. 
13.3 
No PD and intolerable toxicity 
Those patients who have not had PD but have experienced unacceptable toxicity may be 
eligible for retreatment at a lower dose (see Section 8.0). 
13.4 
Observation/Completion of 6 cycles without PD 
Those patients who have  
• 
completed 6 cycles of treatment without PD or  
• 
have documentation of PD prior to completion of 6 cycles or  
• 
who refuse further treatment or  
• 
start alternate treatment or  
• 
have unacceptable toxicities necessitating the stopping of treatment  
will go off treatment and will be followed for observation per the test schedule. Patients 
will stay on observation until 1 year post-PD/alternate treatment per Section 4.0, then go 
to event monitoring. NOTE: Patients who refuse to return for observation will go to event 
monitoring. 
13.5 
Event Monitoring 
Those patients completing observation or refusing to participate in observation will go to 
event monitoring per Section 18.13. If a patient does not have progressive disease at any 

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time during the study (treatment/observation/event monitoring), at least one (1) Event 
Monitoring form is required to be completed preferably at the end of event monitoring. 
13.6 
Replacement 
If a patient enrolled in the phase I component fails to complete the initial course of 
therapy (defined as MSC drug administration on Cycle 2 and four weeks observation) for 
reasons other than toxicity, the patient will be regarded as treatment intolerant and an 
additional patient will be treated at the current dose level; however, all toxicity 
information will be utilized in the analysis. For these instances, a specific notation will be 
made for review by the Scientific Progress Review Committee (SPRC). 
13.7 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol. 
13.8 
Major Violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per section 18.0 of the protocol. 
13.9 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. The patient will go directly to the event-monitoring 
phase of the study, and event monitoring will be required per Section 18.0 of the 
protocol. 
 

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14.0 
Pharmacologic/Correlative  
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
Correlative 
Study (Section 
for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect (# of 
tubes to be 
collected) 
Pre-
Treatment-
At 
peritoneal 
catheter 
placement 
Cycle 1, 
Day 1 
(prior to 
treatmen
t as base-
line) 
Cycles 1 
& 2  
Day 3 
Cycles 1 
& 2  
Day 8 
Cycles 1 
& 2  
Day 15 
and 23 
(±72 hrs) 
Cycles 2-6, 
Day 1 
(prior to 
treatment) 
Cycles 3-
6,  
Day 3, 
23  
(±72 hrs) 
Process at 
CRU 
site? (Yes 
or No) 
Temperature 
Conditions 
for Storage 
Shipping 
Peritoneal 
aspirate 
collection 
(See Section 
14.21) 
Mandatory Peritoneal 
aspirates 
300 mL 
Sterile  
All available 
X3 
 
X 
X 
 
X2 
 
NO draw 
only 
On ice 
Viremia 
Mandatory 
Whole 
Blood 
PAXgene 
Blood 
RNA tubes 
2.5 mL 
 
X 
X 
X 
X 
 
X 
NO draw 
only 
Ambient 
(whole 
blood)  
Viral shedding Mandatory 
Urine 
50 mL 
sterile 
tubes-
falcon 
200 mL -4 
50mL tubes 
 
X 
X 
X 
X1 
 
X 
Yes 
On ice, then 
freeze after 
processing 
Viral shedding Mandatory 
Mouth 
gargle 
50 mL 
sterile 
tubes-
Falcon 
2 X 15mL 
 
X 
X 
X 
X1 
 
X 
Yes 
On ice, then 
freeze after 
processing 
Immune 
response to 
viral 
administration 
Mandatory 
Whole 
Blood 
7 green top 
tubes 
7 x 10 ml  
 
X 
 
 
 
X 
 
NO draw 
only 
Ambient 
(whole 
blood) 
Immune 
response 
against the 
tumor 
Mandatory 
Whole 
Blood 
1 red top 
tube 
1 x 10 ml  
 
X 
 
 
 
X 
 
NO draw 
only 
Ambient 
(whole 
blood) 
1.  Day 23 only 
2. Cycles 3-6 only 
3. Only for patients who have peritoneal catheter placement as part of the trial 

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14.2  
Collection and Processing 
14.21 Evaluation of peritoneal aspirate (ascitic fluid or lavage at the absence of ascites). 
Previous studies of intraperitoneal chemotherapy have shown the feasibility of 
retrieval of carcinoma cells for pathologic evaluation [15,16]. Harvested cellular 
material will be tested prior to treatment and on Days 3 and 8 Cycles 1 and 2, and 
again prior to treatment for Cycles 3-6 for: a) viral replication (RT-PCR and co-
culture with Vero cells); b) in situ hybridization for measles virus N-specific 
mRNA. Supernatant from the peritoneal aspirate will be tested for: a) viral 
replication (co-culture with Vero cells); b) anti-measles virus antibodies at 
baseline, Days 3 and 8 of Cycle 1, Day 1 of Cycle 2 prior to treatment, Day 3 and 
8 of Cycle 2 and prior to treatment Cycles 3-6. If in addition to peritoneal 
aspirate, a biopsy is obtained post treatment, tumor and adjacent peritoneum will 
be examined for cytopathic effect and tested for viral replication and in situ 
hybridization. Testing will be performed in 
laboratory. All 
attempts to obtain peritoneal fluid will be made per Section 14.0, but it will not 
be a protocol deviation if no peritoneal fluid is collected on patients whose port is 
not easily accessed. 
14.22 Assessment of viremia and viral shedding. Patient’s peripheral blood 
mononuclear cells will be monitored for evidence of measles virus viremia. This 
monitoring will be performed by collecting 2.5 ml of blood in PAXgene Blood 
RNA tubes (2 tubes per each time point draw) according to the manufacturer’s 
recommendations (Qiagen). The PAXgene Blood RNA tube, is part of a system 
used to collect blood for RNA extraction ona proprietary reagent that 
immediately stabilizes intracellular RNA for three days at room temperature (18 
to 25C) and five days when kept in a regular fridge (2 to 8C). Tubes will be kept 
at room temperature and 
notified to pick up the samples. 
Quantitative RT-PCR to be performed prior to treatment, on Day 1, then on Day 
3, 8, 15 and 23 of Cycles 1 and 2, and on Day 1, 3, and 23 for Cycles 3-6. Viral 
shedding will be assessed by quantitative RT-PCR of throat gargle specimens(s) 
and urine samples, both being processed under sterile conditions on Days 1, 3 8, 
of Cycles 1 and 2, prior to treatment on Day 1 Cycle 3-6 . Testing will be 
performed in 
laboratory.  
Sample processing in GCRC for Viremia and viral shedding will be done using 
sterile techniques and laminar flow hood. Mouth wash (gargle) samples consist 
of 2 x 15 ml of commercial Scope mouth rinsing fluid (or equivalent) that are 
gargled in the back of the throat (not swished in the mouth) and then are 
collected in 50 ml sterile conical tubes (a total of 15 ml needs to returned for 
further processing), spun down at 3000rpm and the supernatant discarded. The 
remaining pellet is suspended in 1 ml Trizol reagent (Invitrogen Cat #15596026-
100ml, or Cat# 10296028-200ml, mixed well and transferred to sterile 2 ml 
cryovials. The samples are kept in a negative 80 freezer until picked up by 
 
 laboratory personnel. 
will be notified to pick up the 
samples. 
Urine will be collected by clean catch method in a container set up by nursing, 
then transferred to sterile 50ml tubes (a maximum of eight tubes will be 
processed for each time point). The tubes are spun down at 3000 rpm, the 
supernatant discarded and 1 ml Trizol reagent added to each pellet, mixed well 
and each pellet transferred to a 2 ml cryovial. The samples processed will be kept 

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in a negative 80 degree Celsius freezer. 
will be notified to pick 
up the samples.  
If a patient is found to be shedding the virus in urine or throat gargle 
specimens(s), family members who don’t have documentation of immunity, will 
be offered testing to assess anti-measles virus immunity by Enzyme 
Immunoassay (Diamedix, see section 3.18) and testing of throat gargle 
specimens(s) for the presence of MV-NIS. Measles vaccination will be offered to 
seronegative individuals, per standard clinical practice. 
14.23 Assessment of peripheral immune response to viral administration: measles virus 
specific immunity will be measured by means of (a) measuring anti-measles 
virus specific antibodies (IgG) at baseline, and day 1 of cycle 2-6 prior to 
treatment and (b) IFN-γ and IL-10 measles ELISPOT [17] to be performed at 
baseline, and day 1 of cycle 2 prior to treatment and day 1 prior to treatment 
cycle 3 -to 6.  This testing will be performed in 
laboratory.  
Cells received from 
 from 
 
14.24 Assessment of immune response against the tumor. This will be assessed by 
evaluating the immune response against insulin-like growth factor binding 
protein 2 and the folate receptor alpha [18], using IFN-gamma and IL-4 
ELISPOT assays and cytokine multiplex analysis (17-plex) to be performed at 
baseline, and prior to treatment day 1 of cycles 2-6. These assays will be 
performed at the laboratory of 
 as previously described 
[18].  IFN-gamma and IL-4 ELISPOT assays will determine the frequencies of 
Th1 and Th2 tumor antigen specific T cells, respectively.  Cytokine multiplex 
assays will evaluate the levels proinflammatory cytokines in both the cellular 
supernatants and the serum, to identify the breadth (i.e. polyfunctionality) of the 
immune responses. 10 ml of blood will be drawn into 7 green-top heparin tubes 
and 1 red top sera clot tube and kept at room temperature. 
will be 
notified to pick-up the samples and transfer to 
 lab. 
 
 
 

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15.0 
Drug Information 
15.1 
MV-NIS (NIS-Measles Virus – Edmonston Strain) 
15.11 Background: 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.  
15.12 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. 
15.13 Administration: The virus will be administered intraperitoneally over 30 
minutes in 500mL of 0.9% Sodium Chloride under close observation in the 
Clinical Research Unit. 
15.14 Known potential toxicities 
The most common adverse effect noted is burning and stinging at the site of 
injection; however, this is not applicable in this study given intraperitoneal 
administration. Occasionally, moderate fever 38.3°-39.4°C has been noted in the 
month after vaccination, usually within 5-12 days after injection. Rash, which is 
usually minimal, has been noted. Less commonly, high fever (over 39.4°C) or 
mild lymphadenopathy have been reported.  
Occasional reactions: 
• 
Moderate to high fever lasting 1-2 days, starting within a week or two of the 
vaccination 
• 
A rash, lasting 1-2 days 
• 
Cough and rhinitis 
• 
Erythema multiforme (skin rash) 
Unexpected and rare reactions associated with measles vaccines: 
• 
Allergic reactions to the vaccine including anaphylaxis  
• 
Reactions at the injection site such as wheal, flare or pruritus 
• 
Thrombocytopenia 
• 
Diarrhea 
15.15 Nursing guidelines 
Due to the very early investigational nature of this drug, no nursing guidelines 
are known.  Please monitor patients closely and follow Section 10.0.  More than 
90% of the U. S. population has measles virus immunity as a result of natural 
infection or immunization.  Immune status for measles virus is mandatory for 

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Mayo Medical Center personnel.  Therefore administration of the agent is not 
expected to result in any risk for nursing or ancillary staff. 
15.2 
MV-NIS/MSC (Mesenchymal Stem Cell (MSC) infected with NIS-Measles Virus – 
Edmonston Strain) 
15.21 Background: Mesenchymal Stem cells will be processed in Human Cellular 
Therapy Lab (HCTL) in Rochester, MN. The MV-NIS/MSC combination 
facilitates the delivery of the MV-NIS to the tumor cells, by allowing the MSC to 
protect the MV-NIS from immune destruction before arriving at the tumor sites. 
15.22 Preparation and storage: Upon consent and enrollment and prior to Cycle 1, 
patients will undergo fat aspiration at the time of catheter placement. Tissue will 
be transported to the Human Cellular Therapy Lab (HCTL) in Rochester, MN for 
manufacturing and freezing. Manufacturing will start with enzymatic digestion of 
the fat tissue followed by expansion of plastic-adherent cells. Cells will be 
cultured until a sufficient number are obtained for the treatment protocol.  At the 
final passage, cells will be harvested/pooled and pre-freeze characterization 
samples will be removed.  Testing prior to frozen storage will include aerobic 
and anaerobic culture, endotoxin, mycoplasma PCR, karyotype, and flow 
cytometry for markers characteristic of MSC. After release and on the day of 
infusion, i.e. Cycles 2-6, the appropriate number of cryovials/cells will be 
removed from the freezer, thawed, washed (to remove DMSO), infected with 
MV-NIS for 2 hours and combined into a single, final product (500 mL bag of 
Lactated Ringer’s).  Final product assessment will include viability, gram stain, 
aerobic and anaerobic cultures, and endotoxin.  Product will be labeled and made 
available for infusion if all release criteria are met (See Certificate of Analysis 
for specific release criteria). Standard operating procedures (SOPs) have been 
developed solely for production of h-MSC and have been used under previous 
INDs (BB IND 14788, and BB IND 15176) and for production of MV-NIS 
(IND10895)   
15.23 Administration: MV-NIS/MSC will be administered intraperitoneally over 30 
minutes in 500 mL Lactated Ringer’s at the Clinical Reseach Unit. 
15.24 Potential Drug Interactions:  No drug interactions are known at this time.   
15.25  Known potential toxicities 
The most common adverse effect noted is burning and stinging at the site of 
injection; however, this is not applicable in this study given intraperitoneal 
administration. Occasionally, moderate fever 38.3°-39.4°C has been noted in the 
month after vaccination, usually within 5-12 days after injection. Rash, which is 
usually minimal, has been noted. Less commonly, high fever over 39.4°C or mild 
lymphadenopathy have been reported.  
Occasional reactions: 
• 
Moderate to high fever lasting 1-2 days, starting within a week or 
two of the vaccination 
• 
A rash, lasting 1-2 days 
• 
Cough and rhinitis 
• 
Erythema multiforme (skin rash) 
 
Unexpected and rare reactions associated with measles vaccines: 
• Allergic reactions to the vaccine including anaphylaxis  

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• Reactions at the injection site such as wheal, flare or pruritus 
• Thrombocytopenia 
• Diarrhea 
 
15.26 Drug procurement:  MV-NIS is manufactured by the Virus and 
Vector Production Laboratory (VVPL) of the Molecular Medicine Program at 
Mayo Clinic and stored at -80°C.  When administered as a single agent, the virus 
will be thawed and mixed with normal saline prior to administration.  The MV-
NIS/MSC mixture will be prepared in the Human Cellular Therapy 
Laboratory.   Product ready for administration will be delivered by HCTL staff to 
the patient bedside or clinical ward for administration. 
 
15.27 Nursing Guidelines:  Due to the very early investigational nature of this drug, 
no nursing guidelines are known.  Please monitor patients closely and follow 
Section 10.0.  More than 90% of the U. S. population has measles virus immunity 
as a result of natural infection or immunization.  Immune status for measles virus 
is mandatory for Mayo Medical Center personnel.  Therefore administration of 
the agent is not expected to result in any risk for nursing or ancillary staff. 
15.3 
Liothyronine for Oral Administration (Cytomel®, T3) 
15.31 Background: Liothyronine (T3) is a thyroid product. The principal 
pharmacologic effect of exogenous thyroid hormones is to increase the metabolic 
rate of body tissues. Thyroid hormones are also involved in the regulation of cell 
growth and differentiation. Although the precise mechanism of action by which 
thyroid hormones affect metabolism and cellular growth and differentiation is not 
clearly established, it is known that these physiologic effects are mediated at the 
cellular level, principally via triiodothyronine; a major portion of 
triiodothyronine is derived from thyroxine by deiodination in peripheral tissues. 
Sound-alike/look-alike issues: Do not confuse with levothyroxine. T3 is an error-
prone abbreviation (mistaken as acetaminophen and codeine [i.e., Tylenol #3]. 
 
15.32 Formulation: Commercially available for oral administration as:  
Tablets: 5 mcg, 25 mcg, 50 mcg  
 
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).  
 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. Sound-alike/look-alike issues: Do not confuse with levothyroxine. 
T3 is an error-prone abbreviation (mistaken as acetaminophen and codeine [i.e., 
Tylenol #3]. 
 
15.35 Pharmacokinetic information: 
Protein binding: low 
Bioavailability: >95% 
 
15.36 Potential Drug Interactions: 
Oral Anticoagulants: Thyroid agents may potentiate the 
hypoprothrombinemic effect of warfarin and other oral anticoagulants, 
apparently by increasing catabolism of vitamin K-dependent clotting 

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factors. When thyroid agents are administered to patients receiving oral 
anticoagulants, the prothrombin time should be determined frequently and 
anticoagulant dosage adjusted accordingly, and patients should be 
observed closely for adverse effects. It has been suggested that the dosage 
of the oral anticoagulant be reduced by one-third when thyroid therapy is 
started. No special precautions appear to be necessary when oral 
anticoagulant therapy is initiated in patients already stabilized on 
maintenance thyroid replacement therapy. 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, > 10%:   
Because the treatment is short term only for cancer clinical trials only mild 
and transient side effects are expected. These include: 
Cardiac: tachycardia, transient atrial fibrillation, cardiac arrhythmia 
CNS: feeling of warmth, anxiety, insomnia 
Neurologic: tremor 
 
Less common known potential toxicities, 1% - 10%:  
See below 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
 
Liothyronine shares the toxic potentials of other thyroid agents, and the 
usual precautions of thyroid agent therapy should be observed. Adverse 
reactions to Liothyronine result from over dosage and are manifested 
principally as signs and symptoms of hyperthyroidism including fatigue, 
weight loss, increased appetite, palpitations, nervousness, hyperactivity, 
anxiety, irritability, emotional lability, diarrhea, abdominal cramps, 
vomiting, elevated liver transaminase concentrations, sweating, 
tachycardia, increased pulse and blood pressures, angina pectoris, cardiac 
arrhythmias, tremors, muscle weakness, headache, insomnia, intolerant to 
heat, fever, hair loss, flushing, decreased bone mineral density, impaired 
fertility, and menstrual irregularities. Complications of severe over dosage 
may include cardiac decomposition, cardiac failure, myocardial infarction, 
cardiac arrest, and possibly death secondary to cardiac arrhythmia or 
failure. Seizures have been reported rarely with levothyroxine therapy. The 
effects of Liothyronine may appear within 24 to 72 hours after initiation of 
therapy or an increase in dosage.  
 
Hypersensitivity reactions to excipients in formulations of thyroid agents 
have been reported rarely. Manifestations include urticaria, pruitus, skin 
rash, flushing, angioedema, various GI symptoms (abdominal pain, 
nausea, vomiting, and diarrhea), fever, arthralgia, serum sickness, and 
wheezing. Thyroid also may rarely cause GI intolerance in patients highly 
sensitive to pork.  
 

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15.38 Drug procurement:  Provided free of charge to study participants.  Pharmacies 
or clinics shall obtain supplies from normal commercial supply chain or 
wholesaler. 
 
15.39 Nursing Guidelines 
 
15.391 Patients who are on concomitant oral anticoagulants should have their 
PT/INR monitored frequently and adjust doses accordingly. 
  
15.392 Patients may experience tachycardia, transient A-fib or other cardiac 
arrhythmia. Instruct patient to report any palpitations, or chest pain to 
study team immediately. 
 
15.393 Patients may experience mild flushing. Warn patient of side effect 
 
15.394 Insomnia may be seen. Instruct patient in good sleep hygiene methods, 
medicinal sleeping aids may be needed. Monitor for effectiveness. 
 
15.395 Patients may experience tremor.  
 
15.396 Monitor for signs/symptoms of overdose (as listed above). Usually these 
symptoms will present themselves within 24-72 hours of initiating of 
therapy or increase in dosage. 
 
 

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16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This is a Phase I/II study designed to (a) determine the MTD and toxicity of attenuated 
MV-NIS virus with MSC delivery in the treatment of ovarian tumors in the phase I 
component, and to (b) assess 12-month overall survival of ovarian cancer patients 
receiving this regimen, (c) assess 4-month progression free survival of ovarian cancer 
patients receiving the regimen, (d) assess toxicities associated with this regimen, (e) 
assess progression free and overall survival of ovarian cancer patients treated with this 
regimen, and (f) assess translational research endpoints in the phase II component.  
16.2 
Phase I Component 
16.21  Study Design 
The single arm phase I component is using the standard 3+3 design for phase I 
clinical trials [15, 16].  
16.22  MTD Definition and Determination. 
The MTD Definition: MTD is defined as the dose level below the lowest dose 
that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 
2 of a maximum of 6 new patients). A total of 6 patients treated at the MTD will 
be sufficient to identify common toxicities at the MTD. For instance, those 
toxicities with an incidence of at least 25% will be observed with a probability of 
at least 82% (1-(1-0.25)6). 
The MTD Determination: 
16.221 
The first cohort of 3 patients will be treated at the starting dose level 0. 
16.222 
Three patients will be treated at a given dose level and observed for at 
least 4 weeks from start of cycle 2 of treatment to assess toxicity.  
16.223 
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. If DLT is seen 
in 2 or 3 of 3 patients treated at a given dose level, then the next 3 
patients will be treated at the next lower dose level, if only 3 patients 
were enrolled and treated at this lower dose level. 
16.224 
If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. 
If DLT is seen in at least one of these additional three patients (≥2 of 
6), the MTD will have been exceeded, and further accrual will cease to 
this cohort. If dose-limiting toxicity (DLT) is not seen in any of the 
three additional patients, 3 new patients will be accrued and treated at 
the next higher dose level.  
16.225 
After enrolling 6 patients on a specific dose level, if DLT is observed 
in at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at 
this lower dose level such that a total of 6 patients are treated at the 
MTD to more fully assess the toxicities associated with the MTD. 
16.23 Accrual and study duration.  
Patients will be accrued in cohorts of 3. The phase I component may require as 
many as 18 patients (6 each for the 3 dose levels) but is more likely to require 9 

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patients (3 at dose level 0 and 6 at dose level 1). It is expected to take 
approximately 5 months to assess each cohort of 3 (2 months to accrue 3 patients, 
2 months for evaluation of cycle 2, and 1 month for data collection and analysis); 
thus the expected study duration of the phase I component is 15 months. 
16.24  Phase I Analyses 
The number and severity of all adverse events (overall, and by dose-level) will be 
tabulated and summarized. The grade 3+ adverse events will also be described 
and summarized in a similar fashion. Overall toxicity incidence as well as 
toxicity profiles by dose level and patient will be explored. Frequency 
distributions, graphical techniques and other descriptive measures will form the 
basis of these analyses. 
Although correlative samples will be collected for all patients (Phase I and II), 
only the phase I patients treated at the MTD will stay on-study for the Phase II 
portion and be included in the efficacy and translational analyses. 
16.3 
Phase II Component  
16.31  Overview 
The phase II component is a single arm, two stage Simon design to determine 
efficacy of the MV-NIS regimen.  
16.32  Primary Endpoint  
The primary endpoint of this trial is the proportion of patients alive at 12 months 
(i.e., 365 days) after study registration (OS12). An eligible patient who signs the 
consent form, begins study therapy, and are not lost to follow-up before 12 
months will be considered evaluable for assessment of treatment efficacy. To be 
classified as a “success”, a patient must be evaluable and be alive at least 12 
months (i.e., 365 days or more) after registering to the study. If the patient is lost 
to follow-up prior to being on-study for 12 months, they will be considered 
unevaluable and will be replaced for these analyses. 
Note: To obtain estimates of the proportion of patients achieving OS12 under the 
null hypothesis, we reviewed recent literature of clinical trials for recurrent 
platinum resistant ovarian cancer. A recent phase III trial [22] of PLD +/- 
patupilone patients in 829 patients with platinum resistant OVCA (progressed 
within 6 months of most recent platinum regimen) had OS12 of 53% across both 
arms; however, most patients (74%) had received only a single prior regimen. 
Another recent randomized phase II trial [23] of weekly versus 5-day topotecan 
assessed 194 patients with platinum resistant (progressed within 6 months 
following a platinum regimen) or platinum refractory (stable or progressive 
disease while being given platinum) OVCA and found a median survival of 9.3 
and 9.6 months in the two arms, corresponding to an OS12 of approximately 
40%; most patients (74%) had received a single prior regimen. An older [24] 
randomized phase III study of PLD vs. topotecan showed 1 year survival of 
41.5% and 43.2% for platinum refractory patients (n=255) in the two arms. In 
addition, a recent characterization [25] of survival in 2nd through 6th line therapy 
in relapsed ovarian cancer indicated a median OS of 17.6 months at first relapse, 
11.3 months at second relapse, and 8.9 months at third relapse. Thus, given the 
median number of prior therapies in the previous MV-CEA and MV-NIS trials 
was 3 and 4, respectively, using the same eligibility criteria as the currently trial, 
we conservatively estimate an OS12 rate of 40% under the null hypothesis. 

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16.33 Analysis Plans 
The proportion of successes will be estimated by the number of successes divided 
by the total number of evaluable patients. Ninety-five percent binomial 
confidence intervals for the true success proportion will be calculated. 
16.34 Design, Power, and Significance Level 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 40%, and the smallest that would 
warrant further subsequent studies is 62.5%. This design uses 24 evaluable 
patients to test the null hypothesis that the true complete response rate is at most 
40%. Based on the design above, the decision rule has 90% power to detect a true 
success proportion of 62.5% with an alpha of 0.10. 
First Stage: Enter 12 evaluable patients to the study. The 6 patients treated at the 
MTD in the phase I portion of the study will be included in this 12-patient total. 
If at most 5 successes in the first 12 evaluable patients, this regimen will be 
considered ineffective in this patient population and the study will be terminated. 
Otherwise, if the number of successes is at least 6, accrual will continue. 
Final Decision rule: If 12 or fewer successes are observed in the first 
24 evaluable patients, we will consider this regimen ineffective in this patient 
population. Otherwise, if the number of successes is at least 13, this will be 
considered evidence of promising activity, and the treatment may be 
recommended for further testing in subsequent studies. 
16.35  Over Accrual 
If more than the target number of patients is accrued, the additional patients will 
not be used to evaluate the final decision rule. However, they will be included in 
the final analyses, which are described in section 16.33. 
16.36  Adverse Event Stopping Rule:  
If 4 out of the first 12, or 8 out of the first 24 or if at any time after the first 24 
patients enrolled, 33% or more experience an adverse event that follows the DLT 
definition as listed in Section 7.22 on any cycle of treatment, accrual to the trial 
will be temporarily suspended. All AE data will be reviewed by the study team 
and the FDA before a decision can be made regarding whether the trial can re-
open with the same dosing, amended dosing, or permanently closed.  
16.37  Other Considerations:  
Overall survival, time to progression, toxicity, and correlative measurements 
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 
16.38   Secondary/Tertiary Analyses: 
16.381 A confirmed tumor response is defined to be a CR or PR noted as the 
objective status on 2 consecutive evaluations at least 4 weeks apart. All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response. 
16.382 Progression-free survival at 4 months (PFS4). To compare the 
progression-free survival of MV-NIS/MSC in reference to outcomes 
previously observed on patients treated with MV-NIS and MV-CEA, as 
another indicator of improved efficacy we will assess the rate of patients 

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achieving PFS4. Patients who are alive and progression free 4 months 
(121 days) after study registration will be considered a success for PFS4. 
The rate of PFS4 on the prior MV-CEA and MV-NIS trial was 
approximately 24%. 
16.3821 Test of improved PFS4 on MV-NIS/MSC compared to MV-
NIS and MV-CEA. This decision rule uses a single stage 
design with a maximum of 24 patients to test the secondary 
null hypothesis that the true success proportion in the given 
patient population is at most 25%. If 2 or fewer successes are 
observed in the first 24 evaluable patients, we will consider the 
PFS4 in the MV-NIS/MSC regimen to be no greater than the 
PFS4 observed in the MV-NIS and MV-CEA trial. If 3 or 
more successes are observed in the first 24 evaluable patients, 
we will conclude that this treatment regimen has adequate 
evidence of improved efficacy on MV-NIS/MSC as measured 
by PFS4 compared to MV-NIS and MV-CEA.  
With 24 patients, the study has 90% power at an alpha of 0.10 
to conclude the current regimen has improved PFS4 if the true 
PFS4 rate is at least 45% 
16.383 Overall survival is defined to be the length of time from study 
registration to a date of death due to any cause or last follow-up. The 
distribution of survival time will be estimated using the method of 
Kaplan-Meier. 
16.384 Progression-free survival is defined to be the length of time from study 
registration to the first of either death due to any cause or progression. 
Patients that have not died or progressed will be censored on their last 
follow-up date. If a patient dies without documentation of disease 
progression, the patient will be considered to have had tumor progression 
at the time of death unless there is sufficient documented evidence to 
conclude no progression occurred prior to death. The distribution of 
progression-free survival will be estimated using the method of Kaplan-
Meier. 
16.385 Kaplan-Meier survival curves and logrank tests will be used to estimate 
the survival and progression-free time distributions of (a) the study 
patients and (b) study patient subsets defined by disease and/or 
correlative characteristics. These analyses are intended to be hypothesis 
generating and descriptive in manner. In addition, comparisons of overall 
PFS and OS in patients treated with MV-NIS/MSC will be made to 
patients enrolled on the prior MV-CEA and MV-NIS trial in an 
exploratory manner. 
16.386 Toxicity:  
All eligible patients that have initiated treatment will be considered 
evaluable for toxicity analyses. The maximum grade for each type of 
toxicity will be recorded for each patient, and frequency tables will be 
reviewed to determine toxicity patterns. 

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16.387 Translational Research Endpoints: 
All analyses with respect to the translational component of this study are 
intended to be hypothesis-generating and descriptive in nature. Data will 
be gathered for a number of laboratory correlative variables as described 
above (i.e. anti-measles virus antibody and the presence of replicating 
virus, see 2.23) for each patient. Descriptive statistics and simple 
scatterplots will form the basis of presentation of these data. Correlations 
between these laboratory values and other outcome measures will be 
carried out using Spearman’s coefficients, chi-squared tests, Wilcoxon 
rank-sum tests, Kaplan-Meier curves, and Cox proportional hazards 
models, where appropriate. 
16.4 
Routine Monitoring  
This study will be monitored by the Mayo Clinic Cancer Center Data Safety Monitoring 
Board. In addition, efficacy, toxicity, and administrative information for this trial will be 
reviewed by the study team twice per year in conjunction with the DSMB review. The 
study team will monitor the trial for evidence of severe adverse effects and feasibility 
problems. 
16.5 
Inclusion of Women and Minorities 
16.51  This study will be available to all eligible patients regardless of race or ethnic 
group. 
16.52  There is no information currently available regarding differential agent effects of 
this regimen in subsets defined by race or ethnicity, and there is no reason to 
expect such differences exist. Therefore, although the planned analyses will, as 
always, look for differences in treatment effect based on racial groupings, the 
samples sizes are not increased in order to provide additional power for such 
subset analyses. 
16.53 Based on Mayo Clinic Cancer Center studies involving similar disease sites, we 
expect about 5% patients will be classified as minorities by race and 100% of 
patients will be women.  
The expected accrual by gender and racial/ethnic group is summarized in the following 
table (based on goal of 5% minority accrual and 100% accrual of women): 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2 
0 
0 
2 
Not Hispanic or Latino 
34 
0 
0 
34 
Ethnic Category: Total of all subjects 
36 
0 
0 
36 
Racial Category 
 
American Indian or Alaskan Native 
1 
0 
0 
1 
Asian 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
35 
0 
0 
35 
Racial Category: Total of all subjects 
36 
0 
0 
36 
 

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

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17.0 
Pathology Considerations: 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of Tissue to 
Collect 
Block, Slides, 
Core, etc. (# of 
each to submit) 
At peritoneal 
catheter 
implantation 
Process at 
site? (Yes 
or No) 
Temperature 
Conditions for 
Storage /Shipping 
Tumor biopsy 
Mandatory Formalin Fixed 
and Frozen 
Biopsy 
X1 
Yes 
Ambient 
Formalin Fixed 
and (-80º C) snap 
frozen 
Benign sample 
Mandatory 
Formalin Fixed 
and Snap Frozen 
Benign tissue 
Tissue piece 
X1 
Yes 
Ambient 
Formalin Fixed 
and (-80º C) snap 
frozen 
Fat Aspirate 
Mandatory 
Fat Aspirate 
Tissue 
X 
Yes 
Placed in Sterile 
Buffered Saline, 
then freeze after 
processing 
1. If patient already has a port at the time of study enrollment, archived tumor tissue, one H&E 
slide and 5 unstained slides should be requested. 
17.2  
Collection and Processing 
17.21 At the time of the catheter implantation, two samples will be obtained. 
Approximately one teaspoon of fat will be collected through the incision (only fat 
grossly free of tumor will be collected) and a tumor Biopsy is to be performed if 
medically feasible when surgeon is placing the port. When possible, tumor 
and benign tissue will be collected in the OR, processed by the frozen section lab 
(specify one snap frozen and one FFPE, and sent to PRC), with the request to call 
and page 
 
17.22 At the time of catheter implantation, fat aspirate will be collected. The surgeon 
placing the catheter will be performing the procedure. Once it is collected, it will 
be placed in Sterile Buffered Saline and transported to the Human Cellular 
Therapy Laboratory at Hilton 2-68 for manufacturing and freezing. 
Manufacturing will start with enzymatic digestion of the fat tissue followed by 
expansion of plastic-adherent cells. Cells will be cultured until a sufficient 
number are obtained for the treatment protocol. At the final passage, cells will be 
harvested/pooled and pre-freeze characterization samples will be removed. 
Testing prior to frozen storage will include aerobic and anaerobic culture, 
endotoxin, mycoplasma PCR, karyotype, and flow cytometry for markers 
characteristic of MSC. After release and on the day of infusion, i.e. Cycles 2-6, 
the appropriate number of cryovials/cells will be removed from the freezer, 
thawed, washed (to remove DMSO), infected with MV-NIS for 2 hours and 
combined into a single, final product (500 mL bag of Lactated Ringer’s). Final 
product assessment will include viability, gram stain, aerobic and anaerobic 
cultures, and endotoxin. 
Alternatively, the fat aspirate can be obtained by Human Cellular Therapy 
Laboratory (IMPACT) personnel using the IMPACT standard SOP at the 
CRTU/Charlton 7. 

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18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetables 
18.11 Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
≤2 weeks after registration 
Baseline Adverse Event Form  
Laboratory Form Baseline 
Pretreatment RECIST Measurement Form1 
Research Submission Form  
Concomitant Medication (Baseline – Prior to 
Catheter Placement) 
Concomitant Medication (Baseline – Prior to 
Cycle 1) 
 
Research Tissue Submission Form 
(Baseline) 
At peritoneal catheter implantation 
End of Active Treatment/Cancel 
Notification Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1. Post-catheter scan 
18.12 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
(end of 
Cycle 6) 
Observation 
Evaluation/Treatment Form Cycle 1 
X2 
X 
 
Evaluation/Treatment Form Cycles 2-6 
X2 
X 
 
Evaluation/Observation Form 
 
 
X1 
Active Monitoring RECIST Measurement 
Form 
X 
X 
X1 
Nadir/Adverse Event Form 
X 
X 
X1 
Laboratory Form(see section 4.0) 
X 
X 
X1 
Concomitant Medication Form 
X 
X 
 
Research Submission Form 
X (see Section 14.0) 
 
 
End of Active Treatment/Cancel 
Notification Form 
 
X 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
1. Complete at each evaluation during Observation (see Section 4.0). 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
 
 

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18.13 Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
q. 6 mos. 
Death 
Event Monitoring Form2 
X 
X 
1. If a patient is still alive 5 years after registration, no further follow-up is required, but 
at least one (1) event monitoring form must be completed for all patients to record 
progression status. 
2. Note: Submit documentation of progression via attachment in Medidata Rave . 
 
19.0 
Budget Considerations 
MV-NIS 
19.1 
Costs charged to patient 
Routine clinical care 
Participants will not be billed for room and board or nursing charges while at the Clinical 
Research Trials Unit (CRTU). However, the participant may be billed for ancillary 
expenses such as any oral medications prescribed at the time of discharge. 
19.2 
Tests to be research funded 
The MV-NIS and adipose tissue derived mesenchymal stem cells will be provided free-
of-charge by Mayo Clinic. Insertion of the port-a-cath, cost of liothyronine sodium 
(Cytomel®), all pharmacological/correlative studies, and procedures done solely for 
study purposes, such as SPECT/CT scans (covered by the Ovarian SPORE and the 
FAMSEA Study Budget). 
 
 

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