Clinical trial NCT02312245
Conditions: Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma
Sponsor: Mayo Clinic
Start date: 2015-07-21; Completion date: 2023-04-24
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well Avatar-directed chemotherapy works in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that does not respond to platinum anti-cancer drugs. Drugs used in chemotherapy, such as paclitaxel, gemcitabine hydrochloride, pegylated liposomal doxorubicin hydrochloride, topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Using an Avatar, a living tumor sample with similar genetic characteristics to the original tumor, may help determine which chemotherapy is most effective.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the response rate of Avatar-directed salvage chemotherapy in patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival of patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-directed salvage chemotherapy.

II. To determine the overall survival of patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-directed salvage chemotherapy.

III. To determine the adverse events for patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-directed salvage chemotherapy.

IV. To determine the correlation between patient response and response in their Avatar.

V. To enrich the Avatar response signature in response to Avatar-directed therapy using patient outcomes.

VI. To compare the response rates between patients who did or did not receive bevacizumab treatment.

OUTLINE: Patients are assigned to 1 of 4 treatment arms as directed by Avatar results.

ARM A: Patients receive paclitaxel intravenously (IV) over 1-96 hours on days 1, 8, and 15. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

ARM B: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 every 21 days or days 1, 8, and 15 every 28 days. Patients may also receive bevacizumab IV over 90 minutes on day 1 every 21 days or days 1 and 15 every 28 days. Courses repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 3 years.

Arms: arm 1: Patients receive paclitaxel IV over 1-96 hours on days 1, 8, and 15. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity arm 2: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 every 21 days or days 1, 8, and 15 every 28 days. Patients may also receive bevacizumab IV over 90 minutes on day 1 every 21 days or days 1 and 15 every 28 days. Courses repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bevacizumab intervention 2: Gemcitabine Hydrochloride intervention 3: Paclitaxel intervention 4: Pegylated Liposomal Doxorubicin Hydrochloride intervention 5: Topotecan Hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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Mayo Clinic Cancer Center 
 
 
 
MC1463: Avatar-Directed Chemotherapy in Platinum-Resistant Ovarian, Primary 
Peritoneal and Fallopian Tube Cancers 
 
 
 
Principal Investigator: 
 
  
 
 
 
  
 
 Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Statistician: 
   
 
 
 
Investigational Device  
IDE Exempt (NSR status per FDA determination): Mouse Avatar model 
 
Drug Availability 
Commercial Agents:  topotecan (Hycamtin®); paclitaxel (Taxol®); liposomal doxorubicin (Doxil®); 
Gemcitabine (Gemzar®); bevacizumab (Avastin®) 
 
* Investigator having responsibility for this protocol 
 Study contributor(s) not responsible for patient care. 
 
Document History 
Effective Date 
Activation  
July 21, 2015 
Mayo Addendum 1 
July 21, 2015 
Mayo Addendum 2 
July 21, 2015 
Mayo Addendum 3 
June 8, 2016 
Mayo Addendum 4 
April 13, 2018 


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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*; test schedule; 
treatment delays, interruption or 
adjustments; dose modifications; 
adverse events; forms completion  
and submission 
 
 
 
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 
 
Mayo Clinic Cancer Center .......................................................................................................................... 1 
MC1463: Avatar-Directed Chemotherapy in Platinum-Resistant Ovarian, Primary Peritoneal and 
Fallopian Tube Cancers ................................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema  ......................................................................................................................................................... 5 
1.0 
Background ...................................................................................................................................... 7 
1.1 
Avatar Project Overview .................................................................................................... 7 
1.2 
Avatar Engraftment Success ............................................................................................... 9 
1.3 
Use of M-Mode Ultrasonography for Tumor Monitoring ................................................ 10 
1.4 
Characterization of Avatar Models ................................................................................... 11 
1.5 
Concordance of Avatars with Patient Response to Chemotherapy ................................... 13 
1.6 
Directing Chemotherapy in Patients with Platinum Resistant Ovarian Cancer 
with Results from their Own Avatar ................................................................................. 14 
1.7 
Addition of bevacizumab to chemotherapy regimens ....................................................... 14 
2.0 
Goals .............................................................................................................................................. 15 
2.1 
Primary Goal ..................................................................................................................... 15 
2.2 
Secondary Goals ............................................................................................................... 15 
3.0 
Patient Eligibility ........................................................................................................................... 16 
3.1 
Pre-Registration Inclusion Criteria ................................................................................... 16 
3.2 
Registration Inclusion Criteria .......................................................................................... 16 
3.3 
Registration Exclusion Criteria ......................................................................................... 17 
4.0 
Test Schedule (At the time of registration only) ............................................................................ 19 
5.0 
Grouping Factor ............................................................................................................................. 20 
6.0 
Registration Procedures ................................................................................................................. 20 
6.1 
Pre-Registration ................................................................................................................ 20 
6.2 
Registration ....................................................................................................................... 21 
7.0 
Protocol Treatment......................................................................................................................... 22 
7.1 
Treatment Schedule .......................................................................................................... 22 
7.2 
Treatment by a Local Medical Oncologist ........................................................................ 23 
8.0  
Dosage Modification Based on Adverse Events ............................................................................ 23 
9.0 
Ancillary Treatment/Supportive Care ............................................................................................ 24 
9.1 
Antiemetics ....................................................................................................................... 24 
9.2 
Blood Products and Growth Factors ................................................................................. 24 
9.3 
Full Supportive Care ......................................................................................................... 24 
9.4 
Diarrhea ............................................................................................................................ 24 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................................ 24 
10.1 
Adverse Event Characteristics .......................................................................................... 26 
10.2  
Expected vs. Unexpected Events ...................................................................................... 26 
10.3 
Attribution to Agent(s) or Procedure ................................................................................ 27 
10.4  
Expedited Reporting Requirements for Studies using Commercial Agent(s) 
ONLY: .............................................................................................................................. 28 
10.5 
Other Required Reporting ................................................................................................. 30 
10.6 
Required Routine Reporting ............................................................................................. 33 
10.7 
Late Occurring Adverse Events ........................................................................................ 34 
11.0 
Treatment Evaluation ..................................................................................................................... 34 
11.1 
Response Criteria for Ovarian Cancer Patients................................................................. 34 
11.2 
Schedule of Evaluations .................................................................................................... 35 
11.3 
Definitions of Measurable and Non-Measurable (Evaluable) Disease ............................. 35 


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11.4 
Guidelines for Evaluation of Measurable Disease ............................................................ 36 
11.5 
Measurement of Effect ...................................................................................................... 38 
12.0 
Descriptive Factors ........................................................................................................................ 43 
12.1 
Initial Stage ....................................................................................................................... 43 
12.2 
Tumor Histology Type ...................................................................................................... 43 
12.3 
Prior Chemotherapy Regimens ......................................................................................... 43 
12.4 
Platinum Allergy ............................................................................................................... 44 
12.5 
Avatar Results ................................................................................................................... 44 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................... 44 
13.1 
Treatment .......................................................................................................................... 44 
13.2 
Disease Progression .......................................................................................................... 44 
13.3 
Off Treatment for Other Reasons than PD ....................................................................... 44 
13.4 
Ineligible ........................................................................................................................... 44 
13.4 
Major Violation ................................................................................................................. 45 
13.5 
Cancel ............................................................................................................................... 45 
14.0 
Body Fluid Biospecimens .............................................................................................................. 45 
15.0 
Drug Information ........................................................................................................................... 45 
15.1 
Paclitaxel (Taxol®) ........................................................................................................... 45 
15.2 
Gemcitabine (Gemzar®) ................................................................................................... 50 
15.3 
Doxorubicin Liposomal (Doxil®) .................................................................................... 53 
15.4 
Topotecan (Hycamtin®) ................................................................................................... 58 
15.5 
Bevacizumab (Avastin®) ................................................................................................... 61 
16.0  
Statistical Considerations and Methodology .................................................................................. 64 
16.1 
Overview ........................................................................................................................... 64 
16.2 
Statistical Design .............................................................................................................. 65 
16.3 
Analysis Plan .................................................................................................................... 67 
16.4 
Inclusion of Women and Minorities ................................................................................. 68 
17.0 
Pathology Considerations/Tissue Biospecimens ........................................................................... 69 
18.0 
Records and Data Collection Procedures ....................................................................................... 69 
18.1 
Submission Timetable ....................................................................................................... 69 
19.0 
Budget ............................................................................................................................................ 71 
19.1 
Costs Charged to Patient ................................................................................................... 71 
19.2 
Tests to be Research Funded ............................................................................................. 71 
20.0 
References ...................................................................................................................................... 72 
Appendix I: ECOG Performance Status Criteria ........................................................................................ 75 
Appendix II: Local Medical Oncologist Contact Letter (Avatar in Production) ........................................ 76 
Appendix III: Local Medical Oncologist Contact Letter (Existing Avatar) ............................................... 78 
Appendix IV: Patient Contact Letter (Avatar in Production) ..................................................................... 80 
Appendix V: Patient Contact Letter (Existing Avatar) ............................................................................... 81 
 


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Schema 
 
 
 
At the time of platinum resistance 
 
 
 
 
Treatment As Directed by Avatar Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Registration  
Registration  
Arm A1 
       Paclitaxel  
80 mg/m2  
IV weekly  
Days 1, 8 and 15 
± Bevacizumab 
10 mg/kg IV 
Days 1 and 15 
Arm B 1 
Gemcitabine  
1000 mg/m2  
IV weekly 
Days 1, 8 and 15 
 
Arm C1 
Liposomal 
doxorubicin 
40 mg/m2  
IV Day 1 
± Bevacizumab 
10 mg/kg IV 
Days 1 and 15 
Arm D 2 
Topotecan  
1.5 mg/m2 IV  
Days 1-5 
± Bevacizumab 
15 mg/kg IV  
Day 1  
Event Monitoring 3  
Every 3 months until PD;  
After PD, every 6 months until 3 years after registration  
PD at any time* 
Unacceptable Adverse Events 
 
Event Monitoring 
Patient Refusal 
* unless otherwise specified  
 
 


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If a patient is deemed ineligible or a cancel, please refer to Section 18.1 for follow-up 
information. 
1  Cycle length = 28 days.  Note that after Cycle 1, treating physicians may adjust 28-day cycles 
to 21-day cycles at their discretion.  See Section 7.0 for details. 
2  Cycle length = 21 days.  Note that topotecan may be administered at 4 mg/m2 weekly Day 1, 8 
and 15 ± bevacizumab 10 mg/kg IV Days 1 and 15 on a 28 day schedule at treating physicians 
discretion.  See Section 7.0 for details 
3 Event monitoring will take place by means of a patient phone call or chart review to assess 
vital status and progression status only. 
 
 
Generic name: Topotecan  
  
Brand name(s): Hycamtin® 
Mayo Abbreviation: TOPA   
Availability: Commercial  
Generic name: Paclitaxel 
 
 
Brand name(s): Taxol® 
Mayo Abbreviation: TAXOL   
Availability: Commercial 
Generic name: Liposomal Doxorubicin 
Brand name(s): Doxil® 
Mayo Abbreviation: DOXIL   
Availability: Commercial 
Generic name: Gemcitabine  
Brand name(s): Gemzar® 
Mayo Abbreviation: GEMZAR 
  
Availability: Commercial 
Generic name: Bevacizumab 
Brand name (s): Avastin® 
Mayo Abbreviation: AVASTN 
Availability: Commercial 
 
 
 


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1.0 
Background 
 
Ovarian cancer affects an estimated 22,280 women in the US annually.  While it is the 
second most common gynecological malignancy, it is the most lethal gynecological 
malignancy (Siegel et al., 2012). The lethality of OC is due to the high frequency of cases 
diagnosed at a late stage (Horner et al., 2009)).  In addition, most patients who initially 
respond to treatment will eventually relapse and respond only modestly to salvage 
chemotherapy, contributing to lethality of OC.  When compared to other cancers in 
women, the death-to-incidence ratio of epithelial OC (EOC; 70 per 100) is more than four 
times that of breast cancer (17 per 100) and similar to that of lung cancer (Siegel et al., 
2012).  Despite incremental improvements in disease-free survival over the last three 
decades, cure rates are essentially unchanged (Barnholtz-Sloan et al., 2003). Barriers to 
better outcomes include a lack of individualized therapy and limitations of the preclinical 
models used to evaluate novel anticancer agents in EOC.  
 
Multiple agents have activity for the treatment of platinum resistant ovarian cancer (PR-
OC), but the optimal agent is not known.  As a result, one of several agents are chosen 
based on adverse event profiles, schedule and patient/physician preference without 
selection based on which would be most active.  Pegylated liposomal doxorubicin (PLD) 
has response rates in the range of 11 to 19.7%, with progression free survival (PFS) 
ranging from 12-22 weeks (Gordon et al., 2001; Mutch et al., 2007).  The response rates 
of gemcitabine (Gem) range from 9 to 22% with 8-16 weeks PFS ( Mutch et al., 2007; 
Lund et al., 1994; Ojeda Gonzalez et al., 2008; von Minckwitz et al., 1999).  Topotecan 
(TPT) has a response rate between 9 and 19%, depending on study and schedule, with a 
PFS ranging from 16-20 weeks (Gordon et al., 2001; Sehouli et al., 2011).  Weekly 
paclitaxel (PTX) has response rates of 21 to 25% and PFS of 14- 24 weeks, though some 
smaller studies have demonstrated higher response rates (Markman et al., 2006; 
Markman et al., 2002).  Recently, a randomized phase III clinical trial (AURELIA) was 
reported, which incorporated these agents as ‘physicians’ choice’ in the control arm in the 
treatment of PR-OC.  The response rates were 12.6% (95% CI 8.0-18.4%), with a median 
PFS of 3.4 months (95% CI 2.2-3.7 months).  Given these poor outcomes from salvage 
chemotherapy, we believe Avatar-directed chemotherapy can change these outcomes by 
assigning patients to the most effective regimen in their own, personal Avatar.  We 
believe by identifying the correct chemotherapy, we can increase the response rates to 
40% or greater, with an inherent increase of median PFS greater than 6 months.  In 
addition, the significance of having a reliable model of testing sensitivity to individual 
therapies is substantial, as it could be applied to novel therapies and produce tissue that 
would be useful to performing correlative studies, including identification of signature 
profiles, without biopsies.   
 
1.1 
Avatar Project Overview 
 
Beginning in March 2010, viable tumor from consenting ovarian cancer patients 
undergoing primary debulking surgery has been collected and heterotransplanted 
directly into severe combined immunodeficiency (SCID) mice to establish 
primary tumor grafts.  Tumors harvested from patients under sterile conditions are 


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mechanically disrupted and injected into the intraperitoneal cavities of the mice 
using methods developed by Beth Karlan and colleagues (2002).  Engrafted tumor 
is then surgically resected, minced and re-injected into additional mice to generate 
aliquots of tumor for future use, including pathological evaluation, molecular 
characterization and drug treatment studies.  Alternatively, minced tumor aliquots 
are frozen in viable fashion for re-engraftment at a later date.  The molecular and 
histologic characteristics of the patient’s source tumor can then be compared to 
those of the tumor graft. Clinical outcomes from the source patients are correlated 
in a de-identified fashion to these parameters, with the help of the Mayo Ovarian 
SPORE Biospecimens Repositories at Mayo Clinic Rochester, Mayo Clinic 
Florida and Mayo Clinic Arizona. (Figure 3). In addition, two Avatar co-clinical 
trials involving biopsy specimens collected at the time of tumor recurrence 
(MC1464 and MC1561) have helped to define the standard operating procedures 
to demonstrate the feasibility of engrafting Avatar tumors from biopsy specimens 
obtained from patients with ovarian. 
 
  
 


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1.2 
Avatar Engraftment Success 
 
To date, this effort has resulted in a high percentage of engrafted carcinomas 
(failure rate [ > 1 year w/o engraftment] is only 13.2%) with an engraftment rate 
of approximately 74% (Haluksa et al., 2012).  The gap between these two values 
represents models that may have engrafted, but have not been verified as 
epithelial tumors (see Preliminary Studies section on ‘Troubleshooting 
Lymphoma Development in Model System’).  As of April 2013, models from 
over 270 individual patients have been injected and over 160 have engrafted and 
are available for further assessment.  Primary tumor procurement and injection in 
mice continues. The engrafted models represent the gamut of ovarian, primary 
peritoneal and fallopian tube histologic subtypes that are seen in the clinic 
(Figure 4, A), and are unique in the number, range of histologies, volume of 
clinical annotation, and array-based data available.  Since the availability of our 
model to direct therapy in patients in time sensitive, we have been closely 
monitoring time to engraftment (Figure 4, B).  Over the course of our experience 
developing Avatar models, our time to engraftment has improved from a median 
of 153 days to 105 days.  Thus, while this models system could not be used to 
generate response data for directing initial adjuvant therapy, it would be feasible 
for directing recurrent therapy, given the median time to progression of 18-24 
months in OC (Armstrong et al., 2006; McGuire et al., 1996).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
One of the advantages of this approach is that the carcinomas are engrafted in vivo 
without growth on plastic. Thus, these carcinomas develop and interact with 
stroma in an environment more similar to that of the patient. Importantly, as has 
been demonstrated with other patient-derived tumor models, tumor engraftment 
was prognostic (Garrido-Laguna et al., 2011; Nemati et al., 2010;  Weroha et al., 
2013).  Patients with successfully engrafted Avatars have poor outcomes 
compared to patients whose Avatars do not engraft (Figure 5).  As a result, 
development of Avatar-directed therapies will be used for patients in greatest 
need.  
 
2010 a
2010 b
2011 a
2011 b
2012 a
2012 b
0
90
180
270
360
450
540
Time to Moribund
Time Range
A 
B 
Figure 4. Histologic and engraftment characteristics of Avatar models. A) Graphical 
representation of the histologic distribution of 137 engrafted Avatar tumor graft models 
as of July 2012. B) Box and Whisker plots (10-90 percentile) of time-to-moribund state 
as surrogate for Avatar engraftment. Filled circles represent outliers. 


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1.3 
Use of M-Mode Ultrasonography for Tumor Monitoring 
 
Accurate assessment of tumor growth and response to therapy is vital to tumor 
graft-based experiments.  As our orthotopic model necessitates intraperitoneal 
growth in an immunocompromised model, tumor monitoring poses a challenge.  
For instance, small animal CT, PET, or MRI scanners are not located in the 
animal barrier area, thus are not practical for frequent or non-terminal 
measurements.  To overcome these barriers, we have employed transabdominal 
portable ultrasound since it also avoids the need for general anesthesia while 
providing accurate pre- and post-treatment tumor measurements, thereby allowing 
each animal to function as its own reference.  While ultrasound is not typically 
used for monitoring tumor responses in OC patients, due to the large area surface 
area, operator dependence and inferior reproducibility in human patients (van 
Persijn et al., 2010), mice have a much smaller intra-abdominal/pelvic surface 
area and are amenable to repeated ultrasound measurements, which others have 
demonstrated to be accurate and feasible (Dreys et al., 2000; Rooks et al., 2001).  
To assess this on our own model system, tumor diameter in 35 mice bearing 
tumor grafts were assessed using an L-25x 13-6 MHz linear transducer with a 
SonoSite S-Series ultrasound device and plotted to caliper-derived diameter 
measurements at necropsy. An excellent correlation between tumor diameter by 
ultrasounds and caliper measurements was observed (Figure 6).  To improve 
reproducibility, the image representing the largest tumor diameter is captured and 
cross-sectional area is calculated using ImageJ 1.46 platform independent 
software (Schneider et al., 2012)). Although serial CA125 measurements have 
been proposed for ovarian tumor grafts (Baknert et al., 2011), the assay in our 
series did not prove sensitive enough to be useful (Data not shown). 
 
 
 
Figure 5. Avatar Engraftment Predicts Poor 
Survival- Events (recurrence, progression or death) 
in patients from successfully engrafted Avatars (red) 
or unsuccessfully engrafted (blue) are plotted by 
Kaplan-Meier survival analysis. Groups are 
compared using Log-Rank test. 
HR 1.98 
(95% CI 1.04-
3.78) 
p= 0.0372 


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1.4 
Characterization of Avatar Models 
The underlying hypothesis is that the tumor grafts are more likely to share 
characteristics of the patient’s neoplasm compared to in vitro selecting for clonal 
populations of cells capable of growing in culture.  Reassuringly, the histologies 
(including extent of stromal component), was similar in the Avatar tumor graft 
compared to the source patient tumor.  This was assessed by H&E staining for a 
general evaluation of tissue substructures. Pan-cytokeratin staining was done, to 
ensure the presence of a human epithelial tumor and Ki-67 confirmed that the 
proliferative index of the patient and tumor graft were similar.  An example of 
this shown is Figure 7a.  In regards to the stromal component of our tumors, we 
have demonstrated (Appendix 1, submitted manuscript) that this is murine in 
origin, but recapitulates the degree of stromal involvement (low, intermediate, 
high) that is observed in the source patients.  These data support our speculation 
that the epithelial tumor component may be programmed to develop a supportive 
stromal component as individual as each patients’ epithelial component.  As many 
ovarian cancers are characterized by their deficiencies in DNA repair and 
genomic instability, we have also evaluated tumors by array CGH to ensure the 
fidelity of any DNA amplifications/deletions presents.  These evaluations were 
also aided by our collaboration with the Mayo Clinic Ovarian Cancer Repository, 
who were able to provide individual patient match germ line DNA for controls.  
These demonstrated a striking similarity between Avatar tumor graft and source 
patient aberrations in DNA, with the understanding that some differences may be 
due to the presence of murine DNA. An example is shown in Figure 7b.  In 
addition, the most commonly gained/lost genes in ovarian cancer, as determined 
Figure 6. Transabdominal ultrasound assessment 
of tumor change in untreated controls.  (a) 
Representative serial ultrasound images from a 
saline-treated PH015 tumor graft showing growth 
over 15 days. Scale bar = 5 mm. Tumors are 
hypoechoic relative to the surrounding bowel. (b) 
Tumor diameter in 35 mice bearing tumor grafts were 
assessed by ultrasound and plotted to caliper-
derived diameter measurements at necropsy. The 
Spearman correlation was r = 0.941. 
A 
B 


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by gene 
copy 
number 
analysis 
and DNA 
sequencing of 489 ovarian serous carcinomas from The Cancer Genome Atlas 
(TCGA) Research Network, Nature, 474:2011) including RB1, NF1, PTEN, 
TACC3, MYC, KRAS, CCNE1 and others have been demonstrated in our Avatar 
models. 
 
 
To further evaluate the molecular characteristic, we have performed gene 
expression arrays using the Affymetrix U133 Plus 2.0 Whole Genome array 
platform.  Using DNA microarray profiling on 27 early-passage serous ovarian 
tumor grafts, we performed an unsupervised clustering profile on these tumor 
grafts with the raw data set from the 489 serous ovarian tumors evaluated in 
TCGA data set (Nature, 474:2011).  Most models (Weroha et al., 2013)) cluster 
with the proliferative subtype while the remaining cluster with either 
dedifferentiated (Mutch et al., 2007) or immunoreactive (Gordon et al., 2001). No 
samples cluster with mesenchymal subtypes, likely the result of human stroma 
being replaced with murine stroma in our models.  Upon analyzing the genes most 
upregulated in our clustered subtypes, the genes most upregulated in the 
differentiated (SLPI, MUC1, MUC16), proliferative (SOX11, HMGA2) and 
immunoreactive (CXCL10, CXCL11) Avatar sets are also upregulated in the 
TCGA data set(24).  Additional characterization has been performed to determine 
the mutational status of homologous recombination (HR) genes, including 
BRCA1 and 2, which are deficient in many OC(25-28).  This has been performed 
on 50 models to date by a massively parallel sequencing strategy and verified 
Figure 7. Xenograft models closely replicate source neoplasms. Carcinomas
from the patient and tumor graft were compared pathologically (A) by H&E,
cytokeratin (CK) and Ki-67 staining. Array cGH (B) demonstrates similar deletions
and amplifications in tumor graft and the source patient tumor. 
A 
B 


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with Sanger sequencing and copy number variant determination in collaboration 
with Dr. Elizabeth Swisher (University of Washington)(Walsh et al., 2011; Walsh 
et al., 2010).  Mutations in BRCA1, BRCA2, CHEK2, ATM, ATR, XRCC2 and 
others have been identified.  These data are currently being used to select models 
for the development of PARP inhibitors, but are beyond the scope of discussion 
here. 
 
1.5 
Concordance of Avatars with Patient Response to Chemotherapy 
 
Despite the supportive data that demonstrate the similarity between Avatar tumors 
and their source patients on a histological and molecular basis, the clinical 
relevance of the models would be best realized by determining their similarity in 
responsiveness to treatment.  Given the importance of platinum-based 
chemotherapy in the front-line treatment of ovarian cancer, we evaluated the 
responsiveness of Avatar models to paclitaxel/carboplatin.  Models were selected 
from patients who had differential outcomes (platinum-resistant and platinum-
sensitive) following front line therapy with paclitaxel/carboplatin.  Once tumors 
were established, treatment was administered in a blinded fashion, with an 
investigator performing the ultrasound measurements that was unaware of the 
outcome.  We demonstrated that response to chemotherapy was concordant in 
Avatar models from four patients with platinum-resistant ovarian cancer (tumors 
did not regress with platinum chemotherapy) and five patients with platinum-
sensitive ovarian cancer (tumors regressed; Weroha et al., 2013, see Figure 8).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8. Tumor graft response concordant with patient 
response- Tumor grafts procured from patients with 
platinum-sensitive (green) and platinum-resistant (red) 
ovarian cancer were established in SCID mice. Upon 
formation of tumors measurable by ultrasound, tumors were 
then treated with weekly paclitaxel (15 mg/kg) and carboplatin 
(50 mg/kg). 
0
1
2
3
4
-100
0
100
200
Week
Tumorgraft response (% change)
PH013
PH077
PH069
PH053
PH015
PH070
PH037
PH080
PH039


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1.6 
Directing Chemotherapy in Patients with Platinum Resistant Ovarian Cancer with 
Results from their Own Avatar 
 
Given these data, the goals of our proposed research is to use each individual 
patient’s Avatar to determine what salvage chemotherapy their tumors are 
sensitive to and direct the selection of their chemotherapy at the time of 
developing PR-OC.  We believe we are in position to challenge the existing 
paradigm of treating OC patients as a group.  We now have the methodology to 
treat patients as individuals.  For example, the response rates of salvage 
chemotherapy, such as topotecan, are in the 10-20% range when PR-OC patients 
are treated as a group.  However, the response rates with topotecan are surely 
much higher in the patients that have tumors responsive to topotecan.  Our data 
suggests that our Avatars generated for each individual patient can determine 
which chemotherapy agent in patients with PR-OC will be most effective.   By 
directing therapy in PR-OC patients with results from their own Avatar, we 
believe we can increase the effective response rate and clinical benefit of salvage 
chemotherapy agents in patients with PR-OC.  We believe these results will be 
practice changing, in that we will be able to make informed therapy decisions in 
PR-OC, instead of our standard practice of physicians’ choice.   
 
For this trial, eligible patients would have had tumors procured at the time of their 
surgery or at the time of a platinum-sensitive recurrence, had an Avatar 
established and now have recurrence of their ovarian, primary peritoneal or 
fallopian tube cancer that was resistant to platinum.  As we have archived and 
‘live’ tissue on patients at the time of initial surgical debulking, there will be no 
correlative tissue or other specimens collected for such patients. However, for 
patients with recurrent platinum sensitive cancer who are planning to undergo a 
biopsy or surgical resection for clinical indications, the procured tumor would be 
used to attempt Avatar engraftment. Examples include but are not limited to (1) 
patients with suspected recurrent cancer needing a biopsy to confirm recurrence, 
(2) patients needing fresh tissue for molecular profiling (e.g. FoundationOne, 
Caris, TEMPUS, etc.), (3) patients undergoing tumor debulking for palliation or 
curative intent, (4) patients consenting to undergo a procedure for research 
specimens. 
 
Patients will receive standard chemotherapy treatments for this patient population 
- but the delivery will be directed by an investigational methodology.  We will 
test the response rate of Avatar-directed salvage chemotherapy in patients with 
PR-OC. 
 
1.7 
Addition of bevacizumab to chemotherapy regimens 
 


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The addition of bevacizumab was based on the results of the AURELIA study, 
which compared salvage chemotherapy combinations with salvage chemotherapy 
regimens for platinum-resistant ovarian cancer (Product information, Genentech; 
Pujade-Lauraine et al., 2014). Investigators in this study chose between pegylated 
liposomal doxorubicin, weekly paclitaxel or topotecan.  Patients were then 
randomized to receive the single agent chemotherapy or in combination with 
bevacizumab.  The PFS hazard ratio was found to be 0.48 (95% CI, 0.38 to 0.60; 
unstratified log-rank P < .001), favoring the combination arm. Median PFS was 
3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-
containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = 
.001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 
16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more 
common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-
treated patients.  
 
As bevacizumab does not recognize the murine epitope of murine VEGF, 
bevacizumab will not be investigated as part of therapy development as described 
in section 1.6.  Rather, it will be added to the standard chemotherapy backbone at 
the discretion of the treating physician/investigator. 
 
 
2.0 
Goals 
 
2.1 
Primary Goal 
To determine the response rate of Avatar-directed salvage chemotherapy in 
patients with platinum-resistant ovarian, primary peritoneal and fallopian tube 
cancers. 
 
2.2 
Secondary Goals 
 
2.21    To determine the progression-free survival of patients with platinum-
resistant ovarian, primary peritoneal and fallopian tube cancers receiving 
Avatar-directed salvage chemotherapy. 
 
2.22     To determine the overall survival of patients with platinum-resistant 
ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-
directed salvage chemotherapy. 
 
2.23 
To determine the adverse events for patients with platinum-resistant 
ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-
directed salvage chemotherapy. 
 
2.24 
To determine the correlation between patient response and response in 
their Avatar. 
 
2.25 
To enrich the Avatar response signature in response to Avatar-directed 
therapy using patient outcomes.  


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2.26 
To compare the response rates between patients who did or did not receive 
bevacizumab treatment.   
 
 
 
 
3.0 
Patient Eligibility 
 
3.1 
Pre-Registration Inclusion Criteria  
 
3.11 
Females of age  18 years at pre-registration. 
 
3.12 
Histologic confirmation of ovarian, primary peritoneal or fallopian tube 
cancer of any subtype. 
 
3.13 
Prior consent to have tumors used for unspecified future research.   
 
3.14 
Ability to provide written informed consent. 
 
3.15 
Willing to agree to periodic contact with a member of the study team 
during the period that the cancer has not recurred and/or has not become 
platinum resistant. 
 
3.16 
Willing to agree that the local medical oncologist may be informed that 
patient has agreed to participate in the study. 
 
 
3.2 
Registration Inclusion Criteria  
 
3.21 
Platinum resistant or refractory ovarian, primary peritoneal or fallopian 
tube cancer of any subtype. Platinum resistance is defined as cancer 
recurrence < 6 months following completion of platinum-based 
chemotherapy.  Platinum refractory cancers progress while on 
chemotherapy.  Note: Platinum-sensitive disease is allowed in cases where 
there is a contraindication to platinum-based therapy (i.e., allergy to 
platinum).  This must be reviewed and approved by the Principal 
Investigator. 
 
3.22 
Successful Avatar engraftment from initial surgery or surgery/biopsy of 
recurrent cancer with successful expansion and treatment outcome of 
Avatar therapy. 
 
3.23 
ECOG Performance Status (ECOG PS) of 0, 1 or 2. See Appendix I 
 
3.24     Measurable disease or non-measurable disease as defined in Section 11.0.  
For patients with non-measureable disease, they must also have a CA-125 


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measurement of > 35 U/mL or 2 X their documented nadir on 2 separate 
measurements 1 week apart.  
 
3.25 
The following laboratory values obtained  21 days prior to registration. 
CBC, sodium, potassium, AST, bilirubin and creatinine are to be obtained 
pre-study.  Note: Treatment initiation and dosing modification should be 
performed at the individual investigators discretion and be consistent with 
the product label and their medical practice. 
 
3.26 
Negative urine or serum pregnancy test performed ≤ 7 days prior to 
registration, for women of child bearing potential only 
 
3.27 
Willing to return to enrolling institution for follow-up or have a local 
physician willing to submit response and outcome data. 
 
Note: Any and all therapy, potentially in its entirety, may be conducted 
outside of the Mayo Clinic. 
  
 
3.3 
Registration Exclusion Criteria  
 
3.31 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects: 
 Pregnant women 
 Nursing women 
 
3.32 
Prior treatment with Doxil, Topotecan, Gemzar or Taxol  chemotherapy 
for platinum-resistant cancer.  Note: Allowed prior therapy with Doxil or 
Gemzar if given for platinum sensitive disease in combination with a 
platinum drug AND the Avatar data indicates a drug other than Doxil or 
Gemzar would be effective. Note: Allowed prior therapies for patients 
following confirmation of platinum-resistant cancer include: 
Therapeutic antibodies, such as bevacizumab 
Small molecule kinase inhibitors, such as pazopanib 
Vaccines and immunotherapy 
Poly (ADP-ribose) polymerase (PARP) inhibitors 
Endocrine therapies, such as letrozole 
Metronomic oral Cytoxan 
 
All of these exceptions should be confirmed with the PI prior to 
registration 
 
3.33 
Co-morbid systemic illnesses or other severe concurrent disease which, in 
the judgment of the investigator, would make the patient inappropriate for 
entry into this study or interfere significantly with the proper assessment 
of safety and toxicity of the prescribed regimens. 
 


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3.34 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  Note:  Patients known to be 
HIV positive, but without clinical evidence of an immunocompromised 
state, are eligible for this trial. 
 
3.35 
Uncontrolled intercurrent illness judged by the treating investigator to 
preclude treatment with chemotherapy. 
 
3.36 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.37 
Other active malignancy ≤ 3 years prior to registration.  EXCEPTIONS:  
Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  Note:  If 
there is a history of prior malignancy, they must not be receiving treatment 
for their cancer.  
 


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4.0 
Test Schedule (At the time of registration only) 
 
 
Active Monitoring Phase 
Tests and procedures 
 21 days 
prior to 
registration 
Prior to 
subsequent 
treatment cycle 
At the end 
of treatment 
History and exam, weight,  
ECOG Performance Status (PS) 
X 
 
X 
Adverse event assessment 
X 
X 
X 
Hematology group: 
WBC (including ANC),  
hemoglobin, platelets  
X 
X 
X 
Chemistry group: 
Sodium, Potassium, AST,  
Bilirubin, Creatinine 
X 
X 
X 
CA125 2 
X 
X 
X 
Urine or serum pregnancy test 1 
X 
 
 
CT imaging – abdomen/pelvis 3 
X 
X4 
X 
Footnotes for Section 4.0: 
1.  For women of childbearing potential only.  Must be performed ≤ 7 days prior to 
registration. 
2. CA125 is to be performed every other cycle.   
3. Use same imaging throughout the study.  Patients must return to Mayo for imaging prior 
to every other cycle.  Copies of any images performed at LMD are required. Note: After 
discussion with PI, provisions may be made for changing the timing of pre-reg scan or 
use of different imaging modalities.  Copies of any images performed at LMD are 
required. 
 
4. Prior to every other cycle only. 
 
Note:  Cycle length is 28days for paclitaxel, gemcitabine and liposomal doxorubicin.  After 
Cycle 1, treating physicians may adjust 28 day cycles to 21 day cycles at their 
discretion.  See Section 7.0 for details.  Patients receive topotecan by standard labeled 
schedule, which is Day 1-5, every 21 days.  At the discretion of the investigator, 
topotecan may be delivered weekly days 1, 8 and 15, every 28 days. 


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5.0 
Grouping Factor 
Avatar Recommended Treatment (as provided by PI at the time of recurrence): Paclitaxel 
alone vs. paclitaxel plus bevacizumab vs. gemcitabine vs. liposomal doxorubicin alone 
vs. liposomal doxorubicin plus bevacizumab vs. topotecan alone vs. topotecan plus 
bevacizumab  
 
 
6.0 
Registration Procedures 
 
Patient pre-registration and registrations will be performed by Mayo CRA using the 
Mayo Clinic Cancer Center Remote Registration Application. All patients must be 
registered using Mayo Clinic Rochester, Mayo Clinic Arizona or Mayo Clinic Florida as 
the location and under the supervision of a Mayo Medical Oncologist. 
 
 
6.1 
Pre-Registration 
 
6.11 
To pre-register a patient, access the Mayo Clinic Cancer Center (MCCC) 
webpage and enter the registration 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 website.  If unable 
to access the website, 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 application are available on the 
MCCC webpage 
) and detail the 
process for completing and confirming patient registration. Users should 
refer to the section titled “Pre-Registration Components” for details on how 
to pre-register a patient to a study. It is the responsibility of the individual 
pre-registering the patient to confirm the process has been successfully 
completed.  Patient pre-registration via the registration/randomization 
application can be confirmed in any of the following ways: 
 
 Contact the MCCC Registration Office at 
  If the 
patient was pre-registered, the MCCC Registration Office staff can 
access the information from the centralized database and confirm 
the pre-registration. 
 
 Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about a Registered Subject.” 
 
6.12 
Documentation of the initial IRB approval must be on file in the 
Registration Office before an investigator may pre-register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation (no less than annually) will be maintained by the 


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Regulatory Office and stored in the protocol file.  If the necessary 
documentation is not submitted in advance of attempting patient 
registration, the registration will not be accepted and the patient may not 
be enrolled in the protocol until the situation is resolved. 
 
6.13 
At the time of pre-registration, the Registration Application 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 
 
 
6.2 
Registration  
 
 
6.21 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) 
webpage and enter the registration 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 website.  If unable 
to access the website, 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 application are available on the 
MCCC webpage (
 and detail the 
process for completing and confirming patient registration.  Users should 
refer to the section titled “Pre-Registration Components” for details 
on how to register a pre-registered patient to a study.  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/randomization 
application can be confirmed in any of the following ways: 
 
 Contact the MCCC Registration Office at 
  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.” 
 
6.22 
At the time of registration, the Registration Application will verify the 
following: 


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 Patient eligibility  
 
6.23 
Treatment cannot begin prior to registration and must begin  21 days 
after registration. 
 
6.24 
Pretreatment tests/procedures (see Section 4.0) must be completed within 
the guidelines specified on the test schedule.  
 
6.25 
Treatment on this protocol must be given under the care of a medical 
oncologist or gynecology surgical oncologist.  This may include 
physicians outside of the Mayo Clinic. 
 
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule  
 
7.11 
Pre-Treatment Medications 
Pre-treatment medications are to be given as per institutional/investigator 
standards. 
 
7.12 
Protocol Treatment 
Protocol treatment is assigned as per Avatar response.   
 
The Avatar Tumor Review Board is responsible for reviewing Avatar 
mouse response results and relevant clinical details for each patient to 
determine the study treatment.   
 
The Avatar Tumor Review Board is composed of the principal 
investigator and representatives from oncology, the Avatar lab, 
biostatistics and patient advocates.  The Avatar Tumor Review Board 
meets on an as-needed basis and records official minutes to document the 
study treatment. 
 
 
Protocol Specified Dosing of Standard Chemotherapies 
Arm 
Agent 
Dose 
Route 
Days 
Retreatment 
A 
Paclitaxel2 
80 mg/m2 
IV 
1, 8, 15 
Every 
28 days 
Bevacizumab3 
10 mg/kg 
IV4 
1, 15 
B 
Gemcitabine 
1000 mg/m2 
IV 
1, 8, 15 
Every 
28 days 
C 
Liposomal 
Doxorubicin 
40 mg/m2 
IV 
1 
Every 
28 days 
Bevacizumab3 
10 mg/kg 
IV4 
1, 15 
D 1 
Topotecan 
1.5 mg/m2 
IV 
1 through 5 
Every 


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Bevacizumab3 
15 mg/kg 
IV4 
1 
21 days 
1 At the discretion of the investigator, topotecan may be delivered on a weekly schedule of 4 
mg/m2 IV weekly on Days 1, 8 and 15 every 28 days + optional bevacizumab 10 mg/kg IV 
days 1 and 15 every 28 days. 
2 Patients should be premedicated with corticosteroids, an antihistamine and H2 blockers 
prior to each paclitaxel dose as per institutional standard. 
3 
Bevacizumab is optional and may or may not be administered at physician’s discretion 
4 
The initial bevacizumab infusion will be over 90 minutes with subsequent infusions over 
60 minutes and then 30 minutes as tolerated. 
 
Acceptable Alternative Dosing of Standard Chemotherapies After Cycle 1 
 
Arm 
Agent 
Dose 
Route 
Days 
Retreatment 
A 
Paclitaxel1 
80 mg/m2 
IV 
1, 8, 15  
Every 
21 days 
Bevacizumab2 
15 mg/kg 
IV3 
1 
B 
Gemcitabine 
1000 mg/m2 
IV 
1 and 8 
Every 
21 days 
C 
Liposomal 
Doxorubicin 
40 mg/m2 
IV 
1 
Every 
21 days 
Bevacizumab2 
15 mg/kg 
IV3 
1 
D  
Topotecan 
4 mg/m2 
IV 
1 and 8 
Every 
21 days 
Bevacizumab2 
15 mg/kg 
IV3 
1 
 
1 Patients should be premedicated with corticosteroids, an antihistamine and H2 blockers 
prior to each paclitaxel dose as per institutional standard. 
2 
Bevacizumab is optional and may or may not be administered at physician’s discretion 
3 
The initial bevacizumab infusion will be over 90 minutes with subsequent infusions over 
60 minutes and then 30 minutes as tolerated. 
7.2 
Treatment by a Local Medical Oncologist 
 
Treatment may be administered by the local medical oncologist. Local medical 
oncologist must agree to provide required data for study completion.  Treatment 
will be administered by the treating physician’s standard procedures.  
 
8.0  
Dosage Modification Based on Adverse Events 
Dose modifications should be made per the product labeling, investigators decision and 
clinical judgment. The principal investigator may be contacted for counsel regarding any 
dose modification questions. 
 
 


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9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics 
Antiemetics may be used at the discretion of the treating physician. 
 
9.2 
Blood Products and Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors 
should follow published guidelines of the American Society of Clinical Oncology 
2005 Update of Recommendations for the Use of White Blood Cell Growth 
Factors: An Evidence-Based Clinical Practice Guideline.  J Clin Oncol 24: 3187-
3205, 2006.      
 
9.3 
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.  
 
9.4 
Diarrhea 
This could be managed conservatively with loperamide.  The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until 
diarrhea free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are 
allowed:  hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with 
fever or severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be 
prescribed.  Patients with severe diarrhea or any diarrhea associated with severe 
nausea or vomiting should be hospitalized for intravenous hydration and 
correction of electrolyte imbalances. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring  
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
 
Any suspected adverse reaction that is both serious and unexpected. 
 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 


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 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
 
Will automatically be sent to 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form 
  
AND attach 
MedWatch 3500A: 
 
Will automatically be sent to 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team 
becoming aware of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means in 
order to facilitate the review of safety data (may be requested by the FDA or the 
sponsor).  


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Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
 
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 website:  
    
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If 
yes, determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: 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). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in 
Section 10.4. 
 
 
 
10.2  Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the 
study specific consent form, package insert (if applicable), and/or the investigator 
brochure, (if an investigator brochure is not required, otherwise described in the 
general investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 15.0 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have 
not been observed with the drug under investigation. 


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An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the 
discretion of the Principal Investigator; it is possible that this information may 
NOT be included in the protocol or the investigator brochure. Refer to protocol or 
IB for reporting needs. 
 
10.3 
Attribution to Agent(s) or Procedure 
 
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.  
 
10.31 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. These 
events must still be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the 
protocol or investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than 
expected as an expedited event. 
 
System Organ Class 
(SOC) 
Adverse Event/ 
Symptoms 
CTCAE Grade at which  
the event will not be expeditedly 
reported1  
General disorders and 
administrations site 
conditions 
Fatigue 
Grade 3 
Malaise 
Grade 3 
Alopecia 
Any grade 


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1 These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (i.e., there is no untoward medical occurrence) associated with the hospitalization: 
 Hospitalizations for respite care 
 Planned hospitalizations required by the protocol 
 Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
 Hospitalization for elective procedures unrelated to the current disease and/or 
treatment on this trial 
 Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
 Hospitalization for routine maintenance of a device (e.g., battery replacement) that 
was in place before study entry 
 Hospitalization or other serious outcomes for signs and symptoms of progression of 
the cancer. 
 
10.4  Expedited Reporting Requirements for Studies using Commercial Agent(s) 
ONLY: 


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Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE 
trial within 30 Days of the Last Administration of a Commercial Imaging Agent 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 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
section 10.31 of the protocol.  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch 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 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
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 
 


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10.42 General Reporting Instructions 
The Mayo IND Coordinator 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 
or investigational agents 
or commercial/investigational agents on the same arm.  
For commercial agents:  
Submit form MedWatch 3500A to the FDA, 
 
r online at 
 
 
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 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSOS) in general, include any incident, experience, or outcome that 
meets all of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
2. Related or possibly related to participation in the research (in this 
guidance document, possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 


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3. Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of 
the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased 
risk of harm, but no harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is 
not considered an adverse experience for this trial, and if the consent form 
does not indicate that subjects should not get pregnant/impregnate others, 
then any pregnancy in a subject/patient or a male patient’s partner 
(spontaneously reported) which occurs during the study or within 120 days 
of completing the study should be reported as a UPIRTSO. 
 
 
10.52  Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to 
treatment or other cause must be provided. 
 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
Reportable Categories of Death  
 
 Death attributable to a CTCAE term. 
 
 Death Neonatal:  A disorder characterized by cessation of 
life during the first 28 days of life. 
 
 Death NOS:  A cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
 Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
 Death due to progressive disease should be reported as 
Grade 5 “Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) – Other (Progressive Disease)” 


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under the system organ class (SOC) of the same name.  
Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated 
with a disease process) should be submitted. 
 
10.53 Secondary Malignancy 
 
 A secondary malignancy is a cancer caused by treatment 
for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or 
chemotherapy).  A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
 
 All secondary malignancies that occur following treatment 
with an agent under an IND/IDE be reported. Three 
options are available to describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 Any malignancy possibly related to cancer treatment 
(including AML/MDS) should also be reported via the 
routine reporting mechanisms outlined in each protocol. 
 
10.54 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  Second 
malignancies require ONLY routine reporting. 
 
10.55 Pregnancy, Fetal Death and Death Neonatal   
 
If a female subject (or female partner of a male subject) taking 
investigational product becomes pregnant, the subject taking should notify 
the Investigator, and the pregnant female should be advised to call her 
healthcare provider immediately. The patient should have appropriate 
follow-up as deemed necessary by her physician. If the baby is born with a 
birth defect or anomaly, a second expedited report is required. 
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman and 
the newborn infant’s parent or legal guardian before any data collection 


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can occur. A consent form will need to be submitted to the IRB for these 
subjects if a pregnancy occurs. If informed consent is not obtained, no 
information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. 
In cases where the child/fetus experiences a serious adverse event other 
than fetal death, the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports 
for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation. Include this form: 
10.551 Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 
3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome 
is known. 
10.552 Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by 
death in utero; failure of the product of conception to show 
evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without 
possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 
10.553 Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized 
by cessation of life occurring during the first 28 days of life” that 
is felt by the investigator to be at least possibly due to the 
investigational agent/intervention, should be reported 
expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal 
loss)” under the General disorders and administration SOC.  
 
 
10.6 
Required Routine Reporting  
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or 
electronic, as applicable) the following AEs experienced by a patient and 


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not specified in Section 10.6: 
 
10.611 Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
 
10.612   Grade 5 AEs (Deaths) 
 
10.6121  Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
 
10.6122 
Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
 
10.7 
Late Occurring Adverse Events  
 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
 
11.0 
Treatment Evaluation 
 
11.1 
Response Criteria for Ovarian Cancer Patients  
 
Treatment Evaluation in Patients with Measurable or Evaluable (Non-
Measurable) Disease. 
 
Note: Patients may have CA 125 elevation alone to be eligible for this trial. 
However, if they do have radiographic or other evidence of 
measureable/evaluable disease, that disease should continue to be followed to 
assess tumor status. 
 
11.11 Evaluable Disease 
Patients with evaluable disease must have an increase in serum CA 125 
level, as defined as follows:  
1) Normalization of the CA 125 during first-line chemotherapy 
followed by an increase of ≥ 35 units/mL;  
or 
2) Normalization of the CA 125 during first-line chemotherapy 
followed by a doubling of the CA 125 beyond the upper limit of 
normal with a confirmatory measurement within a period of 4 


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weeks or less that shows the same or higher CA 125 level. 
 
11.12 Disease Progression  
Disease progression in evaluable patients will be defined as one or more of 
the following: 
1) Any new disease and/or clear progression of evaluable disease;  
2)  2 fold elevation in CA125 from its lowest level (either initial level 
or nadir, whichever is lowest, since study enrollment) combined 
with CA125 elevation confirmed by re-assay at any time. 
 
11.13  Complete Response 
A complete response (CR) in evaluable patients will be defined as:  
1) Disappearance of any sign of (evaluable) disease, and  
2) Normalization of CA125; if CA 125 normalizes, it should be 
confirmed at any time. 
 
11.14 Partial Response 
A partial response (PR) in evaluable patients will be defined as:  
1) Decrement in CA125 by > 50%, and  
2) Improvement in any additional evaluable disease (if present) as 
assessed by the enrolling physician 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1; Eisenhauer et al., 2009).  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the short axis measurements in 
the case of lymph nodes are used in the RECIST guideline. 
 
 
11.2 
Schedule of Evaluations 
For the purposes of this study, patients should be evaluated at baseline and every 
other cycle (just before cycle 3, 5, 7, etc.) using CT imaging.    
 
11.3 
Definitions of Measurable and Non-Measurable (Evaluable) Disease 
 
11.31 Measurable Disease 
 
11.311 A non-nodal lesion is considered measurable if its longest 
diameter can be accurately measured as  2.0 cm with chest x-ray, 
or as ≥ 1.0 cm with CT scan, CT component of a PET/CT or MRI.     
 
11.312 A superficial non-nodal lesion is measurable if its longest 
diameter is ≥ 1.0 cm in diameter as assessed using calipers (e.g. 
skin nodules) or imaging.  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 


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11.313 A malignant lymph node is considered measurable if its short axis 
is > 1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  
 
Note:  Tumor lesions in a previously irradiated area are not considered 
measurable disease.   
  
11.32 Non-Measurable Disease    
 
11.321 All other lesions (or sites of disease) are considered non-
measurable disease, including pathological nodes (those with a 
short axis ≥ 1.0 to  < 1.5 cm).  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
Note:  ‘Cystic lesions’ thought to represent cystic metastases can 
be considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as 
target lesions. In addition, lymph nodes that have a short axis <  
1.0 cm are considered non-pathological (i.e., normal) and should 
not be recorded or followed. 
 
11.4 
Guidelines for Evaluation of Measurable Disease 
 
11.41 Measurement Methods   
 
 All measurements should be recorded in metric notation (i.e., 
decimal fractions of centimeters) using a ruler or calipers. 
 
 The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. For patients having only lesions measuring at 
least 1 cm to less than 2 cm must use CT imaging for both pre- and 
post-treatment tumor assessments.   
 
 Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used at the same 
evaluation to assess the antitumor effect of a treatment.  
 
11.42  Acceptable Imaging Modalities for Measurable Disease  
 
 
Conventional CT and MRI   


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This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If 
CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.   
 
As with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the evaluation 
of the type and site of disease.  The lesions should be measured on 
the same pulse sequence.  Ideally, the same type of scanner should 
be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
 
PET-CT  
If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.   
 
 Chest X-ray   
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT scans are preferable. 
 
 Physical Examination 
For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the 
case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
 
 FDG-PET or PET/CT 
FDG-PET or PET/CT scanning is allowed to complement CT 
scanning in assessment of progressive disease [PD] and particularly 
possible 'new' disease.  A ‘positive’ FDG-PET or PET/CT scanned 
lesion is defined as one which is FDG avid with an update greater 
than twice that of the surrounding tissue on the attenuation 
corrected image; otherwise, an FDG-PET or PET/CT scanned 
lesion is considered ‘negative.’  New lesions on the basis of FDG-
PET or PET/CT imaging can be identified according to the 
following algorithm:  
 
a. Negative FDG-PET or PET/CT at baseline with a positive 
FDG-PET or PET/CT at follow-up is a sign of PD based on 
a new lesion. 
 


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b. No FDG-PET or PET/CT at baseline and a positive FDG-
PET or PET/CT at follow-up:  
  
i. If the positive FDG-PET or PET/CT at follow-up 
corresponds to a new site of disease confirmed by 
CT, this is PD.   
 
ii. If the positive FDG-PET or PET/CT at follow-up is 
not confirmed as a new site of disease on CT at the 
same evaluation, additional follow-up CT scans (i.e., 
additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression 
occurring at that site.  In this situation, the date of 
PD will be the date of the initial abnormal PDG-PET 
or PET/CT scan.   
 
iii If the positive FDG-PET or PET/CT at follow-up 
corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic 
images, it is not classified as PD. 
 
 
11.43 Measurement at Follow-up Evaluation 
 
 
A subsequent scan must be obtained at least 4 weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
 
 
In the case of stable disease (SD), follow-up measurements must 
have met the SD criteria at least once after study entry at a 
minimum interval of at least 4 weeks (see Section 11.54). 
  
 
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. 
 
 Cytologic and histologic techniques can be used to differentiate 
between PR and CR in rare cases (e.g., residual lesions in tumor 
types such as germ cell tumors, where known residual benign 
tumors can remain.) 
 
11.5 
Measurement of Effect 
 
11.51 Target Lesions & Target Lymph Nodes 


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 Measurable lesions (as defined in Section 11.31) up to a maximum 
of 5 lesions, representative of all involved organs, should be 
identified as “Target Lesions” and recorded and measured at 
baseline.  These lesions can be non-nodal or nodal (as defined in 
11.31), where no more than 2 lesions are from the same organ and 
no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are 
identified (as there often will be), there is no reason to perform 
additional studies beyond those specified in the protocol to discover 
new lesions.   
 
 Target lesions and target lymph nodes should be selected on the 
basis of their size, be representative of all involved sites of disease, 
but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion (or malignant lymph node) does not lend itself to 
reproducible measurement in which circumstance the next largest 
lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.   
 
 Baseline Sum of Dimensions (BSD) 
A sum of the longest diameters for all target lesions plus the sum of 
the short axis of all the target lymph nodes will be calculated and 
reported as the baseline sum of dimensions (BSD).  The BSD will 
be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
 Post-Baseline Sum of the Dimensions (PBSD) 
A sum of the longest diameters for all target lesions plus the sum of 
the short axis of all the target lymph nodes will be calculated and 
reported as the post-baseline sum of dimensions (PBSD).  If the 
radiologist is able to provide an actual measure for the target lesion 
(or target lymph node), that should be recorded, even if it is below 
0.5 cm.  If the target lesion (or target lymph node) is believed to be 
present and is faintly seen but too small to measure, a default value 
of 0.5 cm should be assigned.  If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be 
recorded as 0 cm. 
 
 The minimum sum of the dimensions (MSD) is the minimum of the 
BSD and the PBSD. 
 
11.52 Non-Target Lesions & Non-Target Lymph Nodes 
 


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Non-measurable sites of disease (Section 11.32) are classified as non- 
target lesions or non-target lymph nodes and should also be recorded at 
baseline.  These lesions and lymph nodes should be followed in accord 
with 11.533. 
 
11.53 Response Criteria 
 
11.531 All target lesions and target lymph nodes followed by 
CT/MRI/PET-CT/Chest X-ray/physical examination must be 
measured on re-evaluation at evaluation times specified in 
Section 11.2.  Specifically, a change in objective status to either 
a PR or CR cannot be done without re-measuring target lesions 
and target lymph nodes. 
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first 
response or confirmation of response.  In selected circumstances, 
certain non-target organs may be evaluated less frequently.  For 
example, bone scans may need to be repeated only when 
complete response is identified in target disease or when 
progression in bone is suspected. 
 
11.532 Evaluation of Target Lesions 
 
Complete Response (CR) 
All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short 
axis to < 1.0 cm. 
 
 
Partial Response (PR)  
At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis 
of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.51). 
 
 
Progression (PD) 
At least one of the following must be true: 
a. At least one new malignant lesion, which also includes 
any lymph node that was normal at baseline (<  1.0 cm 
short axis) and increased to ≥ 1.0 cm short axis during 
follow-up. 
 
b.  At least a 20% increase in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short 
axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (see Section 


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11.41).  In addition, the PBSD must also demonstrate 
an absolute increase of at least 0.5 cm from the MSD. 
   
c. See Section 11.42 for details in regards to the 
requirements for PD via FDG-PET or PET/CT 
imaging. 
 
 Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the 
MSD. 
 
11.533 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
Complete Response (CR) 
All of the following must be true:   
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must  
have reduction 
in short axis to < 1.0 cm. 
 
 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesions or non-target 
lymph nodes. 
 
 
Progression (PD) 
 
At least one of the following must be true: 
a. At least one new malignant lesion, which also includes 
any lymph node that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm short axis during 
follow-up. 
 
b. Unequivocal progression of existing non-target lesions 
and non-target lymph nodes.  (NOTE: Unequivocal 
progression should not normally trump target lesion 
and target lymph node status. It must be representative 
of overall disease status change.)    
 
c. See Section 11.42 for details in regards to the 
requirements for PD via FDG-PET or PET/CT 
imaging. 
 
 
11.54 Overall Objective Status 
 
The overall objective status for an evaluation is determined by combining 
the patient’s status on target lesions, target lymph nodes, non-target lesions, 
non-target lymph nodes, and new disease as defined in the following tables:  
 
 


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For Patients with Measurable Disease  
Target Lesions and 
Target Lymph 
Nodes 
Non-Target Lesions and 
Non-Target Lymph 
Nodes 
New Sites  
of Disease 
Overall  
Objective Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated1 
No 
PR2 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated1 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated1 
No 
Not Evaluated 
(NE)3 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated1 
Yes or No 
PD 
CR/PR/SD/PD/ 
Not all Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/ 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated1 
Yes 
PD 
1.  See Section 11.531 
2.  Note:  This study uses the modified protocol RECIST v1.1 template dated 
2/16/2011.  For data collection and analysis purposes the objective status changed 
from SD to PR in the protocol RECIST v1.1 template as of 2/16/2011 and to match 
RECIST v1.1 requirements. 
3. Note: ‘Not Evaluated (NE)’ in the table is equivalent to ‘Not Assessed (NA)’ in the 
Theradex dictionary (CA form), while ‘NE’ in the Theradex dictionary stands for 
‘Not Evaluable’. 


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For Patients with Non-Measurable Disease Only:      
Non-Target Lesions and 
Non-Target Lymph 
Nodes 
New Sites  
of Disease 
Overall  
Objective Status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not All Evaluated1 
No 
Not Evaluated 
(NE)2 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
1. See Section 11.431 
 
2. NOTE: ‘Not Evaluated (NE)’ in the table is equivalent to ‘Not Assessed 
(NA)’ in the Theradex dictionary (CA form), while ‘NE’ in the Theradex 
dictionary stands for ‘Not Evaluable’. 
 
11.55 Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that 
time, and not either related to study treatment or other medical conditions, 
should be reported as PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration.  A patient 
is classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other 
medical conditions: 
 
Weight loss > 10% of body weight. 
 
Worsening of tumor-related symptoms. 
 
Decline in performance status of > 1 level on ECOG scale. 
 
 
12.0 
Descriptive Factors 
 
12.1 
Initial Stage 
I vs. II vs. III vs. IV 
 
12.2 
Tumor Histology Type 
Ovarian (Serous) vs. Fallopian tube (Serous) vs. Primary Peritoneal (Serous) vs. 
Ovarian (Endometrioid) vs. Ovarian (Other) vs. Fallopian tube (Other) vs.  
Primary peritoneal (Other) 
 
12.3 
Prior Chemotherapy Regimens 
Dose dense paclitaxel/carboplatin IV vs. weekly paclitaxel/carboplatin IV vs. 
Q3W paclitaxel/carboplatin IV vs. NOS paclitaxel/carboplatin IV vs. 


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paclitaxel/cisplatin IV vs. paclitaxel/cisplatin IP vs. paclitaxel/carboplatin/ 
bevacizumab IV vs. paclitaxel/cisplatin/bevacizumab IV vs. docetaxel/carboplatin 
IV vs. gemcitabine/carboplatin IV vs. liposomal doxorubicin/carboplatin IV vs. 
other cisplatin-containing regimen NOS vs.  other carboplatin-containing regimen 
NOS 
 
12.4 
Platinum Allergy 
 
Yes vs. No 
 
12.5 
Avatar Results  
First: Paclitaxel vs. gemcitabine vs. liposomal doxorubicin vs. topotecan vs. other, 
specify 
Second, Third or Fourth: Paclitaxel vs. gemcitabine vs. liposomal doxorubicin vs. 
topotecan vs. other, specify vs. failure 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
Treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
13.2 
Disease Progression 
Patients who develop PD while receiving therapy will go to the event-monitoring 
phase. 
 
13.3 
Off Treatment for Other Reasons than PD 
Patients who go off protocol treatment for reasons other than PD will go to the 
event-monitoring phase per Section 18.0. 
 
13.4 
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 follow up phase of the study (or off 
study, if applicable).  
 
 If the patient received treatment, all data up until patient comes off protocol 
treatment 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  
 


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13.4 
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 follow-up 
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. 
 
 
13.5 
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.  No further data 
submission is necessary. 
 
 
14.0 
Body Fluid Biospecimens 
None. 
 
 
15.0 
Drug Information 
 
15.1 
Paclitaxel (Taxol®) 
 
15.11 Background  
Antineoplastic Agent, Antimicrotubular, Taxane derivative. Paclitaxel 
promotes microtubule assembly by enhancing the action of tubulin dimers, 
stabilizing existing microtubules, and inhibiting their disassembly, 
interfering with the late G2 mitotic phase, and inhibiting cell replication. In 
addition, the drug can distort mitotic spindles, resulting in the breakage of 
chromosomes. Paclitaxel may also suppress cell proliferation and 
modulate immune response. 
 
15.12 Formulation 
 Commercially available for injection 6 mg/mL (5 mL, 16.7 mL, 25 mL, 
and 50 mL) [contains alcohol and purified Cremophor EL 
(polyoxyethylated castor oil)]. 
 
15.13 Preparation, Storage, and Stability  
Refer to package insert for complete preparation and dispensing 
instructions. Store intact vials at room temperature and protect from 
light. Dilute in 250-1000 mL D5W or 0.9% NaCl to a concentration 
of 0.3 – 1.2 mg/mL. Solutions in D5W and 0.9% NaCl are stable for 
up to 3 days at room temperature. Chemotherapy dispensing devices 


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(e.g., Chemo Dispensing Pin) should not be used to withdraw 
paclitaxel from the vial. 
 
Paclitaxel should be dispensed in either glass or non-PVC containers 
(e.g., Excel/PAB). Use no polyvinyl (non-PVC) tubing (e.g., 
polyethylene) to minimize leaching.  
 
15.14 Administration  
Infuse IV over 1-96 hours. When administered as sequential infusions, 
taxane derivatives should be administered before platinum derivatives 
(cisplatin, carboplatin) to limit myelosuppression and to enhance efficacy. 
Infuse through a 0.22 micron in-line filter and non-absorbing 
administration set. 
 
 
15.15 Pharmacokinetic Information 
Distribution:  
Vd: Widely distributed into body fluids and tissues; affected by dose 
and duration of infusion 
Vdss: 1- to 6-hour infusion: 67.1 L/m2 
Vdss: 24-hour infusion: 227-688 L/m2 
 
Metabolism:  
Hepatic via CYP2C8 and 3A4; forms metabolites (primarily 6α-
hydroxypaclitaxel). 
 
Half-life elimination 1- to 6-hour infusion: 
Mean (beta): 6.4 hours, 
3-hour infusion: Mean (terminal): 13.1-20.2 hours 
24-hour infusion: Mean (terminal): 15.7-52.7 hours 
 
Excretion:  
Feces (~70%, 5% as unchanged drug); Urine (14%) 
 
Clearance:  
Mean: Total body: After 1- and 6-hour infusions: 5.8-16.3 
L/hour/m2; after 24-hour infusions: 14.2-17.2 L/hour/m2 
 
 
15.16 Potential Drug Interactions   
Cytochrome P450 Effect:  
Substrate (major) of CYP2C8, CYP3A4; Induces CYP3A4 (weak).  
 
Increased Effect/Toxicity:  
CYP2C8 inhibitors may increase the levels/effects of paclitaxel. 
Refer to the package insert or LexiComp1 for example inhibitors. 
 
Decreased Effect:  


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CYP2C8 inducers may decrease the levels/effects of paclitaxel. 
Refer to the package insert or LexiComp1 for example inducers. 
 
Herb/Nutraceutical Interactions:  
Avoid black cohosh, dong quai in estrogen-dependent tumors. 
Avoid valerian, St John’s wort (may decrease paclitaxel levels), 
kava kava, gotu kola (may increase CNS depression). 
 
15.17 Known Potential Adverse Events  
Consult the package insert for the most current and complete 
information. Percentages reported with single-agent therapy.  
 
U.S. Boxed Warning: Bone marrow suppression is the dose-
limiting toxicity; do not administer if baseline absolute neutrophil 
count (ANC) is <1500 cells/mm3 (1000 cells/mm3 for patients with 
AIDS-related KS); reduce future doses by 20% for severe 
neutropenia.  
U.S. Boxed Warning: Severe hypersensitivity reactions have been 
reported. 
 
Common known potential toxicities, > 10%:   
Cardiovascular: Flushing, ECG abnormal, edema, hypotension. 
Dermatologic: Alopecia, rash. 
Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, stomatitis, 
abdominal pain (with intraperitoneal paclitaxel)  
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, 
bleeding. 
Hepatic: Alkaline phosphatase increased, AST increased. 
Local: Injection site reaction (Erythema, tenderness, skin 
discoloration, swelling). 
Neuromuscular & skeletal: Peripheral neuropathy, arthralgia, 
myalgia, weakness. 
Renal: Creatinine increased. 
Miscellaneous: Hypersensitivity reaction, infection. 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Bradycardia, tachycardia, hypertension, rhythm 
abnormalities, syncope, venous thrombosis. 
Dermatologic: Nail changes. 
Hematologic: Febrile neutropenia. 
Hepatic: Bilirubin increased. 
Respiratory: Dyspnea. 
 
Rare known potential toxicities, < 1% (Limited to important or 
life-threatening):  


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Anaphylaxis, ataxia, atrial fibrillation, AV block, back pain, cardiac 
conduction abnormalities, cellulitis, CHF, chills, conjunctivitis, 
dehydration, enterocolitis, extravasation recall, hepatic 
encephalopathy, hepatic necrosis, induration, intestinal obstruction, 
intestinal perforation, interstitial pneumonia, ischemic colitis, 
lacrimation increased, maculopapular rash, malaise, MI, necrotic 
changes and ulceration following extravasation, 
neuroencephalopathy, neutropenic enterocolitis, ototoxicity, 
pancreatitis, paralytic ileus, phlebitis, pruritus, pulmonary embolism, 
pulmonary fibrosis, radiation recall, radiation pneumonitis, pruritus, 
renal insufficiency, seizure, skin exfoliation, skin fibrosis, skin 
necrosis, Stevens-Johnson syndrome, supraventricular tachycardia, 
toxic epidermal necrolysis, ventricular tachycardia  (asymptomatic), 
visual disturbances. 
 
15.18 Drug Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
 
15.19 Nursing Guidelines 
 
15.191  Premedicate with steroids, antihistamines, and H2 blockers as 
per institutional guidelines. 
 
15.192 Mix the infusion bag well.  Thorough admixture of this drug 
often prevents a hypersensitivity reaction.  An inline filter of < 
0.22 micron must be used distal to the infusion pump.  Filter may 
need to be changed if infusion is to be prolonged >12 hours.  
Inspect solution for excessive particulate matter, if present do not 
use. 
 
15.193 Caution patients that the alcohol contained in the infusion may 
cause impairment in operating heavy equipment or in driving a 
vehicle and to assess their ability before trying either.  Advise 
avoidance of any alcohol or depressants such as sedatives and 
opiates if not necessary. 
 
15.194 Assess the patient frequently for the first 30 minutes.  Taxol® 
hypersensitivity reactions, which may include chest pain, back 
pain, flushing, diaphoresis, dyspnea, pruritus, hypotension, 
hypertension, bronchospasm and/or urticaria, usually occur early 
in the infusion.  Have the anaphylaxis tray available. 
 


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15.195 If a reaction occurs, stop the infusion immediately.  Epinephrine, 
IV fluids, diphenhydramine, and methylprednisolone may be 
used as per MD’s order. 
 
15.196 Approximately 60% of patients experience peripheral sensory 
neuropathy (numbness, tingling, burning pain, fine motor skills 
impairment, paresthesias, distal sensory loss).  Patients receiving 
higher doses at shorter infusion times are at greater risk.  Most 
cases have been reported at doses > 170 mg/m2/day and with 
cumulative doses over multiple courses of therapy.  The nerve 
damage may take months to resolve.  Nonsteroidal anti-
inflammatory agents and opiates have not been effective in 
treating neuropathic pain.  Consult MD about trying tricyclic 
antidepressants or possibly Neurontin.   
 
15.197 Increased risk of cardiotoxicity when given in combination with 
doxorubicin, with a sharp increase in risk of CHF once 
cumulative dose of doxorubicin is > 380 mg/m2.  At this point 
Taxol should be continued as a single agent only.  Monitor for 
sign/symptoms of CHF.  Instruct patient to report any swelling in 
the hands, arms, feet, or legs, and any chest pain. 
 
15.198 Mucositis can usually be managed with a salt and soda 
mouthwash (1 tsp. Salt, 1 tsp. Soda and 1 quart boiled water) or 
try OTC oral Lysine or Vitamin E. 
 
15.199a Narcotics and nonsteroidal anti-inflammatory drugs may be used 
to manage the myalgias. 
 
15.199b Monitor CBC closely.  Neutropenia is most severe in patients 
who have had previous chemotherapy.  Instruct patient to report 
signs or symptoms of infection, unusual bruising or bleeding to 
the health care team. 
 
15.199c There is an increased risk of neutropenia and stomatitis when 
given  prior to doxorubicin.  Therefore Taxol should always be 
given after doxorubicin administration. 
 
15.199d  Monitor IV site closely and establish patency before 
administration.  Paclitaxel is an irritant, however rarely rash, 
radiation recall, and ulceration have occurred with infiltration of 
drug. 
 
15.199e Monitor liver function tests 
 
15.199f Inform patient about total alopecia. 


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15.199g If given on the same day as a platinum agent, paclitaxel should 
be administered first to limit myelosuppression and enhance 
efficacy of agent. 
 
 
15.2 
Gemcitabine (Gemzar®) 
 
15.21 Background  
Gemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis by 
inhibition of DNA polymerase and ribonucleotide reductase, specific for 
the S-phase of the cell cycle. Gemcitabine is phosphorylated 
intracellularly by deoxcytidine kinase to gemcitabine monophosphate, 
which is further phosphorylated to active metabolites gemcitabine 
diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate 
inhibits DNA synthesis by inhibiting ribonucleotide reductase; 
gemcitabine triphosphate incorporates into DNA and inhibits DNA 
polymerase. 
 
15.22 Formulation  
Commercially available for injection: 
Powder for reconstitution: 200 mg and 1 gram vials. 
Solution for injection: 38 mg/mL 200 mg, 1 gm, and 2 gm vials.  
MUST BE DILUTED BEFORE USE. 
 
15.23 Preparation, Storage and Stability  
Powder for Reconstitution: 
Store intact vials at room temperature. Reconstitute the 200 mg vial 
with preservative free 0.9% NaCl 5 mL or the 1000 mg vial with 
preservative free 0.9% NaCl 25 mL. Resulting solution is 38 
mg/mL. Dilute with 50-500 mL 0.9% NaCl or D5W to 
concentrations as low as 0.1 mg/mL. Reconstituted vials are stable 
for up to 35 days and infusion solutions diluted in 0.9% NaCl are 
stable up to 7 days at 23ºC when protected from light; however, the 
manufacturer recommends use with 24 hours for both reconstituted 
vials and infusion solutions. Do not refrigerate. 
 
Solution for Injection: 
Store intact vials at refrigeration temperature between 2º to 8ºC (36º 
to 46ºF). Do not freeze.  Each vial contains a gemcitabine 
concentration of 38 mg/mL. The appropriate amount of drug should 
be further diluted with 50-500 mL 0.9% NaCl or D5W to 
concentrations as low as 0.1 mg/mL. When prepared as directed, 
diluted gemcitabine solutions are stable for 24 hours at controlled 
room temperature.  


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15.24 Administration   
Refer to the drug treatment section of the protocol for specific 
administration directions and infusion rates. Gemcitabine is normally 
infused IV over 30 minutes. Note: Prolongation of the infusion time > 60 
minutes has been shown to increase toxicity. Gemcitabine is being 
investigated in clinical trials for fixed dose rate infusion administration at 
doses from 1000 mg/m2 to 2200 mg/m2 at a rate of 10 mg/m2/minute. 
Prolonged infusion times increase the accumulation of the active 
metabolite, gemcitabine triphosphate. Patients who receive gemcitabine 
fixed dose rate infusions experience more grade three and four 
hematologic toxicities.  
 
 
15.25 Pharmacokinetic Information 
Distribution:  
Infusions < 70 minutes: 50 L/m2; Long infusion times: 370 L/m2 
Protein binding: Low 
 
Metabolism: 
Metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside 
metabolites 
 
Half-life elimination: 
Gemcitabine: Infusion time ≤ hour: 32-94 minutes; infusion time 3-4 
hours: 4-10.5 hours 
Metabolite (gemcitabine triphosphate), terminal phase: 1.7-19.4 
hours 
Time to peak, plasma: 30 minutes after completion of infusion 
 
Excretion: 
Urine (92% to 98%; primarily as inactive uridine metabolite); feces 
(< 1%) 
 
 
15.26 Potential Drug Interactions   
Increased Effect/Toxicity: Gemcitabine may increase the 
levels/effects of fluorouracil. Gemcitabine may enhance the adverse 
pulmonary effects of bleomycin. 
Ethanol/Nutrition/Herb Interactions Ethanol: Avoid ethanol (due to 
GI irritation). 
 
15.27 Known Potential Adverse Events  
Consult the package insert for the most current and complete 
information.  
 
Common known potential toxicities, > 10%:   
Cardiovascular: Peripheral edema, edema 


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Central nervous system: Pain, fever, somnolence 
Dermatologic: Rash, alopecia, pruritus 
Gastrointestinal: Nausea/vomiting, constipation, diarrhea, stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia, 
hemorrhage and myelosuppression is the dose-limiting toxicity 
Hepatic: Transaminases increased, alkaline phosphatase increased, 
bilirubin increased 
Renal: Proteinuria, hematuria, BUN increased 
Respiratory: Dyspnea 
Miscellaneous: Flu-like syndrome, infection 
 
Less common known potential toxicities, 1% - 10%:  
Local: Injection site reactions 
Neuromuscular & skeletal: Paresthesia 
Renal: Creatinine increased 
Respiratory: Bronchospasm 
 
Rare known potential toxicities, < 1% (Limited to important or 
life-threatening):  
Adult respiratory distress syndrome, anaphylactoid reaction, 
anorexia, arrhythmias, bullous skin eruptions, cellulitis, 
cerebrovascular accident, CHF, chills, cough, desquamation, 
diaphoresis, gangrene, GGT increased, headache, hemolytic uremic 
syndrome (HUS), hepatotoxic reaction, hypertension, insomnia, 
interstitial pneumonitis, liver failure, malaise, MI, peripheral 
vasculitis, Petechiae, pulmonary edema, pulmonary fibrosis, 
radiation recall, renal failure, respiratory failure, rhinitis, sepsis, 
supraventricular arrhythmia, weakness 
 
15.28 Drug Procurement   
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
  
15.29 Nursing Guidelines 
 
15.291 Monitor CBC, differential, PLTs prior to each dose.  
Myelosuppression is the principal dose-limiting factor.  
Modification may be considered by physician when bone 
marrow suppression is suspected. 
 
15.292 Evaluate hepatic and renal function prior to initiation of therapy 
and periodically thereafter.  Closely observe those patients with a 
history of preexisting mild renal impairment or hepatic 
insufficiency.  Encourage hydration. 
 
15.293 Gemzar clearance is affected by age and gender.  Grade 3/4 


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thrombocytopenia has been more common in elderly women. 
 
15.294 Antiemetics may be required for probable mild to moderate 
nausea and vomiting. Assess for their effectiveness. 
 
15.295 Instruct patient in management of possible mild diarrhea and 
stomatitis. 
 
15.296 Gemzar may cause fever in the absence of clinical infection.  
Fever can be accompanied by other flu-like symptoms.  Instruct 
patient to report fever or flu-like symptoms to healthcare team.  
Treat symptoms as they occur. 
 
15.297 Macular or finely granular maculopapular eruptions were 
experienced by 30% of patients tested.  Instruct patients to report 
any skin changes. 
 
15.298  Instruct patient to report any respiratory changes. 
 
15.299 Burning may occur at the injection site.  May apply heat during 
infusion to minimize pain. 
 
15.3 
Doxorubicin Liposomal (Doxil®) 
 
15.31 Background 
Doxorubicin Liposomal inhibits DNA and RNA synthesis by intercalating 
between DNA base pairs causing steric obstruction and inhibits 
topoisomerase-II at the point of DNA cleavage.  Doxorubicin Liposomal 
is also a powerful iron chelator.  The iron-doxorubicin complex can bind 
DNA and cell membranes, producing fee hydroxyl (OH) radicals that 
cleave DNA and cell membranes.  Doxorubicin is active throughout entire 
cell cycle.  Doxorubicin Liposomal is a pegylated formulation which 
protects the liposomes, and thereby increases blood circulation time. 
 
15.32 Formulation  
Commercially available for injection, solution: 2 mg/mL (10 mL, 30 mL) 
 
15.33 Preparation, Storage, and Stability  
Store intact vials of solution under refrigeration at 2ºC to 8ºC (36ºF 
to 46ºF); avoid freezing.  Prolonged freezing may adversely affect 
liposomal drug products, however, short-term freezing (< 1 month) 
does not appear to have a deleterious effect.  See the treatment 
section of the protocol for specific dilution instructions.  Generally, 
dose of doxorubicin liposomal less than or equal to 90 mg should be 
diluted in 250 mL of D5W prior to administration.  Doses greater 
than 90 mg should be diluted in 500 mL D5W.   Diluted doxorubicin 


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liposomal may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF); 
administer within 24 hours. Do not infuse with in-line filters. 
 
15.34 Administration   
Refer to the treatment section of the protocol for specific administration 
instructions.  Doxorubicin Liposomal is usually administered IVPB over 
60 minutes; manufacturer recommends administering at initial rate of 1 
mg/minute to minimize risk of infusion reactions until the absence of a 
reaction has been established, then increase the infusion rate for 
completion over 1 hour.  Do not administer I..M. or S.C.  Do not infuse 
with in-line filters.  Avoid extravasation (irritant), monitor site; 
extravasation may occur without stinging or burning.  Flush with 5-10 mL 
of D5W solution before and after drug administration, incompatible with 
heparin flushes.  Monitor for local erythematous streaking along vein 
and/or facial flushing (may indicate rapid infusion rate).  
 
 
15.35 Pharmacokinetic Information 
 
Distribution: Vdss: 2.7-2.8 L/m2 
Protein binding, plasma: Unknown; non-liposomal (conventional) 
doxorubicin: 70% 
Metabolism: Hepatic and in plasma to doxorubicinol and the sulfate 
and glucuronide conjugates of 4-demethyl,7-deoxyaglycones 
Half-life elimination: Terminal: Distribution: 4.7-5.2 hours, 
Elimination: 44-5 hours 
Excretion: Urine (5% as doxorubicin or doxorubicinol) 
 
 
15.36 Potential Drug Interactions   
Cytochrome P450 Effect: Substrate (major) of CYP2D6; 3A4;  
Inhibits CYP2B6 (moderate), 2D6 (weak), 3A4 (weak) 
 
Increased Effect/Toxicity: Bevacizumab and trastuzumab may 
enhance the cardiotoxic effect of anthracycline antineoplastics. 
Cyclosporine may increase the levels/effects of doxorubicin; may 
increase neurotoxicity and/or enhance hematologic toxicity. 
Doxorubicin may potentiate the toxicity of cyclophosphamide 
(hemorrhagic cystitis) and mercaptopurine (hepatotoxicity). 
CYP2D6 inhibitors may increase the levels/effects of doxorubicin. 
CYP3A4 inhibitors may increase the levels/effects of doxorubicin. 
Sorafenib may increase the levels/effects of doxorubicin. Paclitaxel 
may reduce doxorubicin clearance and increase toxicity, including 
cardiotoxicity of doxorubicin. 
 
Decreased Effect: Doxorubicin Liposomal may decrease the 
absorption of cardiac glycosides. CYP3A4 inducers may decrease 
the levels/effects of doxorubicin. Doxorubicin may diminish the 
therapeutic effect of stavudine and zidovudine. 


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Ethanol/Nutrition/Herb Interactions 
Ethanol: Avoid ethanol (due to GI irritation). 
Herb/Nutraceutical: St John’s wort may decrease doxorubicin levels. 
 
15.37 Known Potential Adverse Events  
Consult the package insert for the most current and complete 
information. 
 
 
U.S. Boxed Warnings: 
Doxorubicin may cause cumulative, dose-related myocardial 
toxicity (concurrent or delayed). 
Acute infusion reactions may occur, some may be serious/life-
threatening. 
Use with caution in patients with hepatic impairment. 
Severe myelosuppression may occur. 
Liposomal formulations of doxorubicin should NOT be substituted 
for conventional doxorubicin hydrochloride on a mg-per-mg basis. 
 
Common known potential toxicities, > 10%:   
Cardiovascular: Peripheral edema 
Central nervous system: Fever, headache, pain 
Dermatologic: Alopecia, palmar-plantar erythrodysesthesia/hand-
foot syndrome, rash 
Gastrointestinal: Stomatitis, vomiting, nausea, mucositis, 
constipation, anorexia, diarrhea, dyspepsia, intestinal obstruction 
Hematologic: Myelosuppression, neutropenia, leukopenia, 
thrombocytopenia, anemia 
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Pharyngitis, dyspnea 
Miscellaneous: Infection 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Cardiac arrest, chest pain, edema, hypotension, 
pallor tachycardia, vasodilation 
Central nervous system: Agitation, anxiety, chills, confusion, 
depression, dizziness, emotional lability, insomnia, somnolence, 
vertigo 
Dermatologic: Acne, bruising, dry skin, dermatitis, furunculosis, 
maculopapular rash, pruritus, skin discoloration, vesiculobullous 
rash 
Endocrine & metabolic: Dehydration, hyperbilirubinemia, 
Hypercalcemia, hyperglycemia, hypokalemia, hyponatremia 
Gastrointestinal: Abdomen enlarged, anorexia, ascites, cachexia, 
dyspepsia, dysphagia, esophagitis, flatulence, gingivitis, glossitis, 


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ileus, mouth ulceration, oral moniliasis, rectal bleeding, taste 
perversion, weight loss, xerostomia 
Genitourinary: Cystitis, Dysuria, leucorrhea, pelvic pain, Polyuria, 
urinary urgency, vaginal bleeding, vaginal moniliasis 
Hematologic: Hemolysis, prothrombin time increased 
Hepatic: ALT increased 
Local: Thrombophlebitis 
Neuromuscular & skeletal: Arthralgia, hypertonia, myalgia, 
neuralgia, neuritis (peripheral), neuropathy, paresthesia, pathological 
fracture 
Ocular: Conjunctivitis, dry eyes, retinitis 
Otic: Ear pain 
Renal: Albuminuria, hematuria 
Respiratory: Apnea, cough, epistaxis, pleural effusion, pneumonia, 
rhinitis, sinusitis 
Miscellaneous: Allergic reaction; infusion-related reactions; 
moniliasis, diaphoresis 
 
Rare known potential toxicities, < 1% (Limited to important or 
life-threatening):  
Abscess, acute brain syndrome, abnormal vision, acute myeloid 
leukemia (secondary), alkaline phosphatase increased, anaphylactic 
or anaphylactoid reaction, asthma, balanitis, blindness, bone pain, 
bronchitis, BUN increased, bundle branch block, cardiomegaly, 
cardiomyopathy, cellulitis, CHF, colitis, creatinine increased, 
cryptococcosis, diabetes mellitus, erythema multiforme, erythema 
nodosum, eosinophilia, fecal impaction, flu-like syndrome, gastritis, 
glucosuria, hemiplegia, hemorrhage, hepatic failure, hepatitis, 
hepatosplenomegaly, hyperkalemia, hypernatremia, hyperuricemia, 
hyperventilation, hypoglycemia, hypolipidemia, hypomagnesemia, 
hypophosphatemia, hypoproteinemia, hypothermia, injection site 
hemorrhage, injection site pain, jaundice, ketosis, lactic 
dehydrogenase increased, kidney failure, lymphadenopathy, 
lymphangitis, migraine, myositis, optic neuritis, palpitation, 
pancreatitis, pericardial effusion, petechia, pneumothorax, 
pulmonary embolism, radiation injury, sclerosing cholangitis, 
seizure, sepsis, skin necrosis, skin ulcer, syncope, tenesmus, 
thromboplastin decreased, thrombosis, tinnitus, urticaria, visual field 
defect, ventricular arrhythmia 
 
15.38 Drug Procurement   
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
 
15.39 Nursing Guidelines  
 


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15.391 Check CBC and platelet counts.  Instruct patient to watch for 
signs of infection, bleeding, and anemia. 
 
15.392 Advise patient that their urine may turn pink in color for 
approximately 24 hours after administration of the drug. 
 
15.393 Adriamycin is a vesicant.  Check IV patency before and 
frequently during administration.  If extravasation occurs, refer 
to institutional extravasation policy. 
 
15.395 Hair loss occurs 2-4 weeks after initial injection and can be 
complete.  Regrowth begins 2-3 months after discontinuation. 
 
15.396  Beware of Adria “flare” that can occur during administration.  
The reaction consists of an erythematous streak up the vein 
receiving the infusion.  Adjacent veins may also demonstrate red 
streaks.  Urticaria and pruritus can be associated with the 
reaction.  The use of corticosteroids and/or antihistamines has 
been helpful. 
 
15.397  Administer antiemetics to minimize nausea and vomiting. 
 
15.398 Assess for alterations in mucous membranes.  Stomatitis occurs 
within 7-10 days after injection.  It begins with burning sensation 
and can progress to ulceration, which can last 3 days.  Carafate 
slurry may be useful.  Adequate nutritional counseling is 
important.  Topical anesthetics such as viscous Xylocaine can be 
used symptomatically. 
 
15.399a Advise patient that there is often significant malaise and fatigue  
1-2 weeks after injection. 
 
15.399b Adriamycin may potentiate toxicity of other antineoplastic 
therapies.  It has reportedly exacerbated Cyclophosphamide 
(Cytoxan, CTX) induced hemorrhagic cystitis. 
 
15.399c Assess heart and lung sounds.  Monitor vital signs (resting pulse).  
Be alerts to early signs of cardiotoxicity, i.e., dyspnea, steady 
weight gain, nonproductive cough, arrhythmias, tachycardia, and 
pulmonary rales. Instruct patients to report any of these signs or 
symptoms to their health care provider. 
 
15.399d Document cumulative dose, which should not exceed maximum 
cumulative dose. 
 


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15.399e Advise patient of probable facial flushing for several hours after 
drug administration, especially if given quickly. 
 
 
15.4 
Topotecan (Hycamtin®) 
 
15.41 Background  
Topotecan binds to topoisomerase I and stabilizes the cleavable complex 
so that relegation of the cleaved DNA strand cannot occur. This results in 
the accumulation of cleavable complexes and single-strand DNA breaks. 
Topotecan acts in S phase of the cell cycle. 
 
15.42 Formulation  
Commercially available Injection, powder for reconstitution, as 
hydrochloride: 4 mg [base] 
 
15.43 Preparation, Storage, and Stability  
Store intact vials at room temperature and protect from light. 
Reconstitute with 4 mL Sterile Water for Injection. This solution is 
stable for up to 28 days at room temperature. Topotecan should be 
further diluted in 50-100 mL of D5W or 0.9% Sodium Chloride. 
Refer to the treatment section for final dilution volume. This 
solution is stable for 24 hours at room temperature or up to 7 days 
under refrigeration.  
 
15.44 Administration   
Administer IV piggyback over 30 minutes or by 24-hour continuous 
infusion. See specific administration instructions in the treatment section 
of the protocol. 
 
 
15.45 Pharmacokinetic Information 
Distribution:  
Vdss of the lactone is high (mean: 87.3 L/mm2; range: 25.6-186 
L/mm2), suggesting wide distribution and/or tissue sequestering 
 
Protein binding: ~35% 
 
Metabolism: Undergoes a rapid, pH-dependent hydrolysis of the 
lactone ring to yield a relatively inactive hydroxyl acid in plasma; 
metabolized in the liver to N-demethylated metabolite 
 
Half-life elimination: I.V.: 2-3 hours; renal impairment: 5 hours 
 
Excretion: I.V.: Urine (51%; 3% as N-desmethyl topotecan); feces 
(18%; 2% as N-desmethyl topotecan) 
 
 


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15.46 Potential Drug Interactions  
Increased Effect/Toxicity: 
Filgrastim may cause prolonged and sever neutropenia and 
thrombocytopenia if administered concurrently with topotecan; 
initiate filgrastim at least 24 hours after topotecan.  Platinum 
derivatives (carboplatin, cisplatin, oxaliplatin) may enhance the 
adverse/toxic effects of topotecan; monitor for hematologic toxicity, 
especially if the platinum derivative is administered prior to 
topotecan. 
 
15.47 Known Potential Adverse Events  
Consult the package insert for the most current and complete 
information including U.S. Boxed Warnings pertaining to severe 
diarrhea and severe myelosuppression. 
 
Common known potential toxicities, > 10%:   
Central nervous system: Fatigue, fever, pain, headache 
Dermatologic: Alopecia, rash 
Gastrointestinal: Nausea, vomiting, diarrhea, constipation, 
abdominal pain, anorexia, stomatitis 
Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia, 
neutropenic fever/sepsis 
Neuromuscular & skeletal: Weakness 
Respiratory: Dyspnea, cough 
 
Less common known potential toxicities, 1% - 10%:  
Hepatic: Transient increase in liver enzymes 
Neuromuscular & skeletal: Paresthesia 
Miscellaneous: Sepsis 
 
Rare known potential toxicities, < 1% (Limited to important or 
life-threatening):  
Abdominal pain, allergic reactions, anaphylactoid reactions, 
angioedema, bleeding (severe, associated with thrombocytopenia), 
dermatitis (severe), injection site reactions (mild erythema, 
bruising), neutropenic colitis, pancytopenia, pruritus (severe) 
 
15.48 Drug Procurement   
Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
 
 
15.49 Nursing Guidelines 
 
15.491 Monitor CBC.  The dose-limiting toxicity is leukopenia.  WBC 
count decreases with increasing doses.  When drug is 


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administered at  1.5 mg/m2/day for 5 days, an80-90% decrease in 
WBC count at nadir is typically seen after the first cycle. 
 
 
 
 
15.492 Neutropenia is not cumulative.  Grade 4 neutropenia (<500 
cells/mm3) is most common during the first cycle (60% of the 
patients) and occurs in approximately 39% of all cycles, with a 
median duration of 7 days.  Nadir occurs at approximately the 
median of 12 days.  Sepsis is possible.  Watch for profound 
neutropenia and instruct patient in low count precautions and to 
report signs of infection to health care team immediately. 
 
 
 
 
15.493 Monitor PLT count.  Grade 4 thrombocytopenia (< 25,000/mm3) 
occurs in approximately 27% of patients and in 9% of cycles, 
with a median duration of 5 days and platelet nadir at a median of 
15 days.  Platelet transfusion may be needed.  Instruct patient to 
report any unusual bleeding or bruising. 
 
 
 
15.494 Monitor HGB.  Grade 3 or 4 anemia occurs in approximately 
37% of patients and in 14% of cycles.  Median nadir is seen at 
day 15.  Transfusions have been needed in approximately 50% of 
patients. 
 
 
 
 
15.495 Myelosuppression can be more severe when drug is given with 
cisplatin. 
 
 
 
 
15.496 Nausea is experience by approximately 65% of patients.  
Vomiting is experienced by approximately 45%.  Diarrhea by 
approximately 30%.  Premedicate with anti-emetics and monitor 
for their effectiveness. Administer anti-diarrheals as indicated.  
Assess status. 
 
 
 
 
15.497 Encourage paced activities and frequent rest periods to deal with 
the fatigue which is experienced by approximately 30% of 
patients. 
 
15.498 Approximately 28% of patients experience stomatitis.  Advise 
patient in cryotherapy preventive measures, try treating with 
vitamin E oil if stomatitis occurs. 
 
15.499a Monitor LFT’s and renal function. Dose reductions may be 
necessary in those with hepatic and renal dysfunction. 
 
15.499b Advise patients of possible reversible alopecia which has been 
seen in 49% of patients. 
 
 


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15.5 
Bevacizumab (Avastin®)   
 
15.51 Background 
Bevacizumab is classified as an Anti-VEGF Monoclonal Antibody and a 
Vascular Endothelial Growth Factor (VEGF) Inhibitor. Bevacizumab is a 
recombinant, humanized monoclonal immunoglobulin G1 (IgG1) antibody which 
binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing 
its association with endothelial receptors, Flt-1 and KDR. VEGF binding initiates 
angiogenesis (endothelial proliferation and the formation of new blood vessels). 
The inhibition of microvascular growth is believed to retard the growth of all 
tissues (including metastatic tissue).  
 
15.52 Formulation 
Commercially available for injection 25 mg/mL (4 mL, 16 mL). 
 
15.53 Preparation, storage, and stability 
Refer to package insert for complete preparation and dispensing instructions. 
Store intact vials at refrigeration temperature (2ºC to 8ºC), protect from light, do 
not freeze or shake. Prior to infusion, dilute prescribed dose of bevacizumab in 
100 mL 0.9% NaCl. Do not mix with dextrose-containing solutions. Diluted 
solutions are stable for up to 8 hours under refrigeration. 
 
15.54 Administration   
IV infusion, usually after the other antineoplastic agents. Refer to treatment 
section for specific order of administration. Infuse the initial dose over 90 
minutes. Infusion may be shortened to 60 minutes if the initial infusion is well 
tolerated. The third and subsequent infusions may be shortened to 30 minutes if 
the 60-minute infusion is well tolerated. Monitor closely during the infusion for 
signs/symptoms of an infusion reaction. Some institutions use a 10-minute 
infusion (0.5 mg/kg/minute) for bevacizumab dosed at 5 mg/kg. 
 
 
15.55 Pharmacokinetic information 
Distribution: Vd: 46 mL/kg (limited extravascular distribution) 
Half-life elimination: ~20 days (range: 11-50 days) 
Clearance: 2.75-5 mL/kg/day. A low serum albumin and high tumor 
burden increase clearance by 30% and 7% respectively.  Clearance 
increases with increasing body weight, and is 15% slower in women than 
men. 
Time to steady state: 100 days 
 
 
15.56 Potential Drug Interactions   
Increased Effect/Toxicity: Bevacizumab may increase the levels/effects of 
anthracyclines, Irinotecan, Sorafenib, and Sunitinib. Serum concentrations 
of irinotecan’s active metabolite may be increased by bevacizumab; an 
approximate 33% increase has been observed. 
 
15.57 Known potential adverse events 
Consult the package insert for the most current and complete information. 
U.S. Boxed Warnings include severe or fatal hemorrhage, including 
hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, 
epistaxis, and vaginal bleeding. Avoid use in patients with serious 


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hemorrhage or recent hemoptysis. Percentages reported as Monotherapy 
and as part of combination chemotherapy regimens.  
Common known potential toxicities, > 10%:   
Cardiovascular: Hypertension, thromboembolic events, hypotension. 
Central nervous system: Pain, headache, dizziness, fatigue, sensory 
neuropathy. 
Dermatologic: Alopecia, dry skin, exfoliative dermatitis, skin 
discoloration. 
Endocrine & metabolic: Hypokalemia. 
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, 
stomatitis, gastrointestinal hemorrhage, dyspepsia, taste disorder, 
flatulence, nausea, vomiting, weight loss. 
Hematologic: Hemorrhage, neutropenia, leukopenia. 
Neuromuscular & skeletal: Weakness, myalgia, back pain. 
Ocular: Tearing increased. 
Renal: Proteinuria. 
Reproductive system and breast disorders: Ovarian failure, vaginal 
hemorrhage. As an IgG1, bevacizumab may be secreted in human milk. 
Women should avoid breast feeding. 
Respiratory: Upper respiratory infection, epistaxis, dyspnea, rhinitis 
Miscellaneous: Infection, pneumonia, catheter infection, wound infections. 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: DVT, venous thrombus/embolus, arterial thrombosis, 
syncope, intra-abdominal venous thrombosis, cardio-/cerebrovascular 
arterial thrombotic event, CHF, left ventricular dysfunction, 
supraventricular tachycardia. 
Central Nervous System: Confusion, abnormal gait, CNS hemorrhage, 
reversible posterior leukoencephalopathy syndrome (RPLS), syncope 
Dermatologic: Acne, nail disorder, pruritus, rash desquamation, skin ulcer, 
urticaria, and wound dehiscence. 
Ear and labyrinth disorders: Vertigo 
Endocrine& metabolic: Dehydration, hyperglycemia, hyponatremia.   
Gastrointestinal: Xerostomia, colitis, ileus, gingivitis, fistula, 
gastroesophageal reflux, gastrointestinal perforation, intra-abdominal 
abscess, mouth ulceration, tooth abscess, gastritis, gingival pain, ileus, 
gastrointestinal ulcer 
Genitourinary: Polyuria/urgency, vaginal hemorrhage. 
Hematologic: Anemia, febrile neutropenia/infection, thrombocytopenia, 
decreased hemoglobin, increased prothrombin time  
Hepatic: Bilirubinemia. 
Nervous system disorders: Peripheral sensory neuropathy 
Neuromuscular & skeletal: Bone pain  
Renal: Acute kidney injury, hematuria 
Respiratory: Voice alteration (hoarseness), cough, pneumonitis/pulmonary 
infiltrates, hemoptysis, pulmonary embolism 
Miscellaneous: Infusion reactions may include rash, urticaria, fever, rigors, 
hypertension, hypotension, wheezing, or hypoxia. Anaphylactic and 
anaphylactoid-type reactions.  
 


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Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Anastomotic ulceration, angina, cerebral infarction, gall bladder 
perforation, hemorrhagic stroke, hypertensive crises, hypertensive 
encephalopathy, intestinal necrosis, intestinal obstruction, mesenteric 
venous occlusion, microangiopathic hemolytic anemia (when used in 
combination with Sunitinib), acute coronary syndrome, heart failure, 
myocardial infarction, ventricular arrhythmia, ventricular fibrillation, nasal 
septum perforation, nephrotic syndrome, renal failure, pancytopenia, 
polyserositis, pulmonary hemorrhage, pulmonary hypertension, renal 
failure, renal thrombotic microangiopathy, subarachnoid hemorrhage, 
toxic anterior segment syndrome, transient ischemic attack, ureteral 
stricture, wound healing complications 
 
15.58 Drug procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal 
commercial supply chain or wholesaler. 
 
 
15.59 Nursing Guidelines  
15.591 
Monitor patients closely for infusion type reactions, including fever, 
chills, myalgias, rigors, or other allergic reactions.  While this is less 
likely given that bevacizumab is a humanized antibody, there still 
exists the potential for severe allergic reactions.  If these signs or 
symptoms occur stop the infusion immediately and contact MD.  Have 
emergency equipment nearby and be prepared to administer emergency 
treatment as ordered by MD. 
 
15.592 
Monitor urine dipstick or UPC as required by the test schedule 
 
15.593 
Evaluate IV site regularly for signs of infiltration. 
 
15.594 
Bleeding in the absence of thrombocytopenia is a dose limiting 
toxicity.  Monitor patient closely for hemorrhagic events, including 
CNS hemorrhage, epistaxis, hematemesis and hemoptysis.  Most cases 
of bleeding have occurred at the tumor site.  Advise patient about the 
potential for bleeding or thrombosis. 
 
15.595 
In patients receiving treatment for lung cancer, hemoptysis and 
pulmonary hemorrhage occurred in up to 10% of patients in one study.  
Monitor these patients especially closely.  
 
15.596 
Patient may experience Grade 1-2 nausea, however vomiting is 
uncommon.  Medicate as ordered and monitor for effectiveness.  
 
15.597 
Monitor for skin rash, instruct patient to report to MD. 
 
15.598  
Monitor blood pressure.  Administer antihypertensives as ordered by 
MD. 
  
15.599a  Monitor for signs and symptoms of deep vein thrombosis (DVT) or 
pulmonary embolism (PE), or myocardial infarction (MI) including 


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new or worsening angina.  These have been reported with therapy.  
Instruct patient to report any calf pain, chest pain or shortness of breath 
to MD immediately.  
 
15.599b  Asthenia and headache were reported commonly during therapy (in up 
to 70% and 50% of patients respectively).  Administer acetaminophen 
as needed.  Monitor for its effectiveness.  Avoid the use of aspirin, or 
ibuprofen as this may interfere with the coagulation cascade and 
further add to the risk of bleeding. 
 
15.599c  Monitor CBC, including platelets.  Instruct patient to report signs and 
symptoms of infection, unusual bruising or bleeding to the MD. 
  
15.599d  Patients receiving warfarin therapy for thrombosis should have their 
PT or INR monitored weekly until two stable therapeutic levels are 
attained.  For patients on warfarin for venous access prophylaxis, 
routine monitoring is satisfactory. 
 
15.599e  A rare but serious complication of bevacizumab is wound dehiscence.  
Patients who have had recent surgery or have other open wounds 
should be monitored carefully. 
 
15.599f  Gastrointestinal perforation with or without abdominal abscess is rare 
but possible.  This may present itself as vague abdominal pain 
associated with constipation and vomiting.  Instruct patient to report 
abdominal pain to the MD.  
 
15.599g  Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a 
rare (<1%) but serious condition.  Presenting symptoms may include 
changes in mental status, visual disturbance, seizure, or other CNS 
changes.  Patients with this syndrome generally had HTN as well, 
therefore BP monitoring is important.  Instruct patient to report any 
mental status changes, visual changes, seizures, or other CNS changes 
to the MD immediately.  These may be a sign of RPLS or more 
serious condition, such as hemorrhagic event in the CNS.  
 
15.599h  Warn female patients of the possibility of ovarian failure and 
subsequent infertility. Vaginal hemorrhage is also possible. Instruct 
patients to report any heavy or unusual vaginal bleeding to health care 
team. 
 
 
16.0  Statistical Considerations and Methodology  
 
16.1 
Overview 
This study will be a single-stage phase II study to determine the initial clinical 
benefit of Avatar directed chemotherapy.  Patients will receive any one of 4 
treatment arms (A-D) based on the result of their Avatar.  The primary endpoint 
will be the percentage of patients with a confirmed tumor response, pooled across 
all 4 treatment arms. The null hypothesis will be set at a 20% for a confirmed 


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response, which is the typical response rate observed with standard treatment (see 
section 1 for details).  The Avatar directed chemotherapy approach will be 
deemed worthy of further investigation if 40% or more of patients have a 
confirmed response.  Secondary endpoints will consist of progression-free 
survival (PFS), overall survival (OS), and adverse events.  In addition, this study 
will also assess a couple translational endpoints as well.   
 
 
16.11 
Primary Endpoint 
The primary endpoint of this trial is the proportion of patients with a 
confirmed tumor response, where we will pool across all patients.  The 
confirmed response rate will be estimated using RECIST 1.1 criteria.  A 
confirmed tumor response is defined to be either a CR or PR noted as the 
objective status on 2 consecutive evaluations at least 4 weeks apart.  
Confirmed tumor response will be evaluated using the first 6 cycles of 
treatment.  All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for tumor 
response.  Eligible patients who go off treatment early, prior to being 
evaluated for response, will be considered as failures.   
 
16.12 Sample Size  
The one-stage study design is fully described in Section 16.2.  Fifty-three 
evaluable patients will be accrued onto this phase II study unless undue 
toxicity is encountered.  We anticipate accruing an additional 7 patients to 
account for ineligibility, cancellation, major treatment violation, or other 
reasons.  Therefore, maximum accrual is expected to be 60 patients.  We 
anticipate pre-registering 240 patients in order to register a total of 60 
patients per the study design. 
 
16.13 Accrual Time and Study Duration 
The anticipated accrual rate is approximately 2 patients per month.  
Therefore, the accrual period for this phase II study is expected to be 
approximately  30 months.  The final analysis can begin approximately 40 
months after the trial begins, i.e. as soon as the last patient has been 
followed for around 6 months plus time for data entry and clean-up. 
 
16.2 
Statistical Design 
 
16.21 Decision Rule  
The largest confirmed response rate where the proposed Avatar directed 
chemotherapy approach would be considered ineffective in this population 
is 20%, and the smallest confirmed response rate that would warrant 
subsequent studies with this approach in this patient population is 40%.  
The following one-stage design uses 53 evaluable patients to test the null 
hypothesis that the true confirmed response rate in this patient population 
is at most 20%.  
 


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16.211 Final Analysis Decision Rule 
Enter 53 evaluable patients into the study.  If 15 or fewer patients 
have a confirmed tumor response, we will consider this Avatar 
directed chemotherapy approach to be ineffective in this patient 
population.  If 16 or more patients have a confirmed tumor 
response (30%), we may recommend further testing of this 
approach in subsequent studies in this patient population. 
 
16.212 Over Accrual  
If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or 
used in any decision making process.  Analyses involving over 
accrued patients is discussed in Section 16.35. 
 
16.213 Data and Safety Monitoring   
The principal investigator(s) and the study statistician will 
review the study at least twice a year to identify accrual, 
adverse event, and any endpoint problems that might be 
developing. The trial is monitored continually by the study 
team who are notified of every grade 4 and 5 event in real 
time. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing 
accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
Any safety issues requiring protocol changes are 
communicated through protocol amendments. 
 
Adverse Event Stopping Rule: Based on previous 
experience with this disease, we expect approximately 30% 
of patients to experience Grade 4+ adverse events.  If at any 
time, 8 of the initial 20 patients or 40% of all patients (i.e., 
when accrual is greater than 20 patients), have experienced 
any Grade 4 or 5 adverse event (at least possibly related to 
the study treatment), accrual to the study will be suspended 
to allow for a full review of the data.  Each grade 5 event 
will be reviewed on a case by case basis in a real time 
fashion to determine whether study accrual should be 
suspended.  After consideration by the study team [ie, 
Study Chair(s), Statistician, Operations Office, etc] and 
consultation with representatives at the primary Internal 
Review Board (IRB) affiliated with the Operations Office, 
a decision will be made as to whether and how the study 
will proceed.  
 
16.22 Power and Significance Level 
Assuming that the number of confirmed responses is binomially 
distributed, the significance level is 5% when the true confirmed response 


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rate is 20% and the power is 95% when the true confirmed response rate is 
40%.   
 
16.23 Other Considerations  
Toxicity, quality/duration of response, and patterns of treatment failure 
observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the 
study. 
 
16.3 
Analysis Plan 
 
16.31 Primary Endpoint   
The proportion of confirmed responses (i.e. successes) will be estimated 
by the number of successes divided by the total number of evaluable 
patients.  Ninety-five percent confidence intervals for the true success 
proportion will be calculated according to the exact Binomial method.  
The primary analysis will pool across all patients, but we will also look at 
the tumor reponse rate by treatment arm as well in an exploratory fashion.   
 
16.32 Definitions and Analyses of Secondary Endpoints 
Note:  All of these secondary analyses will be conducted across all 
patients and by treatment arm). 
 
16.321 Progression-Free Survival (PFS)  
PFS is defined as the time from registration to the first of either 
disease progression or death from any cause.  Patients who 
receive the study drug, but then never return for an evaluation 
will be censored on their last follow-up date.  PFS will be 
estimated using the method of Kaplan-Meier. 
 
16.322 Overall survival (OS) is defined as the time from registration to 
death from any cause.  OS will be estimated using the method of 
Kaplan-Meier. 
 
16.323 As a descriptive analysis, we will also compare the response 
rates between patients who did or did not receive bevacizumab 
treatment.  For this analysis, we will use the Chi-square or 
Fisher’s Exact test.  We will also report the response rates by 
treatment type as well (bevacizumab or no bevacizumab).  
 
16.33 Adverse Events  
All patients that have intitiated treatment will be considered evaluable for 
adverse event (AE) analyses.  The maximum grade for each type of AE 
will be recorded for each patient, and frequency tables will be reviewed to 
determine AE patterns.   
 
16.34 Translational Endpoints 


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 To determine the correlation between patient response and 
response in their Avatar.  This analysis will be highly exploratory 
and will focus on the frequency (%) of patients who had an Avatar 
response and a clinical tumor response for the same treatment.  We 
will report the overall concordance rate and confidence interval as 
well.     
 
 To enrich the Avatar response signature in response to Avatar-
directed therapy using patient outcomes.  This will be an 
exploratory analysis that will use the outcome data from this trial 
to inform future work using Avatar directed therapy.    
 
 
16.35 Over Accrual  
If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals as though they were accrued for the 
final analysis. 
 
16.4 
Inclusion of Women and Minorities 
 
16.41 This study will be available to all eligible women, regardless of race or 
ethnic origin. 
 
16.42 There is no information currently available regarding differential effects of 
this regimen in subsets defined by race or ethnicity, and there is no reason 
to expect such differences to exist.  Therefore, although the planned 
analysis will, as always, look for differences in treatment effect based on 
racial groupings, the sample size is not increased in order to provide 
additional power for subset analyses. 
 
16.43 Based on prior studies involving similar disease sites, we expect about  
10% of patients will be classified as minorities by race and all will be 
women.  Expected sizes (per study design) of racial by gender subsets are 
shown in the following table: 
 
Accrual Estimates by Gender/Ethnicity/Race  
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
0 
3 
Not Hispanic or Latino 
57 
0 
57 
Ethnic Category: Total of all subjects 
60 
0 
60 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 


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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Asian 
3 
0 
3 
Black or African American 
3 
0 
3 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
White 
54 
0 
54 
Racial Category: Total of all subjects 
60 
0 
60 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 
 
17.0 
Pathology Considerations/Tissue Biospecimens  
 
None.  
 
 
18.0 
Records and Data Collection Procedures   
 
 
 
18.1 
Submission Timetable  
 
Pre-Registration Material(s) 
 
Case Report Form (CRF) 
Pre-Screen Phase  
(No active testing) 
Pre-Registration Screening Failure  
Complete only if patient is NOT registered 
 after he/she is pre-registered 
 


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Initial Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study  
≤ 14 days after registration 
 
RECIST Measurement - Baseline 
End of Active Treatment/Cancel 
Notification  
Submit  14 days after registration if 
withdrawal/refusal occurs prior to  
beginning protocol therapy 


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Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation  
during treatment 
At end of treatment 
Evaluation/Treatment  
X 
X 
Adverse Event  
X 
X 
RECIST Measurement  
X 
X 
End of Active Treatment/Cancel 
Notification  
 
X 
ADR/AER 
At each occurrence 
(See Section 10.0) 
 
 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase 1 
Every 3 
months  
Until PD 2 
At PD 2 
Every 6 Months  
After PD 
Death 
New Primary 
Event Monitoring  
X 2 
X  
X 
X 
At each 
occurrence 
 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Submit relevant radiographic images as a digital image with a viewing tool free of marks 
that may obscure the lesions or bias the evaluation of the independent reviewer(s) of tumor 
response at baseline, tumor response and/or progression.  Submit copy of documentation of 
response or progression to the MC1463 Principal Investigator, 
 
 
 
19.0 
Budget  
 
19.1 
Costs Charged to Patient 
 
 
Routine Clinical Care 
 
19.2 
Tests to be Research Funded 
None. 


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20.0 
References 
 
Armstrong D.K., Bundy B., Wenzel L., Huang H.Q., Baergen R., Lele S. et al. Intraperitoneal 
cisplatin and paclitaxel in ovarian cancer. NEJM. 354:34-43, 2006. 
http://www.ncbi.nlm.nih.gov/pubmed/16394300.  
 
Barnholtz-Sloan J.S., Schwartz A.G., Qureshi F., Jacques S., Malone J., Munkarah A.R. Ovarian 
cancer: changes in patterns at diagnosis and relative survival over the last three decades. Am J 
Obstet Gynecol. 189:1120-7, 2003. http://www.ncbi.nlm.nih.gov/pubmed/14586365. 
 
Bankert R.B., Balu-Iyer S.V., Odunsi K., Shultz L.D., Kelleher R.J., Jr., Barnas J.L. et al. 
Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites 
formation, and metastasis. PloS one. 6:e24420, 2011.  PMC3174163. 
 
D'Andrea A.D. The Fanconi Anemia/BRCA signaling pathway: disruption in cisplatin-sensitive 
ovarian cancers. Cell Cycle. 2:290-2, 2003. 
 
Drevs J., Hofmann I., Hugenschmidt H., Wittig C., Madjar H., Muller M. et al. Effects of 
PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine 
kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell 
carcinoma model. Cancer Res. 60:4819-24, 2000. 
http://www.ncbi.nlm.nih.gov/pubmed/10987292.  
 
Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R. et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
J Cancer. 45:228-47, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19097774. 
 
Elkas J.C., Baldwin R.L., Pegram M., Tseng Y., Slamon D., Karlan B.Y.  A human ovarian 
carcinoma murine xenograft model useful for preclinical trials. Gynecol Oncol. 87:200-6, 2002.  
http://www.ncbi.nlm.nih.gov/pubmed/12477452.  
 
Garrido-Laguna I., Uson M., Rajeshkumar N.V., Tan A.C., de Oliveira E., Karikari C. et al. 
Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor 
survival and resistance to gemcitabine in patients with pancreatic cancer. Clin Cancer Res. 
17:5793-800, 2011. PMC3210576. 
 
George J., Alsop K., Etemadmoghadam D., Hondow H., Mikeska T., Dobrovic A.  et al. Non-
equivalent gene expression and copy number alterations in high-grade serous ovarian cancers 
with BRCA1 and BRCA2 mutations. Clin Cancer Res. 19:3474-84, 2013.  
 
Gordon A.N., Fleagle J.T., Guthrie D., Parkin D.E., Gore M.E., Lacave A.J. Recurrent epithelial 
ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus 
topotecan. J. Clin Oncol 19:3312-22, 2001. http://www.ncbi.nlm.nih.gov/pubmed/11454878.  
 
 


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Haluska P., Oberg A.L., Glaser G., Gonzalez S.E., Becker M.A., Jacob K.A. et al. Ovarian 
Avatar Project: A Model System for Individualizing Ovarian Cancer Therapy. Ann Oncol. 23:75. 
2012.  http://annonc.oxfordjournals.org/content/23/Suppl_1/i26.full.pdf+html.  
 
Horner M.J., Ries L.A.G., Krapcho M., Neyman N., Aminou R., Howlader N. et al. SEER 
Cancer Statistics Review, 1975-2006. National Cancer Institute. Bethesda, MD; 2009. 
 
Integrated genomic analyses of ovarian carcinoma. Nature. 474:609-15, 2011. 
http://www.ncbi.nlm.nih.gov/pubmed/21720365.  
 
Konstantinopoulos P.A., Spentzos D., Karlan B.Y., Taniguchi T., Fountzilas E., Francoeur N. et 
al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy 
and with outcome in patients with epithelial ovarian cancer. J. Clin Oncol 28:3555-61, 2010. 
PMC2917311. 
 
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difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst. 
86:1530-3, 1994. http://www.ncbi.nlm.nih.gov/pubmed/7932808.  
 
Markman M., Hall J., Spitz D., Weiner S., Carson L., Van Le L. et al. Phase II trial of weekly 
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9, 2002. http://www.ncbi.nlm.nih.gov/pubmed/11981009. 
 
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paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal 
cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 101:436-40, 2006. 
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Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III 
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Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in 
patients with platinum-resistant ovarian cancer. J Clin Oncol. 25:2811-8, 2007. 
http://www.ncbi.nlm.nih.gov/pubmed/17602086.  
 
Nemati F., Sastre-Garau X., Laurent C., Couturier J., Mariani P., Desjardins L. et al. 
Establishment and characterization of a panel of human uveal melanoma xenografts derived from 
primary and/or metastatic tumors. Clin Cancer Res 16:2352-62, 2010. 
 
Ojeda Gonzalez B., Gonzalez Martin A., Bover Barcelo I., Fabregat i Mayol X., Mellado B., 
Rubio Perez M.J. et al. A phase II trial of fixed-dosed rate gemcitabine in platinum-resistant 
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Product Information: AVASTIN® intravenous injection solution, bevacizumab intravenous 
injection solution. Genentech, Inc. (per FDA), South san Francisco, CA 2014. 
 
Pujade-Lauraine E., Helpert F., Weber B. et al.  Bevacizumab combined with chemotherapy for 
platinum-resistance recurrent ovarian canner: The AURELIA open-lable randomized phase III 
trial. J Clin Oncol 32(13): 1302-08, 2014. 
 
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Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian 
Cancer: a randomized multicenter phase II trial of the North-Eastern German Society of 
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Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nature 
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in ovarian cancer. Ann Oncol. 10:853-5, 1999. http://www.ncbi.nlm.nih.gov/pubmed/10470434  
  
van Persijn van Meerten E.L., Gelderblom H., Bloem J.L. RECIST revised: implications for the 
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Appendix I: ECOG Performance Status Criteria 
 
  
 
ECOG Performance Status Scale 
 
Grade 
Description 
0 
 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
 
3 
 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
 
4 
 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
 
5 
 
Dead. 
 
 


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Appendix II: Local Medical Oncologist Contact Letter (Avatar in Production) 
 
 
Date 
 
Re: (Patient Name),  
(Mayo Clinic Patient Registration Number) 
 
Dear Dr. (Name), 
 
When your patient (name) had surgery at the Mayo Clinic, she agreed to participate in a study 
that allowed use of her tumor specimen for research purposes.  We would like to share with you 
information about a research study that used her tumor specimen.  We are attempting to develop 
a patient-derived xenograft, also known as an Avatar, which may be able to guide treatment 
should the patient have a platinum-resistant recurrence of her disease.  We have implanted tumor 
specimens in research mice and are propagating them in hopes that we can grow the tumors and 
then treat the mice with the most common second-line chemotherapy agents such as paclitaxel, 
doxil, topotecan or gemcitabine.  Should the Avatar be successfully established and your patient 
experience a platinum resistant recurrence of her disease, we would ask (Name) to return to 
Mayo Clinic to discuss participating in Avatar directed chemotherapy, with the most successful 
agent being disclosed to you or her treating medical oncologist. 
 
Key points about the study: 
 
 Platinum resistance will be defined as recurrence of disease <6 months from the 
completion of platinum-based chemotherapy.  If you are unsure whether the patient is 
platinum-sensitive or platinum-resistant, please contact us prior to initiating treatment, as 
treatment for platinum-resistant disease prior to learning of the Avatar data would make 
her ineligible for the study. 
 
 The patient may receive her chemotherapy in your office – we would simply ask that you 
stay in contact with us as to her treatment status 
 
 If the patient has treatment in your office, we would ask that she comes to Mayo for 
evaluation and then for scans every other cycle as required by the study.  We will share 
these scans with you. 
 
 The patient can receive bevacizumab (Avastin) as an AURELIA-eligible regimen. 
 
 There is no cost to the patient for the Avatar generation. Treatment and evaluation by CT 
or MRI imaging is a standard of care treatment.  There are no further biopsies or research 
blood draws needed. 
 
If you have any questions or concerns, please feel free to contact me.  I have included citations 
for some recent publications on the Avatars.  
 
 


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Sincerely, 
(Mayo Site PI) 
(Telephone number) 
 
Citations: 
1.  Clin Cancer Res. 2014 Mar 1;20(5):1288-97. doi: 10.1158/1078-0432.CCR-13-2611. Epub 
2014 Jan 7 
 
2.  Biochim Biophys Acta. 2015 Mar 14;1855(2):223-234. doi: 10.1016/j.bbcan.2015.03.002 
 
3. Front Oncol. 2013 Dec 4;3:295. doi: 10.3389/fonc.2013.00295 
 


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Appendix III: Local Medical Oncologist Contact Letter (Existing Avatar) 
 
 
Date 
 
Re: (Patient Name),  
(Mayo Clinic Patient Registration Number) 
 
Dear Dr. (Name), 
 
When your patient (name) had surgery or a biopsy at the Mayo Clinic, she agreed to participate 
in a study that allowed use of her tumor specimen for research purposes.  We would like to share 
with you information about a research study that used her tumor specimen.  We have developed 
a patient-derived xenograft, also known as an Avatar, which may be able to guide treatment 
should the patient have a platinum-resistant recurrence of her disease.  We have implanted tumor 
specimens in research mice and grown the tumors.  We are treating the mice with the most 
common second-line chemotherapy agents such as paclitaxel, doxil, topotecan or gemcitabine.  
Should your patient experience a platinum resistant recurrence of her disease, we would ask 
(Name) to return to Mayo Clinic to discuss participating in Avatar directed chemotherapy, with 
the most successful agent being disclosed to you or her treating medical oncologist. 
 
Key points about the study: 
 
 Platinum resistance will be defined as recurrence of disease <6 months from the 
completion of platinum-based chemotherapy.  If you are unsure whether the patient is 
platinum-sensitive or platinum-resistant, please contact us prior to initiating treatment, as 
treatment for platinum-resistant disease prior to learning of the Avatar data would make 
her ineligible for the study. 
 
 The patient may receive her chemotherapy in your office – we would simply ask that you 
stay in contact with us as to her treatment status 
 
 If the patient has treatment in your office, we would ask that she comes to Mayo for 
evaluation and then for scans every other cycle as required by the study.  We will share 
these scans with you. 
 
 The patient can receive bevacizumab (Avastin) as an AURELIA-eligible regimen. 
 
 There is no cost to the patient for the Avatar generation. Treatment and evaluation by CT 
or MRI imaging is a standard of care treatment.  There are no further biopsies or research 
blood draws needed. 
 
If you have any questions or concerns, please feel free to contact me.  I have included citations 
for some recent publications on the Avatars.  
 
 


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Sincerely, 
(Mayo Site PI) 
(Telephone number) 
 
Citations: 
1.  Clin Cancer Res. 2014 Mar 1;20(5):1288-97. doi: 10.1158/1078-0432.CCR-13-2611. Epub 
2014 Jan 7 
 
2.  Biochim Biophys Acta. 2015 Mar 14;1855(2):223-234. doi: 10.1016/j.bbcan.2015.03.002 
 
3. Front Oncol. 2013 Dec 4;3:295. doi: 10.3389/fonc.2013.00295 
 


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Appendix IV: Patient Contact Letter (Avatar in Production) 
 
 
 
Date 
 
(Patient Name) 
(Mayo Clinic Patient Registration Number) 
(Patient Home Address) 
 
Dear (Title) (Name), 
 
Previously, you granted permission for tumor tissue removed during your surgery or biopsy at 
Mayo Clinic to be used for future research.  As part of this future research, we have transferred 
tumor tissue to a mouse in an attempt to successfully produce an ‘Avatar’, a tumor model that 
reproduces the original tumor.   
 
We have previously shown that patients respond to chemotherapy very much like their Avatars.  
We are hoping now to be able to produce and use the Avatar to help identify the best 
chemotherapy for the patient in a clinical research study. 
 
This research study would be conducted only if the cancer recurs and becomes resistant to 
treatment with platinum-based chemotherapy (such as carboplatin).  We would ask patients to 
return to Mayo Clinic at this time to  sign consent and register for the study.  All chemotherapy 
treatments are FDA-approved and may be given by your local medical doctor at home; however, 
please note that you would be asked to return to Mayo Clinic every 8 weeks to have a CT or MRI 
scan to determine if your cancer is responding well to the treatment.  
 
There is no cost to participate in this study beyond the normal clinical costs of treating the cancer 
(such as chemotherapy drugs and CT or MRI scans, etc.). 
 
If you are interested in possibly taking part in this study, or if you would like more information, 
please contact (study coordinator) at (telephone). 
 
Sincerely, 
(Mayo Clinic Site PI) 
 
 
 
 
 
 
 
 
 


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Appendix V: Patient Contact Letter (Existing Avatar) 
 
 
 
Date 
 
(Patient Name) 
(Mayo Clinic Patient Registration Number) 
(Patient Home Address) 
 
Dear (Title) (Name), 
 
Previously, you granted permission for tumor tissue removed during your surgery at Mayo Clinic 
to be used for future research.  As part of this future research, we have transferred tumor tissue to 
a mouse and successfully produced an ‘Avatar’, a tumor model that reproduces the original 
tumor.   
 
We have previously shown that patients respond to chemotherapy very much like their Avatars.  
We are hoping now to use the Avatar to help identify the best chemotherapy for the patient in a 
clinical research study. 
 
This research study would be conducted only if the cancer recurs and becomes resistant to 
treatment with platinum-based chemotherapy (such as carboplatin).  We would ask patients to 
return to Mayo Clinic at this time to sign consent and register for the study.  All chemotherapy 
treatments are FDA-approved and may be given by your local medical doctor at home; however, 
please note that you would be asked to return to Mayo Clinic every 8 weeks to have a CT or MRI 
scan to determine if your cancer is responding well to the treatment.  
 
There is no cost to participate in this study beyond the normal clinical costs of treating the cancer 
(such as chemotherapy drugs and CT or MRI scans, etc.). 
 
If you are interested in possibly taking part in this study, or if you would like more information, 
please contact (study coordinator) at (telephone). 
 
Sincerely, 
(Mayo Clinic Site PI)