Clinical trial NCT03456700
Conditions: Ovarian Serous Tumor Recurrent Ovarian Carcinoma
Sponsor: Mayo Clinic
Start date: 2018-03-30; Completion date: 2019-07-31
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well auranofin and sirolimus work in treating participants with ovarian cancer. Immunosuppressive therapy, such as auranofin and sirolimus, is used to decrease the body?s immune response and may increase blood cell count.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the overall tumor response rate (ORR, that is, complete response \[CR\] + partial response \[PR\]) of the combination of auranofin and sirolimus in the setting of metastatic serous ovarian cancer across all patients.

SECONDARY OBJECTIVES:

I. To estimate the overall tumor response rate (ORR, that is, complete response \[CR\] + partial response \[PR\]) of the combination of auranofin and sirolimus in the setting of metastatic serous ovarian cancer within patients that have overexpression of PKCiota.

II. To estimate progression-free survival, overall survival, and adverse events from the combination of auranofin and sirolimus.

CORRELATIVE OBJECTIVES:

I. To explore whether PKCiota-relevant biomarkers in serous ovarian cancer tumors are associated with treatment response patterns, such as ORR, progression free survival, and overall survival.

OUTLINE:

Participants receive auranofin orally (PO) once daily (QD) and sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

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

Arms: arm 1: Participants receive auranofin PO QD and sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Interventions: intervention 1: Auranofin intervention 2: Laboratory Biomarker Analysis intervention 3: Sirolimus
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
MC1761 
Protocol Version Date: 11Jul2018 
Mayo Clinic Cancer Center 
Phase II Trial to Evaluate the Efficacy of Auranofin and Sirolimus in Serous Ovarian Cancer 
Patients with Recurrent Disease 
 
Study Chairs: 
Aminah Jatoi MD 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
507/284-2511 
 
Study Co-investigators: 
 
 
 
 
Statistician: 
 
 
 
 
√Study contributor(s) not responsible for patient care 
Funded in part by Mayo Clinic Ovarian SPORE 
Drug Availability 
Supplied Commercial Agents: auranofin and sirolimus (IND 136802) 
 
 
Document History 
(Effective Date) 
Activation 
30Mar2018 
MCCC Amendment 1 
03Aug2018 
 
 
 
 
 
 
 




MC1761 
3 
 
Protocol Version Date: 11Jul2018 
Table of Contents 
Phase II Trial to Evaluate the Efficacy of Auranofin and Sirolimus in Serous Ovarian Cancer Patients 
with Recurrent Disease ................................................................................................................................. 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 9 
3.0 
Registration Patient Eligibility .................................................................................................... 10 
4.0  
Study Calendar ............................................................................................................................ 11 
5.0 
Grouping Factors: None .............................................................................................................. 12 
6.0 
Registration Procedures .............................................................................................................. 13 
7.0 
Protocol Treatment ...................................................................................................................... 15 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 16 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 18 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 18 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 27 
12.0 
Descriptive Factors ..................................................................................................................... 31 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 32 
14.0 
Biospecimen Collection: None ................................................................................................... 32 
15.0 
Drug Information ........................................................................................................................ 33 
16.0  
Statistical Considerations and Methodology ............................................................................... 38 
17.0  
Pathology Considerations/Tissue Biospecimens......................................................................... 43 
18.0 
Records and Data Collection Procedures .................................................................................... 46 
19.0  
Budget ......................................................................................................................................... 46 
20.0 
References ................................................................................................................................... 47 
Appendix I 
ECOG Performance Status ............................................................................................... 50 
Appendix II 
Patient Medication Diary .................................................................................................. 51 
Appendix III 
Strong CYP3A4 Inhibitors ................................................................................................ 53 
 


MC1761 
4 
 
Protocol Version Date: 11Jul2018 
Schema 
Registration 
↓ 
auranofin + sirolimus 
↓ 
At any time: 
disease progression or 
intolerable adverse effects or 
patient refusal 
↓ 
Event Monitoring 
Cycle = 28 days  
 
Generic name: auranofin 
Brand name(s): Ridura® 
Mayo Abbreviation: AURANOFIN 
Availability: Supplied Commercial 
Generic name: sirolimus 
Brand name(s): Rapamune® 
Mayo Abbreviation: RAPA 
Availability: Supplied Commercial 




MC1761 
6 
 
Protocol Version Date: 11Jul2018 
Figure 3: The combination of a gold compound 
(in this instance, ATM) and an mTOR inhibitor (in 
this instance, Rapamycin) yielded synergistic 
tumor kill that exceeded what was observed with 
either drug alone (unpublished). 
Figure 2: A) PKCι launches the PKCι-Par6-Ect2-Mek-Erk signaling pathway in 
ovarian cancer, as shown with a schematic overview of this pathway. B) PKCι 
leads to a decrease in Ect2 phosphorylation as well as a decrease in pMek and 
pErk. C) PKCι inh bits MMP10 (*p<0.05 compared to no treatment (NT) controls). 
D) Of note, PRKCI and ECT2 are co-amplified in ~80% of primary ovarian serous 
carcinomas. E) Also, PRKCI, ECT2 and MMP10 mRNA are strongly expressed in 
primary ovarian serous tumors. 
 
in ovarian cancer initiation 
and growth. PKCι directly 
phosphorylates AMOT at 
Thr750, thereby directly 
inhibiting YAP1 binding; 
conversely, inhibition of 
PKCι decreases YAP1 
nuclear localization and 
blocks ovarian tumor 
growth both in vitro and in 
vivo [13] (Figure 1). Third, 
from a practical standpoint, 
the Fields’ Laboratory has 
used high throughput 
screening to identify gold 
compounds as inhibitors of 
PKCι [21,22]. Auranofin 
have been available for 
years, can be purchased for 
clinical use, and can now 
be “repurposed” for 
further testing in the clinic 
as an antineoplastic agent.  
 
1.4 
The Addition of mTOR Inhibition.  
mTOR is downstream of PI3K and is often co-
amplified (PIK3CA) with PRKCI on 3q26 in 
high grade ovarian serous carcinoma, as per 
data from the Cancer Genome Atlas (TCGA). 
The Fields Laboratory has shown that 
inhibition of the mTOR pathway with 
clinically available agents such as sirolimus 1) 
invokes inhibition of a separate, independent 
antineoplastic pathway for treating ovarian 
cancer; 2) is synergistic (Figure 1); and 3) is 
feasible in view of the clinical availability of 
two drugs – auranofin and sirolimus – both of 
which lend themselves to drug repurposing and 
provide a scientifically compelling argument 
for testing these drugs in combination.  
This approach of combining drugs is very 
much in keeping with the widespread use of 
multi-drug regimens in cancer treatment. For 
this reason, our group sought synergy between 
inhibition of the PKCι pathway and inhibition of the mTOR pathway. The latter was chosen 
because it represents a distinctly independent pathway that leads to tumor cell survival and 
chemoresistance (Figure 1). The gold compound, aurothiomalate (ATM), in combination with an 
mTOR inhibitor (Rapamycin) yields synergistic tumor kill and marked reduction in tumor 




MC1761 
8 
 
Protocol Version Date: 11Jul2018 
auranofin and sirolimus in NSCLC (MC1213) started at 3mg and reduced to 1mg but also 
increased to 6mg and 9mg if tolerated. 
1.7 
Summary 
This protocol represents the culmination of a well-delineated approach that builds on decades of 
preclinical data from the Fields’ Laboratory, is eminently feasible with 2 clinically available 
drugs that can be repurposed to treat cancer, and has already shown clinical signs of 
therapeutic promise. The foregoing justifies the study of this combination in patients with 
ovarian cancer. 
NOTE: While patient care fot this trial is being done in Rochester, MN, the Fields’ Laboratory in 
Jacksonville, FL will receive available patient specimens from this trial for analysis as delineated 
on the title page. 
 
 
 


MC1761 
9 
 
Protocol Version Date: 11Jul2018 
2.0 
Goals  
2.1 
Primary Goal 
To estimate the overall tumor response rate (ORR, that is, complete response (CR) + 
partial response (PR)) of the combination of auranofin and sirolimus in the setting of 
metastatic serous ovarian cancer across all patients 
2.2 
Secondary Goal 
2.21 
Key secondary endpoint: To estimate the overall tumor response rate (ORR, that 
is, complete response (CR) + partial response (PR)) of the combination of 
auranofin and sirolimus in the setting of metastatic serous ovarian cancer within 
patients that have overexpression of PKCι.  
2.22 
To estimate progression-free survival, overall survival, and adverse events from 
the combination of auranofin and sirolimus 
2.3 
Correlative Research 
To explore whether PKCiota-relevant biomarkers in serous ovarian cancer tumors are 
associated with treatment response patterns, such as ORR, progression free survival, and 
overall survival 
 
 


MC1761 
10 
 
Protocol Version Date: 11Jul2018 
3.0 
Registration Patient Eligibility 
3.1 
Inclusion Criteria  
3.11 
Age ≥18 years. 
3.12 
Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (see 
Appendix I) 
3.13 
 Subjects must have histologically confirmed high grade ovarian, fallopian tube, 
or primary peritoneal carcinoma of serous histology (any of these three are 
referred to in this protocol as “ovarian cancer”) 
3.14 
Incurable cancer 
3.15 
Willingness to provide paraffin-embedded tissue blocks of ovarian cancer 
3.16 
Measurable disease (see Section 11.0) 
3.17 
The following laboratory values obtained ≤14 days prior to registration: 
• 
ANC ≥1500 µL 
• 
PLT ≥100,000 µL 
• 
Hgb ≥9 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) or direct bilirubin 
≤ULN 
• 
SGOT (AST) and SGPT (ALT) ≤3 x ULN or SGOT (AST) and SGPT 
(ALT) ≤5 x ULN is acceptable if liver has tumor involvement 
• 
Creatinine ≤1.5 x ULN 
• 
Fasting serum glucose ≤1.5 x ULN 
• 
Total cholesterol ≤1.5 x ULN 
• 
Triglycerides ≤1.5 x ULN 
3.18 
Life expectancy ≥12 weeks 
 
3.2 
Exclusion criteria 
3.21 
Platinum-sensitive disease (exceptions allowed: patient has had a hypersensitivity 
reaction to platinum or the treating oncologist thinks that further platinum 
therapy is not in the patient’s best interest). 
3.22 
Morbidities or concurrent major illness (for example, bowel obstruction or a 
second active malignancy) that, in the opinion of the treating healthcare provider, 
would make participation in the trial problematic 
3.23 
Leptomeningeal disease or uncontrolled brain metastasis. 
3.24 
Failure to recover from acute, reversible effects of prior therapy regardless of 
interval since last treatment.  
NOTE: Patients can have peripheral (sensory) neuropathy. 
3.25 
History of hypertriglyceridemia or hypercholesterolemia and currently on 
medication(s). 
3.26 
Use of St. John’s Wort ≤7 days prior to registration. 
3.27 
Unable to discontinue use of a strong CYP3A4 inhibitor (see Appendix III). 
 
 


MC1761 
11 
 
Protocol Version Date: 11Jul2018 
4.0  
Study Calendar 
4.1 
Test schedule for ovarian cancer 
 
 
 
 
 
 
Tests and procedures 
≤28 days prior 
to registration 
≤14 days prior 
to registration 
≤7 days prior 
to registration 
Prior to the start of 
each treatment cycle, 
Cycle 2 and beyond  
End of all protocol 
treatment for any reason 
window 
 
 
 
±3 days 
±7 days 
History and exam, weight, PS  
X 
 
 
X 
X 
Height 
X 
 
 
 
 
Adverse event assessment 
 
X 
 
X 
X 
Urine pregnancy test1 
 
 
X 
 
 
Hematology group: CBC with differential 
 
X 
 
X 
X 
Chemistry panel 
Alanine aminotransferase (ALT) 
Aspartate aminotransaminase (AST)  
Alkaline phosphatase  
Total or direct bilirubin 
Creatinine  
 
X 
 
X 
X 
Lipid profile including cholesterol, triglycerides 
Fasting serum glucose 
 
X 
 
X 
 
Urinalysis/urine protein dipstick 
 
X 
 
X2 
 
CA-1253 
X 
 
 
X 
 
Tumor measurement4 
X 
 
 
X 
X 
Patient Medication Diary (Appendix II)5 
 
 
 
X 
X 
Mandatory submission of archived research tissue 
specimens (see Section 17.0) R 
X6 
 
 
 
 
Optional submission of tissue obtained at the time of 
progression (See Section 17.0)R 
 
 
 
 
X 
                                                     
1 For persons of childbearing potential only. NOTE: Most patients (99%) will be unable to bear children due to the cancer being studied. 
2 If nephrotic range proteinuria is suspected, then a 24-hour urine collection is suggested. 
3 Use same timing as tumor measurements: to be done at the completion of Cycles 2, 4, 6, etc., until disease progression or treatment discontinuation. 
4 Tumor measurements (CT or MRI) are to be done at the completion of Cycles 2, 4, 6, etc., until disease progression or treatment discontinuation. Use same 
imaging throughout the study. 
5 The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution OR compliance 
must be documented in the medical record by any member of the care team. 
6 If the patient makes every effort to submit a tissue block, but this material is unable to be obtained, this mandatory submission can be waived. 


MC1761 
12 
 
Protocol Version Date: 11Jul2018 
Cycle = 28 days; R=Research funded (see Section 19.0) 
 
4.2 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 6 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. 
If a patient is still alive 3 years after registration, no further follow-up is required. 
 
 
5.0 
Grouping Factors: None 
 
 


MC1761 
13 
 
Protocol Version Date: 11Jul2018 
6.0 
Registration Procedures 
6.1 
Registration 
6.11 
Patient registration 
Access the Mayo Clinic Cancer Center (MCCC) web page and enter the 
registration/randomization application. The registration/randomization application 
is available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the Web site. If unable to access the Web site, call the 
MCCC Registration Office at 
 between the hours of 8 a.m. and 4:30 
p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page (http://hsrwww.mayo.edu/ccs/training) and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions. It is the responsibility of the 
individual and institution registering the patient to confirm the process has been 
successfully completed prior to release of the study agent. Patient registration via 
the registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact the MCCC Registration Office 
. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Verification 
Prior to accepting the registration, the registration application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
6.2 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval of the study 
• 
Patient eligibility 
• 
Grouping factor 
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
). If the necessary documentation is not submitted in advance of attempting 


MC1761 
14 
 
Protocol Version Date: 11Jul2018 
patient registration, the registration will not be accepted and the patient may not be enrolled 
in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.4 
Correlative studies 
6.41 
A mandatory correlative research component is part of this study; the patient will 
be automatically registered onto this component. 
6.42 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered to this component. 
• 
Patient has/has not given permission to give tissue specimens for research 
purposes 
At the time of registration, the following will also be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.5 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist or endocrinologist  
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.7 
Baseline symptoms 
All required baseline symptoms must be documented and graded. 
6.8 
Study drug is available on site  
Study drug is available on site for this patient. 
 
 


MC1761 
15 
 
Protocol Version Date: 11Jul2018 
7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Treatment medication table 
Agent 
Dose Level 
Route 
Day 
ReRx 
auranofin 
6 mg/day 
PO 
1-28 (continuous) 
every 28 days 
sirolimus 
5 mg/day 
PO 
1-28 (continuous) 
every 28 days 
7.12 
For the purposes of this study, a treatment cycle is 28 days. 
7.2 
Auranofin and sirolimus 
Take both drugs together as one dose. Each dose is to be taken at the same time of the day 
under the same conditions, i.e., if fasting, then should be fasting every time; if taken with 
food, should be taken with food every time. Each dose should be separated by 24 hours 
(±4 hours).  
Definition of fasting conditions: At least 2 hours after last food consumption and at least 1 
hour before next food consumption. 
If patient misses a dose and it is more than 5 hours after usual time, then patient should 
skip that dose and resume regular dose the next day. 
7.3 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
 
 


MC1761 
16 
 
Protocol Version Date: 11Jul2018 
8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The 
patient does make up the delayed dose(s) when the patient meets the protocol 
criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at 
the start of the next cycle, then the dose will remain lowered for that entire subsequent 
cycle.  
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
 
Dose 
Level 
Auranofin 
Sirolimus 
0* 
6 mg/day 
5 mg/day 
-1 
6 mg/day 
2 mg/day 
-2 
3 mg/day 
2 mg/day 
*Dose level 0 refers to the starting dose. 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current  
version 4.03* unless otherwise specified   
 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
 
 


MC1761 
17 
 
Protocol Version Date: 11Jul2018 
8.2 
Dose Modifications for Auranofin and Sirolimus 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
Investigations 
Cholesterol high 
Grade 2 
 
Institute appropriate lipid/cholesterol lowering 
therapy 
Hold auranofin and sirolimus until levels return 
to Grade 1 
If unresolved by four weeks, discontinue 
auranofin and sirolimus and go to event 
monitoring 
 
Grade 3 or 4 
 
Discontinue auranofin and sirolimus and go to 
event monitoring 
 
Neutrophil count 
decreased  
Grade 4 
Platelet count 
decreased  
Grade 4 
 
Delay therapy until ANC ≥1500 
and/or PLT ≥100,000, and decrease by 1 dose 
level 
Discontinue auranofin and sirolimus if AE 
persists beyond 14 days or if patient is already at 
dose level -2 and go to event monitoring  
 
Neutrophil count 
decreased  
Grade 3 
Platelet count 
decreased  
Grade 3 
auranofin 
sirolimus 
Delay therapy until ANC ≥1500 and/or PLT 
≥100,000 
If delay is 1 week or less, resume at prior dose 
If delay exceeds 7 days but is not more than 
14 days, decrease by 1 dose level 
Discontinue auranofin and sirolimus if AE 
persists beyond 14 days or if subject is already 
at dose level -2 and go to event monitoring 
Metabolism and 
nutrition disorders 
Hypertriglyceridemia 
Grade 2 
 
Institute appropriate lipid/cholesterol lowering 
therapy 
Hold auranofin and sirolimus until levels return 
to Grade 1 
If unresolved by four weeks, discontinue 
auranofin and sirolimus therapy and go to event 
monitoring 
 
Grade 3 or 4  
 
Discontinue auranofin and sirolimus and go to 
event monitoring. 
Respiratory, thoracic 
and mediastinal 
disorders 
Interstitial pneumonitis 
any grade 
 
Discontinue auranofin and sirolimus and go to 
event monitoring 
Other non-hematologic 
adverse events (includes 
gastrointestinal 
symptoms) 
Grade 3 or 4 
 
Discontinue auranofin and sirolimus and go to 
event monitoring 
If patient is deriving benefit, then discuss further 
treatment with PI 
Renal and urinary 
disorders 
Proteinuria 
auranofin 
Hold auranofin if 1-3.4 grams of protein are 
detected in a 24 hour urine collection 
For Grade 3 proteinuria (>3.5 grams) 
discontinue auranofin and sirolimus and go to 
event monitoring. 
 
 
 




MC1761 
19 
 
Protocol Version Date: 11Jul2018 
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).  
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 4.03 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.03. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site: 
 
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. 




MC1761 
21 
 
Protocol Version Date: 11Jul2018 
10.32 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. 
CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the 
event will not be reported in an 
expedited manner1 
General disorders and 
administrations site 
conditions 
Fatigue  
≤Grade 3 
Malaise 
≤Grade 3 
Skin and subcutaneous 
tissue disorders 
Alopecia 
Any Grade 
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. 
 
 










MC1761 
26 
 
Protocol Version Date: 11Jul2018 
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. In addition, any 
infant death after 28 days that the Investigator suspects is related to the 
in utero exposure to the study drug should also be reported. 
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 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation. Grading is per CTCAE v4.03 unless alternate 
grading is indicated in the table below: 
CTCAE 
System/ Organ/ Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic system 
disorders 
Anemia 
X 
X 
Gastrointestinal disorders 
# of stools 
X 
 
Diarrhea 
 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Mucositis Oral 
X 
X 
General disorders and  
Fever 
X 
X 
administration site conditions 
Fatigue 
X 
X 
Immune system disorders 
Allergic reaction 
X 
X 
Investigations 
Platelet Count Decreased  
X 
X 
 
Neutrophil Count Decreased 
X 
X 
 
White Blood Cell Decreased 
X 
X 
Musculoskeletal and  
Myalgia 
X 
X 
connective tissue disorders 
Arthralgia 
X 
X 
Nervous system disorders 
Dizziness 
X 
X 
Renal and urinary disorders 
Proteinuria 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
X 
X 
Skin and subcutaneous 
Palmar-plantar erythrodysesthesia 
syndrome 
X 
X 
tissue disorders 
Rash maculo-papular 
X 
X 
 


MC1761 
27 
 
Protocol Version Date: 11Jul2018 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in Section 
10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study treatment 
or procedure regardless of attribution to the study treatment or 
procedure. 
10.6232 
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/Measurement of Effect  
This protocol uses RECIST 1.1 criteria {Eisenhauer & Therasse 2009} [26] 
11.1 
Schedule of Evaluations 
Evaluations using RECIST will then be performed at completion of Cycles 2, 4, 6, etc until 
disease progression or discontinuation of all protocol treatment. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21  Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
11.212 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.  
11.22 Non-Measurable Disease 
11.221 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, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable as well. 


MC1761 
28 
 
Protocol Version Date: 11Jul2018 
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. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 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.  
11.32 Acceptable Modalities for Measurable Disease: 
Conventional CT and MRI: 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: 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.  
11.33 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 6 weeks 
(see Section 11.44). 
• 
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 ATC after chemoradiation can 
represent fibrotic tissue) 
 
 


MC1761 
29 
 
Protocol Version Date: 11Jul2018 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.21) 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 11.21), 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 measurements 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 diameter 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 diameter 
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 target lesion or target 
lymph node 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. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) 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 11.433. 
11.43 Response Criteria 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT 
must be measured on re-evaluation 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,  
 
 


MC1761 
30 
 
Protocol Version Date: 11Jul2018 
11.432 
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 11.41). 
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 
(Section 11.41). In addition, the PBSD must also demonstrate an 
absolute increase of at least 0.5 cm from the MSD.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
11.433 
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 
a reduction in short axis to <1.0 cm. 
c. Tumor markers, such as Ca125, if 
followed, has normalized. 
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.)  
 
 
 




MC1761 
32 
 
Protocol Version Date: 11Jul2018 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who have not had disease progression and have experienced acceptable toxicity are 
to continue treatment per protocol until documentation of progressive disease, unacceptable 
toxicity or refusal.  
13.2 
Criteria for discontinuation of all protocol treatment 
• 
Disease progression 
• 
Request by patient to discontinue all protocol treatment 
• 
Unacceptable toxicity 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree or require discontinuation of all protocol 
treatment 
• 
Administration of radiotherapy, non-protocol chemotherapy, immunotherapy, 
biological agents, or an experimental drug  
• 
Development of new primary cancer 
• 
Ineligibility 
Patients who discontinue protocol treatment due to any of the above reasons will proceed to 
event monitoring phase of the trial where patient and disease status until death or a 
maximum of 3 years post-registration. Further treatment is at the discretion of the patient’s 
medical team. 
13.3 
Definition of 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.  
• 
If the patient received protocol treatment and is deriving benefit, the patient may 
continue on study per protocol as if the patient was eligible. If the patient chooses to 
end protocol treatment, then all data up until the point of treatment discontinuation 
must be submitted. No further data submission is necessary. 
• 
If the patient never received any protocol treatment, on-study material (except 
biospecimens) and the End of Active Treatment/Cancel Notification Form must be 
submitted. No further data submission is necessary. 
13.4 
Definition of cancel 
A patient who cancels before any study treatment is given does not need to be followed 
further. On-study material (except biospecimens) and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
14.0 
Biospecimen Collection: None 
 


MC1761 
33 
 
Protocol Version Date: 11Jul2018 
15.0 
Drug Information 
15.1  
Auranofin for Oral Administration (Ridaura®) 
15.11 Background: Auranofin is a gold compound which has anti-inflammatory 
effects. Gold compounds can alter the immune response and have been shown to 
inhibit prostaglandin synthesis. 
15.12 Formulation: Commercially available for oral administration as: Capsules: 3 mg 
[gold 29%] 
15.13 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room temperature. 
Dispense in a tight, light-resistant container. 
15.14 Administration: Refer to the treatment section for specific administration 
instructions. 
15.15 Pharmacokinetic information: 
Absorption: ~25% of the gold in a dose of Auranofin is absorbed from the 
gastrointestinal tract 
Protein binding: Moderate. In blood, approximately 60% of the gold is bound to 
plasma proteins; the remainder is present in red blood cells 
Metabolism: Rapidly metabolized (the intact molecule has not been detected in 
blood) 
Half-life elimination: Blood: 21 – 31 days. Tissue: 42 -128 days Excretion: 
60% of the absorbed gold (15% of the administered dose) is excreted in the urine; 
the remainder of the dose is excreted in the feces 
15.16 Potential Drug Interactions: 
In a single patient-report, there is the suggestion that concurrent administration of 
Auranofin and phenytoin may have increased phenytoin blood levels. 
15.17 Known potential adverse events: 
Consult the package insert for the most current and complete information. 
Auranofin is contraindicated in patients with a history of any gold-induced 
disorders: anaphylactic reactions, necrotizing enterocolitis, pulmonary fibrosis, 
exfoliative dermatitis, bone marrow aplasia or other severe hematologic 
disorders. 
Common known potential toxicities, >10%: 
Dermatologic: pruritus, skin rash (acneiform or macular popular) 
Gastrointestinal: diarrhea, loose stools, stomatitis 
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Alopecia, urticaria 
Gastrointestinal: Nausea, vomiting, anorexia, flatulence, dyspepsia, constipation, 
dysgeusia, glossitis 
Genitourinary: Proteinuria, hematuria 
Hematologic and oncologic: Anemia, eosinophilia, leukopenia, 
thrombocytopenia 
Heaptic: Increased serum transaminases 
Ophthalmic: Conjunctivitis 
 
 


MC1761 
34 
 
Protocol Version Date: 11Jul2018 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Agranulocytosis, aplastic anemia, angioedema, bronchitis (gold), corneal 
deposits, dysphagia, exfoliative dermatitis (other gold compounds), fever, 
gastrointestinal hemorrhage, gingivitis, hepatotoxicity, interstitial pneumonitis, 
jaundice, metallic taste, melena, neutropenia, pancytopenia, peripheral 
neuropathy, pure red cell aplasia, ulcerative enterocolitis 
15.18 Drug procurement 
Commercial supplies: Study will purchase for enrolled patients. 
15.19 Nursing Guidelines: 
15.191 
Auranofin is contraindicated in patients with history of gold- induced 
disorders. Assess patients for any of these conditions, hold drug and 
notify study team. 
15.192 
Dermatitis is common and is exacerbated by sunlight. Instruct patients 
to avoid prolonged sun exposure without protection (i.e sunscreen SPF 
30+ and covering up with clothing). 
15.193 
Patients may experience hair loss. Warn patients of this possibility. 
15.194 
Gastrointestinal side effects are common (diarrhea, constipation, 
nausea, vomiting, etc.) Treat symptomatically and assess for 
effectiveness. 
15.195 
Monitor LFTs as elevated liver enzymes have been seen. Report 
elevations to study physician. 
15.196 
Cytopenias can be seen. Rarely these can be serious. Monitor CBC 
w/differential. Instruct patients to report any excessive bruising or 
bleeding and/or signs/symptoms of infection to study team. 
15.197 
Instruct patients to report any hematuria to the study team. 
15.198 
Pneumonitis has been reported rarely, but can be serious and life- 
threatening. Instruct patients to report any cough, shortness of breath, 
and/or chest pain to the study team immediately. 
 
15.2 
Sirolimus for Oral Administration (Rapamune®) 
15.21 Background: Sirolimus inhibits T-lymphocyte activation and proliferation in 
response to antigenic and cytokine stimulation and inhibits antibody production. 
Its mechanism differs from other immunosuppressants. Sirolimus binds to FKBP- 
12, an intracellular protein, to form an immunosuppressive complex which 
inhibits the regulatory kinase, mTOR (mammalian target of Sirolimus). This 
inhibition suppresses cytokine mediated T-cell proliferation, halting progression 
from the G1 to the S phase of the cell cycle. It inhibits acute rejection of 
allografts and prolongs graft survival. 
15.22 Formulation: Commercially available for oral administration as: Solution, oral: 
1 mg/mL (60 mL) Tablet: 1 mg, 2mg 
15.23 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral solution under refrigeration 
and protect from light. Store tablets at room temperature and protect from light. 


MC1761 
35 
 
Protocol Version Date: 11Jul2018 
15.24 Administration: Refer to the treatment section for specific administration 
instructions. 
Tablet: Administer consistently either with or without food. Do not crush, split 
or chew. 
Solution: Mix with at least 2 ounces (60mL) of water or orange juice. No other 
liquids should be used for dilution. Patient should drink diluted solution 
immediately. The cup should then be refilled with an additional 4 ounces 
(120mL) of water or orange juice, stirred vigorously, and the patient should drink 
the contents at once. 
15.25 Pharmacokinetic information: (Note: Sirolimus tablets and oral solution are not 
bioequivalent, due to differences in absorption) 
Absorption: Rapid 
Distribution: 12 L/kg (range: 4-20 L/kg) 
Protein binding: 92%, primarily to albumin Bioavailability: Oral solution: 
14%; Oral tablet:18% Time to peak, serum: 1-2 hours 
Metabolism: Extensively via P-glycoprotein and hepatic via CYP3A4; to 7 
major metabolites Half-life elimination: 62 hours (range: 46-78 hours); 
extended in hepatic impairment (Child-Pugh class A or B) to 113 hours 
Excretion: Feces (91% due to P-glycoprotein-mediated efflux into gut lumen); 
urine (2%) 
15.26 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major), P-glycoprotein; 
Inhibits CYP3A4 (weak) 
Increased Effect/Toxicity: Cyclosporine may increase sirolimus concentrations 
during concurrent therapy; Sirolimus should be taken 4 hours after cyclosporine 
oral solution (modified) and/or cyclosporine capsules (modified). CYP3A4 
inhibitors may increase the levels/effects of Sirolimus. Refer to package insert for 
a list of CYP3A4 inhibitors. 
Concurrent use of ACE inhibitors may increase the risk of angioedema. 
Concurrent live organism vaccines may increase the adverse/toxic effect of the 
vaccine; vaccinial infections are possible (avoid concurrent use). 
Voriconazole may decrease the metabolism (via CYP isoenzymes) of sirolimus 
(avoid concurrent use). Concurrent therapy with calcineurin inhibitors 
(cyclosporine, tacrolimus) may increase the risk of HUS/TTP/TMA. 
Decreased Effect: CYP3A4 inducers may decrease the levels/effects of 
sirolimus. Vaccination (dead organisms) may be less effective with concurrent 
sirolimus (monitor). 
Ethanol/Nutrition/Herb Interactions: 
Food: Do not administer with grapefruit juice; may decrease clearance of 
sirolimus. Ingestion with high-fat meals decreases peak concentrations but 
increases AUC by 23% to 35%. Sirolimus should be taken consistently either 
with or without food to minimize variability. 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. 
Warnings: 
• 
Anaphylactic or hypersensitivity reactions 


MC1761 
36 
 
Protocol Version Date: 11Jul2018 
• 
Angioedema 
• 
Infections (immunosuppressive agents, including sirolimus, increase 
the risk of infection) 
• 
Interstitial lung disease 
• 
Hyperlipidemia 
• 
Lymphocele/fluid accumulation 
• 
Malignancy (immunosuppressive agents including sirolimus, may be 
associated with the development of lymphoma and other malignancies 
including skin cancer) 
• 
Proteinuria 
• 
Renal effects (increased serum creatinine and decreased GFR) 
• 
Wound dehiscence/healing 
Common or severe toxicity: Hypertension, edema, capillary leak syndrome, 
hypertriglyceridemia, hypokalemia, constipation, diarrhea, dyspepsia, nausea and 
vomiting, deep venous and arterial thrombosis, abnormal liver function tests, 
sepsis, arthralgia, headache, renal failure, pulmonary hemorrhage, 
thrombocytopenia and leukopenia. 
Note that abnormal liver function tests could rarely lead to severe liver damage 
associated with pulmonary edema, ascites and/or pericardial effusion. 
Note that rarely thrombocytopenia can be prolonged for more than 2 weeks. 
15.28 Drug procurement: Commercial supplies. Study will purchase for enrolled 
patients. 
15.29 Nursing Guidelines: 
15.291 
Patients should be instructed that tablets should be swallowed whole, 
and not crush, split or chewed. If solution is used, it should be mixed 
with at least 2 ounces of water or orange juice. No other liquids should 
be used for dilution. Mixed solution should be drunk immediately, then 
add an additional 4 ounces of water or juice to the cup, stir vigorously 
and again drunk immediately. 
15.292 
Patients should not receive vaccination with live vaccination 
preparations while on study medication. Patients should be instructed 
to check with the study team prior to receiving any vaccine. 
15.293 
Hypertension is a known side effect. Monitor patients BP as outlined in 
the protocol or as symptoms dictate. 
15.294 
Elevated lipid levels, specifically triglycerides can be seen. Monitor 
lipid levels as outlined in the protocol.55 MC1111 
15.295 
Thrombosis (venous and arterial) can be seen. Instruct patient in the 
warning signs of this and to seek out proper medical treatment. 
15.296 
Cytopenias (thrombocytopenia/leukopenia) can be a side effect of 
agent. Instruct patient in signs and symptoms of infection and to report 
any unusual bruising or bleeding to the study team. 
15.297 
Infection (including sepsis) and delayed wound healing are possible. 
Instruct patients to check with the study team prior to having any 


MC1761 
37 
 
Protocol Version Date: 11Jul2018 
invasive procedure done. Instruct patients to report any fever or 
infection symptoms to the study team immediately. 
15.298 
Pneumonitis is seen with this agent. Instruct patients to report any 
cough or shortness of breath to the team. 
15.299a Headache is a known side effect. Administer analgesics as ordered and 
assess for their effectiveness. 
15.299b GI disturbances are common and vary (diarrhea, constipation, nausea, 
vomiting, dyspepsia). Treat symptomatically and assess for 
effectiveness. 
 
 
 


MC1761 
38 
 
Protocol Version Date: 11Jul2018 
16.0  
Statistical Considerations and Methodology 
16.1 
Overview: 
This is a phase 2 trial that seeks to obtain tumor response data and other clinically 
relevant data on the novel combination of auranofin and sirolimus in patients with 
metastatic serous ovarian cancer. The primary endpoint is the confirmed response rate, 
with secondary endpoints of progression-free survival, overall survival, and adverse 
events from the combination of auranofin and sirolimus. 
16.11 Primary Endpoint 
The primary endpoint of this trial is the proportion of patients with a confirmed 
tumor response (PR or CR at least 4 weeks apart). All patients meeting the 
eligibility criteria who have signed a consent form and have begun treatment will 
be evaluable for the confirmed response rate. This response rate primary endpoint 
will be estimated across all patients.  
16.12 Sample Size 
The 1-stage study design with an interim analysis is fully described in 
Section 16.2. 44 evaluable patients will be accrued onto this phase II study unless 
undue toxicity is encountered. We anticipate accruing an additional 4 patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, maximum accrual is expected to be 48 patients. 
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 24 months. 
The final analysis can begin approximately 36 months after the trial begins, i.e. 
as soon as the last patient has been followed for 8 months plus time for data entry 
and clean-up. 
 
16.2  
Statistical Design 
16.21 Decision Rule 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 15%. The smallest response rate that 
would warrant further subsequent studies is 35%. The following Simon optimal 
2-stage design (i.e. one-stage design with an interim analysis) uses 44 evaluable 
patients to test the null hypothesis that the true confirmed response rate in this 
patient population is at most 15%. 
16.211 Final Analysis Decision Rule (full 44 eligible patients):  
Enter 44 evaluable patients. If 10 or fewer patients have a confirmed 
response, we will consider this regimen ineffective in this patient 
population. If 11 or more patients have a confirmed response (25%), we 
may recommend further testing of this regimen in subsequent studies in 
this patient population. If the study is negative based on this endpoint, 
but the key secondary endpoint is positive (see 16.321), we may still 
recommend further testing of this regimen in subsequent studies. 
16.212 Interim Analysis 
An interim analysis will be performed after enrollment of the first 19 
eligible patients. If 3 or fewer responses are observed in these 19 eligible 
patients, the trial will be stopped early for negative results. Otherwise, 
we will continue to full accrual. 


MC1761 
39 
 
Protocol Version Date: 11Jul2018 
16.213 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. 
16.214 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, 4 of the 
initial 10 patients or 40% of all patients (i.e., when accrual is 
greater than 10 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 responses is binomially distributed, the significance 
level is 5% when the true confirmed response rate is 15% and the power is 90% 
when the true confirmed response rate is 35%. See table below.  
If the true success proportion (p) is . . . . . . 
0.15 
0.20 
0.25 
0.30 
0.35 
then the probability of declaring that the 
regimen warrants further studies is . . . . . . 
0.05 
0.22 
0.50 
0.76 
0.90 
and the probability of stopping at the interim 
analysis is. . . . . . . . 
0.68 
0.46 
0.26 
0.13 
0.06 
 
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. 
 
 


MC1761 
40 
 
Protocol Version Date: 11Jul2018 
16.3 
Analysis Plan 
16.31 Primary Endpoint 
The proportion of responses 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. 
16.32 Definitions and Analyses of Secondary Endpoints  
16.321  Key Secondary Endpoint 
The key secondary endpoint of this trial is the proportion of patients with 
a confirmed tumor response (PR or CR at least 4 weeks apart) in the 
subset of patients that have overexpression of PKCι. The hope is that in 
this subset, we’ll see a higher response rate than across all patients. We 
expect that around 60% of patients will have overexpression of PKCι, so 
we expect that around 30 patients will be positive for this marker (27 or 
so eligible). The hypothesis is that the observed response rate in this 
subgroup should be around 40% or higher. With 27 eligible patients, 
we’d have 88% power to detect a true response rate of 50%, assuming a 
5% significance level if the true response rate is 25%. To consider this 
subgroup significant and positive, we need to observe 11+ responses in 
the first 27 eligible patients (41%). If the primary endpoint is negative, 
but this key secondary endpoint is positive, we will still consider moving 
this treatment regimen forward into future trials.  
16.322 Progression-Free Survival 
Progression-free survival (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. 
16.323 Overall Survival 
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. 
16.33 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 Analysis of Translational Component 
We will use previously-described immunohistochemistry methods and 
expression assessment methods [2-4]. Overexpression of PKCι will be compared 
to response using 2x2 tables and chi-square or Fisher exact tests. Assuming 
around 60% of patients have overexpression of PKCι, we expect around 27 
eligible patients with overexpression and 17 eligible without (44 eligible total); if 
the tumor response rate across all patients is around 30%, we expect around 12 
responses. The trial has 86% power at an alpha of 10% to declare a significant 
association between PKCι and response if most of the responses occur within the 
PKCι overexpression group (11/27 (41%)) vs. 6% in the unexpressed group 


MC1761 
41 
 
Protocol Version Date: 11Jul2018 
(1/17). This is based on a 2-sided Chi-square test of equal proportions using 
nQuery Advisor 7.0. 
We will also correlate overexpression of PKCι with PFS and OS using Kaplan-
Meier methods and the log-rank test. This translational study is considered 
exploratory and hypothesis generating due to the small proposed sample size for 
this study.  
16.4 
Inclusion of Women and Minorities 
16.41 Study availability 
This study will be available to all eligible women, regardless of race or ethnic 
origin. 
16.42 Differential effects by race or ethnicity 
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 Study population 
Based on prior studies involving similar disease sites, we expect about 20% 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 
5 
0 
5 
Not Hispanic or Latino 
43 
0 
43 
Ethnic Category: Total of all subjects 
48 
0 
48 
Racial Category 
American Indian or Alaskan Native 
2 
0 
2 
Asian 
2 
0 
2 
Black or African American 
4 
0 
4 
Native Hawaiian or other Pacific Islander 
2 
0 
2 
White 
38 
0 
38 
Racial Category: Total of all subjects 
48 
0 
48 
 
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 


MC1761 
42 
 
Protocol Version Date: 11Jul2018 
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. 
 
 
 
 




MC1761 
44 
 
Protocol Version Date: 11Jul2018 
Expression of these markers will be evaluated as described below for correlation with 
response to Auranofin/Sirolimus therapy with the primary clinical endpoint being 
progression free survival. 
Standardization of IHC scoring: A drawback of IHC staining for detection and 
quantification of biomarkers is the inherent variability in IHC staining from analysis to 
analysis and from sample to sample. We will minimize this variability by constructing a 
“standard curve” of staining intensity on a scale from 0 to +3 for each of the potential 
biomarkers using well-characterized archival primary NSCLC tumor tissues. We have 
already constructed such a standard curve TMA for PKCι as follows: First, we performed 
immunohistochemical analysis for PKCι on 4 tissue microarrays (TMAs) containing 
~100 well-characterized archived primary NSCLC cases. Each of the 100 samples were 
scored on a 0 to+3 scale based on PKCι staining intensity by a board certified pathologist. 
A 0 score corresponds to tumor PKC staining equivalent to the surrounding stroma, and 
scores of +1, +2 and +3 correspond to increasing intensity of PKCι staining in the tumor 
specimen compared to the surrounding stroma. 
Tissue blocks from cases corresponding to each numerical value on the intensity scale 
were retrieved and used to construct a new TMA. This “standard curve” TMA contains 4 
NSCLC cases that exhibit a gradient of PKCι staining representative of the full range of 
staining intensity across the original 100 samples (Figure 1). The standard curve will be 
validated by a second pathologist. For our proposed analysis, tissue sections from each 
enrolled patient will be subjected to IHC for PKCι in parallel with a section from this 
“standard curve” TMA. The sections will be analyzed at the same time using the same 
reagents and protocol to ensure uniformity of scoring across samples. 
Each experimental sample will be assigned a score, based on the standard curve on a 0 to 
+3 scale, by two pathologists independently with joint review and resolution of 
discrepancies as necessary. Additionally, image analysis will be performed using 
ImageScope and associated image quantification software. 
A similar approach will be used to generate “standard curve” TMAs for each of the 
potential predictors of response, phospho-Ser 298-Mek, phospho- Thr202/Tyr204-Erk, 
phospho-Ser473-Akt, phospho-Thr70-4E-BP1 and phospho- Ser240/244-S6. IHC scoring 
criteria and interpretation will be guided by published reports evaluating these markers in 
NSCLC cases, and will take into account, as appropriate, not only staining intensity, but 
also percent of tumor cells stained positively and nuclear versus cytoplasmic distribution 
of phospho- antigens. Phospho-Erk scoring will follow the criteria established by 
Cappuzzo et al. Specifically, sections will be scored on the following scale: 0=no tumor 
cells stain positively; +1= more than 10% of the tumor cells stained weakly; +2= more 
than 10% of the tumor cells stained moderately; and +3=more than 10% of the tumor 
cells stained strongly. Phospho-Akt staining will be evaluated based on the criteria 
established by David et al. Scoring will be on the following scale: 0=no staining in tumor 
cells; +1=slightly elevated staining in cytoplasm and/or nucleus as compared with 
stromal elements; +2=moderate staining in tumor cell cytoplasm and/or nucleus; and 
+3=dark staining in tumor cells completely obscuring cytoplasm and/or nucleus. 
Phospho-S6 staining will be scored using the criteria established by Conde et al. 
Specifically, samples will be scored for staining intensity as follows: 0=no tumor 
staining; +1=weak cytoplasmic staining; +2=moderate cytoplasmic staining; and 
+3=strong cytoplasmic staining. Extent of staining will also be scored according to the 
percentage of tumor cells that stain positively for antigen as follows: 0=0% of cells 
staining; +1=≤50% staining; +2=51-75% cells staining; +3=76-85% cells staining; and 
+4=>85% cells staining. The sum of the intensity and extent of scoring will be used as 


MC1761 
45 
 
Protocol Version Date: 11Jul2018 
the final staining score (0-7). In their study, Conde et al. considered tumors with a final 
score of ≥5 as being positive or high-intensity, whereas those with a final score of <5 
were negative or low-intensity. This binary model will be considered in our patient 
sample as described below. No scoring scale has been published for phospho-Ser298- 
Mek or 4E-BP1 staining in primary NSCLC tumors. However, we will consider the 
criteria established by Akcakanat et al. for analysis of 4E-BP1 immunohistochemical 
staining in primary breast cancer tumors. We will establish such interpretation criteria 
based on the staining patterns exhibited by our analysis of the TMA containing our 100 
archival NSCLC cases. Staining intensity, percent positive cells, staining relative to 
surrounding stroma and nuclear/cytoplasmic distribution will be considered as potential 
criteria in devising standard curve TMAs and scoring paradigms for these antigens. Data 
from IHC scoring will be analyzed for correlation with clinical response using standard 
statistical treatments by our staff statistician. 
Specifically, the association of the endpoint of PFS at 4 months with the predictor 
variables PRKCI gene copy number (presence of ≥1 extra copy of the gene) and IHC 
scoring for the given marker will be evaluated using logistic regression models, where an 
odds ratio and 95% confidence interval will be estimated. A separate logistic regression 
model will be utilized for each predictor variable. For each marker, IHC scores will be 
considered as a numerical variable to assess evidence of a linear association, and also as a 
binary categorical variable based on the sample median IHC score for the given marker. 
Given availability of information regarding PFS beyond the time point of interest of 4 
months, in exploratory analyses, associations of the aforementioned predictor variables 
with PFS at any time point will be evaluated using the Kaplan-Meier method and Cox 
proportional hazards models (censoring at the date of last follow-up), which will account 
for the varying lengths of follow-up between patients.  
 


MC1761 
46 
 
Protocol Version Date: 11Jul2018 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.0 and data submission table for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for a cancer diagnosis prior to study entry. 
It also requires documentation (to explain why the patient has come off study therapy.  
These documents should be submitted within 14 days of registration (for prior to study 
entry materials) or within 14 days after the patient comes off study. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete data 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data will be flagged by edit checks in the database. 
18.8 
Overdue lists 
A list of overdue materials is automatically available to each site at any time. A list of 
overdue materials and forms for study patients will be generated monthly. The listings 
will be sorted by location and will include the patient study registration number. The 
appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
18.9 
Data corrections 
If a correction is necessary the QAS/DM will query the site. The query will be sent to the 
appropriate site to make the correction in the database and respond back to the QAS/DM.  
19.0  
Budget 
19.1 
Costs charged to patient: Routine clinical care including tumor assessment scans and 
blood work (labs) related to adverse event assessment 
19.2 
Tests to be research funded: Research studies on paraffin-embedded tissue 
19.3 
Other budget concerns: Supplies of auranofin and sirolimus will be purchased with study 
funds 
 


MC1761 
47 
 
Protocol Version Date: 11Jul2018 
20.0 
References 
1.  https://www.cancer.gov/about-cancer/treatment/drugs/ovarian; last accessed February 10, 2017 
2. Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP. Atypical protein 
kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol 
Chem. 2005;280(35):31109-15. PubMed PMID: 15994303. 
3. Regala RP, Weems C, Jamieson L, Khoor A, Edell ES, Lohse CM, Fields AP. Atypical protein 
kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res. 
2005;65(19):8905-11. PubMed PMID: 16204062. 
4. Erdogan E, Lamark T, Stallings-Mann M, Jamieson L, Pellechia M, Thompson EA, Johansen T, 
Fields AP. Aurothiomalate inhibits transformed growth by targeting the PB1 domain of atypical 
protein kinase Ciota. J Biol Chem. 2006. PubMed PMID: 16861740. 
5. Han Y, Wei F, Xu X, Cai Y, Chen B, Wang J, Xia S, Hu H, Huang X, Han Y, Wu M, Wang M. 
[Establishment and comparative genomic hybridization analysis of human esophageal carcinomas 
cell line EC9706]. 2002;19(6):455-7. PubMe2-4d PMID: 12476413. 
6. Balsara BR, Sonoda G, du Manoir S, Siegfried JM, Gabrielson E, Testa JR. Comparative 
genomic hybridization analysis detects frequent, often high-level, overrepresentation of DNA 
sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas. Cancer Res. 
1997;57(11):2116-20. PubMed PMID: 9187106. 
7. Brass N, Racz A, Heckel D, Remberger K, Sybrecht GW, Meese EU. Amplification of the genes 
BCHE and SLC2A2 in 40% of squamous cell carcinoma of the lung. Cancer Res. 
1997;57(11):2290-4. PubMed PMID: 9187134. 
8. Frederick LA, Matthews JA, Jamieson L, Justilien V, Thompson EA, Radisky DC, Fields AP. 
Matrix metalloproteinase-10 is a critical effector of protein kinase Ciota-Par6alpha-mediated lung 
cancer. Oncogene. 2008;27(35):4841-53. Epub 2008/04/23. doi: 
10.1038/onc.2008.119onc2008119 [pii]. PubMed PMID: 18427549; PubMed Central PMCID: 
PMC2750877. 
9. Yang YL, Chu JY, Luo ML, Wu YP, Zhang Y, Feng YB, Shi ZZ, Xu X, Han YL, Cai Y, Dong 
JT, Zhan QM, Wu M, Wang MR. Amplification of PRKCI, located in 3q26, is associated with 
lymph node metastasis in esophageal squamous cell carcinoma. Genes Chromosomes Cancer. 
2008;47(2):127-36. Epub 2007/11/09. doi: 10.1002/gcc.20514. PubMed PMID: 17990328. 
10. Regala RP, Davis RK, Kunz A, Khoor A, Leitges M, Fields AP. Atypical protein kinase C{iota} 
is required for bronchioalveolar stem cell expansion and lung tumorigenesis. Cancer Res. 
2009;69(19):7603-11. Epub 2009/09/10. doi: 0008-5472.CAN-09-2066 [pii] 
10.1158/0008-5472.CAN-09-2066. PubMed PMID: 19738040; PubMed Central PMCID: 
PMC2756303. 
11. Fields AP, Frederick LA, Regala RP. Targeting the oncogenic protein kinase Ciota signalling 
pathway for the treatment of cancer. Biochem Soc Trans. 2007;35(Pt 5):996-1000. PubMed 
PMID: 17956262. 
12. Fields AP, Regala RP. Protein kinase C iota: human oncogene, prognostic marker and therapeutic 
target. Pharmacol Res. 2007;55(6):487-97. PubMed PMID: 17570678. 


MC1761 
48 
 
Protocol Version Date: 11Jul2018 
13. Wang Y, Justillien V, Brennan KI, Jamieson L, Murray NR, Fields AP. PKCι regulates nuclear 
YAP1 localization and ovarian cancer tumorigenesis. Oncogene 2017; 36:534-545. 
14. Justilien V, Fields AP. Ect2 links the PKCiota-Par6alpha complex to Rac1 activation and cellular 
transformation. Oncogene. 2009. PubMed PMID: 19617897. 
15. Patel R, Win H, Desai S, Patel K, Matthews JA, Acevedo-Duncan M. Involvement of PKC-iota 
in glioma proliferation. Cell Prolif. 2008;41(1):122-35. PubMed PMID: 18211289. 
16. Eder AM, Sui X, Rosen DG, Nolden LK, Cheng KW, Lahad JP, Kango-Singh M, Lu KH, 
Warneke CL, Atkinson EN, Bedrosian I, Keyomarsi K, Kuo WL, Gray JW, Yin JC, Liu J, Halder 
G, Mills GB. Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity 
and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(35):12519-
24. PubMed PMID: 16116079. 
17. Weichert W, Gekeler V, Denkert C, Dietel M, Hauptmann S. Protein kinase C isoform expression 
in ovarian carcinoma correlates with indicators of poor prognosis. Int J Oncol. 2003;23(3):633-9. 
PubMed PMID: 12888898. 
18. Zhang L, Huang J, Yang N, Liang S, Barchetti A, Giannakakis A, Cadungog MG, O'Brien-
Jenkins A, Massobrio M, Roby KF, Katsaros D, Gimotty P, Butzow R, Weber BL, Coukos G. 
Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker 
and potential oncogene in ovarian carcinoma. Cancer Res. 2006;66(9):4627-35. PubMed PMID: 
16651413. 
19. Jatoi A, Radecki Breitkopf C, Foster NR, Block MS, Grudem M, Wahner Hendrickson A, 
Carlson RE, Barrette B, Karlin N, Fields AP. A mixed methods feasibility trial of protein kinase 
C iota inhibition with auranofin in asymptomatic ovarian cancer patients. Oncology 2015; 
88:208-13. 
20. Mansfield AS, Fields AP, Jatoi A, Qi Y, Adjei AA, Erlichman C, Molina JR. Phase 1 dose 
escalation study of the PKC iota inhibitor aurothiomalate for advanced non-small cell lung 
cancer, ovarian cancer, and pancreatic cancer. Anticancer Drugs 2013; 24:1079-83. 
21. Regala RP, Thompson EA, Fields AP. Atypical protein kinase C iota expression and 
aurothiomalate sensitivity in human lung cancer cells. Cancer Res. 2008;68(14):5888-95. Epub 
2008/07/18. doi: 68/14/5888 [pii] 10.1158/0008-5472.CAN-08-0438. PubMed PMID: 18632643; 
PubMed Central PMCID: PMC2662432. 
22. Stallings-Mann M, Jamieson L, Regala RP, Weems C, Murray NR, Fields AP. A novel small-
molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung 
cancer cells. Cancer Res. 2006;66(3):1767-74. PubMed PMID: 16452237. 
23. Patel K, Foster NR, Farrell A, Le-Lindqwister NA, Mathew J, Costello B, Reynolds J, Meyers JP, 
Jatoi A. Oral cancer chemotherapy adherence and adherence assessment tools: a report from the 
North Central Cancer Treatment Group N0747 and a systematic review of the literature. J Cancer 
Educ 2013; 28:770-6. 
24. Halfdanarson TR, Jatoi A. Oral chemotherapy: the critical interplay between patient education 
and patient safety. Curr Oncol Rep 2010; 12:247-52. 


MC1761 
49 
 
Protocol Version Date: 11Jul2018 
25. Jatoi A, Smith EL, Gunderson HD, Hartgers ML, Looker SA, Santana-Davila R, McWilliams 
RR. Capecitabine and temezolomide: design, implementation, and preliminary outcomes from a 
pilot project to ensure safe prescribing of oral chemotherapy. J Oncol Pract 2010; 6:210-2. 
26. Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J 
Cancer 45(2): 228-247, 2009. 
 
 


MC1761 
50 
 
Protocol Version Date: 11Jul2018 
Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From 
 
 
 


MC1761 
51 
 
Protocol Version Date: 11Jul2018 
Appendix II 
Patient Medication Diary 
 
Patient Name  
 
Study ID Number  
 
 
Please complete this diary on a daily basis. Write in the dose of auranofin and sirolimus that you 
took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
Take both drugs together as one dose. Each dose is to be taken at the same time of the day under the same 
conditions, i.e., if fasting, then should be fasting every time; if taken with food, should be taken with food 
every time. Each dose should be separated by 24 hours (±4 hours).  
Definition of fasting conditions: At least 2 hours after eating and at least 1 hour before eating. 
If you miss a dose and it is more than 5 hours after your usual time, then skip that dose and resume your 
regular dose the next day. 
Both your medications must be stored at room temperature. Keep out of reach of children. The 
study medication may not be taken by anyone but you. 
Return any unused medications your dispensed at the time of your next visit. 
 
Week of: 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
auranofin 
 
 
 
 
 
 
 
sirolimus 
 
 
 
 
 
 
 
 
Week of: 
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
auranofin 
 
 
 
 
 
 
 
sirolimus 
 
 
 
 
 
 
 
 
Week of: 
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
auranofin 
 
 
 
 
 
 
 
sirolimus 
 
 
 
 
 
 
 
 
Week of: 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
auranofin 
 
 
 
 
 
 
 
sirolimus 
 
 
 
 
 
 
 
 
 
Patient signature: ___________________________________________ 
Date: _____________________________  
 




MC1761 
53 
 
Protocol Version Date: 11Jul2018 
Appendix III Strong CYP3A4 Inhibitors 
Strong CYP3A4/5 inhibitors: 
Macrolide antibiotics 
Antivirals 
(Protease inhibitors) 
Antifungals 
Others 
clarithromycin 
indinavir 
itraconazole 
conivaptan 
telithromycin 
lopinavir 
ketoconazole 
elvitegravir 
troleandomycin 
nelfinavir 
posaconazole 
mibefradil 
ritonavir 
ritonavir 
voriconazole 
nefazodone 
 
saquinavir 
 
saquinavir 
 
 
 
tipranavir