Clinical trial NCT01737502
Conditions: Extensive Stage Small Cell Lung Carcinoma Lung Adenocarcinoma Recurrent Non-Small Cell Lung Carcinoma Recurrent Small Cell Lung Carcinoma Squamous Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer
Sponsor: Mayo Clinic
Start date: 2014-05-14; Completion date: 2023-04-24
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of auranofin when given together with sirolimus and to see how well it works in treating patients with lung cancer that has spread or other places in the body and cannot be cured or controlled by treatment or has come back after a period of time during which the cancer could not be detected. Auranofin and sirolimus may stop or slow the growth of lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose of auranofin plus sirolimus after at least one line of platinum based chemotherapy for lung cancer (squamous, ras-mutated adenocarcinoma, or small cell lung cancer) patients with no acceptable standard treatment options. (Phase I) II. To assess the progression-free survival at four months of patients treated with auranofin after at least one line of platinum based chemotherapy for lung cancer (squamous, ras-mutated adenocarcinoma, or small cell lung cancer) patients with no acceptable standard treatment options. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the overall survival in this population in comparison to recent historical controls.

II. To determine the adverse events (AE) profile and safety of the regimen. III. To determine the overall response rate, per Response Evaluation Criteria In Solid Tumors (RECIST) criteria, and duration of tumor response in those patients with measurable disease.

TERTIARY OBJECTIVES:

I. To assess the relationship between molecular correlates and progression-free survival (PFS), overall survival (OS), response and adverse events.

OUTLINE: This is a phase I, dose-escalation study of auranofin followed by a phase II study.

Patients receive auranofin orally (PO) on days 1-28 and sirolimus PO on days 1-28 (days 8-28 of course 1). Courses repeat every 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 5 years.

Arms: arm 1: Patients receive auranofin PO on days 1-28 and sirolimus PO on days 1-28 (days 8-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Auranofin intervention 2: Sirolimus intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
MC1125 / 11-001987 
A Phase I-II Trial of Combined PKCι and mTOR Inhibition for 
Patients with Advanced or Recurrent Lung Cancer (NSCLC and 
SCLC) without Standard Treatment Options 
NCT01737502 
Document Date: 12/07/2021 


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Mayo Clinic Cancer Center 
A Phase I-II trial of combined PKCι and mTOR inhibition for patients with advanced or recurrent 
lung cancer (NSCLC and SCLC) without standard treatment options. 
 
 
 
 
Study Chairs: 
Yanyan Lou, MD 
 
Mayo Clinic in Florida 
 
4500 San Pablo Road 
 
Jacksonville, FL 32224 
 
 
Study Co-chairs:  Panayiotis Savvides, M.D., Ph.D.,  
Alan Fields, PhD  
 
Statistician: 
Amylou C. Dueck, PhD  
 
 
Drug Availability 
 
Commercial Agents:  Sirolimus, Auranofin 
 
*Investigator having NCI responsibility for this protocol, if applicable 
 
Study contributor(s) not responsible for patient care. 
 
Document History 
(Effective Date) 
Activation 
November 29, 2012 
MCCC Amendment 1 
November 29, 2012 
MCCC Amendment 2 
August 16, 2013 
MCCC Amendment 3 
February 13, 2014 
 
 
 
      MCCC Amendment 4      November 6, 2017 
      MCCC Amendment 5      September 25, 2018 
      MCCC Amendment 6      October 29, 2018 
      MCCC Amendment 7      January 17, 2019       
      MCCC Amendment 8      May 1, 2019 
MCCC Amendment 9      October 29, 2020 
MCCC Amendment 10    December 7, 2021 


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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment 
delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Lisa Finstuen, Quality Assurance Specialist 
Phone: 507-284-1328 
E-mail: finstuen.lisa@mayo.edu 
Protocol document, consent form, 
regulatory issues 
David Harwood/ Research Protocol 
Specialist Phone:  (904) 953-0558 
Email: Harwood.David@mayo.edu  
Non-paraffin biospecimens 
Laura Pacheco-Spann 
Phone: (904) 953-6015 
Email: flaprc@mayo.edu 
Serious Adverse Events  
Patricia G. McNamara, SAE C 
Phone:  (507) 266-3028 
E-mail: mcnamara.patricia@mayo.edu 
*No waivers of eligibility per NCI 


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Index 
Schema 
1.0 
Background 
2.0 
Goals 
3.0 
Patient Eligibility 
4.0 
Test Schedule 
5.0 
Grouping Factor 
6.0 
Registration/Randomization Procedures 
7.0 
Protocol Treatment 
8.0 
Dosage Modification Based on Adverse Events 
9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring 
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
Consent Form 
Appendix I - ECOG Performance Status 
Appendix II - Patient Medication Diary 
Appendix III - Percent of Normal Bone Marrow Irradiated using Standard Radiation Ports 
Appendix IV - Selected drugs known to be metabolized by CYP3A4 


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Schema 
PHASE I only: Prior to discussing protocol entry with the patient, call the Registration 
Office (507-284-2753) to ensure that a place on the protocol is open to the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
-PD at any time 
→ 
-Unacceptable 
→ 
Event 
adverse events 
Monitoring 
-Patient refusal 
→ 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up 
information. 
 
Cycle length=28 Days 
 
Generic name: Sirolimus 
Generic name: Auranafin 
Brand name(s): Rapamune 
Brand name(s): Ridaura 
Mayo Abbreviation: RAPA 
Mayo Abbreviation: Auranofin 
Availability:  Commercial supply 
Availability:   Commercial supply 
• 
Auranofin Days 1-28 
• 
Sirolimus Days 8-28 in Cycle 1; Days 1-28 in Cycle 2 
and beyond 
Event Monitoring 
Registration 


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1.0 
Background 
1.1 
Treatment 
Lung cancer 
Lung cancer is the most common cause of cancer death in the United States with 
estimated annual mortality in excess of 160,000 as of 2012.The vast majority of 
patients with lung cancer are not cured and the overall 5-year survival rate is a 
disappointing 16%. More than 80% of lung cancer patients have non-small cell 
lung cancer (NSCLC) and the mainstay of curative treatment for these patients is 
surgical resection, but only 25% to 30% of patients with NSCLC have resectable 
disease (Stage I or II) at diagnosis. Patients with Stage III lung cancer are treated 
with chemoradiotherapy with curative intent with long term survivals for a 
minority of patients. Survival for localized or locally advanced disease range from 
25-70% at five years depending on stage. For most patients, however, diagnosis is 
made too late for curative therapy. Chemotherapy is the mainstay of palliative 
treatment and produces survivals in the 12 month range for patients with good 
performance status {Scagliotti, 2008 #24}. For small cell lung cancer, surgery is 
not a standard part of treatment for any stage and chemoradiotherapy cures about 
25% of patients with localized cancer and a few of those with more advanced 
extensive stage cancer. In both cases, relapse is frequent and standard treatment 
options are few. 
 
1.11 
Palliative treatment (radiation and/or chemotherapy with supportive 
symptom management) is the main option for most patients with stage IV 
NSCLC. Response rates in the 20-30% range are expected with standard 
chemotherapy. Optimal therapy consists of a platinum doublet for good PS 
patients. Selected patients may benefit from treatment with targeted agents 
such as erlotinib or crizotinib in addition to or instead of chemotherapy 
{Sandler, 2007 #37}. 
 
1.12 
Until recently, it was felt that all commonly used chemotherapy regimens 
were equivalent in efficacy. The Eastern Cooperative Oncology Group 
(ECOG) tested four common chemotherapy regimens for Stage IIIB and 
IV NSCLC {Schiller, 2002 #40}. These regimens (24-hour 
paclitaxel/cisplatin; 3-hour paclitaxel/carboplatin; gemcitabine/cisplatin 
and docetaxel/cisplatin) yielded response rates (15 – 21%) and median 
survival rates (7.4 – 8.2 months) that were not statistically different. The 
poor outlook for patients with advanced lung cancer despite the best 
available therapy has prompted a search for new treatment options. ECOG 
tested carboplatin and paclitaxel with or without bevacizumab and showed 
that addition of the VEGF inhibitor improved overall survival in good PS 
patients with adenocarcinomas despite increase in bleeding {Sandler, 2006 
#37}. Patients with squamous cancers were not enrolled due to excess 
bleeding risk discovered in earlier trials. Post hoc subset analysis 
suggested the majority of benefit in males and younger patients. The 


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subsequent AvAIL trial with cisplatin gemcitabine plus or minus 
bevacizumab produced superior response and survival in the control arm 
than the paclitaxel carboplatin backbone used in E4599 and did not show a 
survival benefit in any subset for addition of bevacizumab to 
chemotherapy {Reck, 2009 #43}. Scagliotti et al studied pemetrexed or 
gemcitabine with cisplatin in good PS patients with previously untreated 
advanced NSCLC. While the regimens were equivalent overall, a small 
but significant survival advantage was seen for pemetrexed in patients 
with adenocarcinomas and large cell cancers while gemcitabine had a 
similar advantage in patients with squamous cancers. {Scagliotti, 2008 
#24} Analyses of previous trials with pemetrexed confirms the superior 
outcomes in non-squamous NSCLC {Scagliotti, 2009 #8} Histology must 
now be considered in choice of chemotherapy regimens for patients with 
stage IV NSCLC. 
 
Maintenance: 
Recent studies have shown a small but reproducible survival benefit to 
maintenance or early second line therapy with pemetrexed or erlotinib in 
NSCLC. These two agents have expected benefit primarily for non- 
squamous lung cancers ({Ciuleanu, 2009 #44}, Cappuzzo et al 2009). 
Agents with expected efficacy in squamous cancers are under active 
investigation but no standard maintenance is in common use for patients 
with squamous NSCLC although erlotinib is sometimes prescribed. 
 
Small cell lung cancer: 
Chemotherapy with etoposide and a platinum is standard for both limited 
and extensive stage with addition of radiation to the chest and/or 
prophylactic brain radiation recommended in the appropriate clinical 
circumstances. While topotecan or combination cyclophosphamide, 
doxorubicin and vincristine have been given in the second line setting, 
responses are modest and short lived. There is no standard maintenance or 
third line therapy for small cell patients. 
 
1.2 
Protein Kinase C is a Novel Target 
 
1.21 
Protein Kinase C is an oncogene that can mediate K-ras induced lung 
carcinogenesis. The protein kinase C (PKC) family of serine/threonine 
kinases has been implicated in many forms of cancer, including lung 
cancer, and is therefore a potential therapeutic target for cancer treatment. 
 
We recently demonstrated that the atypical protein kinase C, PKCι, is an 
oncogene in non-small cell lung cancer (NSCLC) {Regala, 2005 #50}. 
PKCι is overexpressed in NSCLC and SCLC tumors and tumor PKCι 
expression is predictive of poor clinical outcome independent of tumor 
stage {Regala, 2005 #50 & personal communication, Dr. Alan Fields}. 
The PKCι gene is a target of frequent, tumor-specific alteration by gene 


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amplification in a significant subset of NSCLCs {Stallings-Mann, 2006 
#49}. Genetic disruption of PKCι signaling blocks the transformed growth 
of NSCLC cells in vitro and in vivo {Regala, 2005 #51}. Oncogenic PKCι 
signaling requires the N-terminal PB1 domain on PKCι {Stallings-Mann, 
2006 #49}. 
 
Using a high throughput screen, we identified the anti-arthritic gold salt 
aurothiomalate (ATM) and subsequently a similarly acting oral agent, 
Auranofin (Ridaura), as potent inhibitors of oncogenic PKCι signaling. 
ATM and auranofin both inhibit transformed growth of NSCLC cells by 
binding to the PB1 domain of PKCι, and blocking the interaction between 
PKCι and downstream adaptor molecules {Erdogan, 2006 #52}. 
 
These agents exhibit potent anti-tumor activity against NSCLC in vitro 
and in vivo. We have demonstrated a correlation between the sensitivity of 
NSCLC cells to the anti-tumor effects of ATM, and the level of expression 
of PKCι. NSCLC cells that express high levels of PKCι are more sensitive 
to ATM than those with relatively low levels of PKCι expression.  A 
phase I clinical trial conducted at our institution demonstrated feasibility 
of the approach. Because of drug shortages, we were unable to obtain 
ATM for the clinical trial described here. We therefore tested the oral, 
similarly acting agent auranofin in the laboratory. This drug is FDA 
approved for arthritis with the same indications as ATM. In vitro, its 
activity is at least equal to that of ATM at concentrations mirroring those 
found in human serum with standard clinical use. We hypothesize that 
auranofin will be an effective therapy for the treatment of NSCLC, 
especially those subsets of NSCLC exhibiting PKCι over-expression. 
 
1.22 
Gold compounds 
The use of gold compounds for the treatment of rheumatoid arthritis (RA) 
was pioneered in 1929. Gold has also been used in some patients with 
psoriatic arthritis, ankylosing spondylitis with polyarthritis, and juvenile 
rheumatoid arthritis. Despite extensive clinical experience and an 
abundance of experimental data, the mechanism of action of gold 
compounds is poorly defined. The use of gold has declined since 1990 due 
to the increasing popularity of methotrexate and more recent 
immunomodulator therapies such as infliximab. Gold compounds occur in 
several oxidation states, with only complex gold compounds in clinical 
use. Most are administered only by intramuscular injection, however in 
this study an oral drug will be used: auranafin (Ridaura). 
 
 
1.23 
Pharmacokinetics of Gold 
After intramuscular injection, gold salts are rapidly absorbed with 
maximal plasma levels at two hours {Forestier, 1935 #53}. Gold levels 
gradually rise with treatment until a plateau is reached after six to eight 


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weeks. The serum gold concentration correlates with the dose of gold 
administered; maintenance doses of 50 mg every four weeks result in a 
serum concentration ranging from 75 to 125 μg/dL. Intramuscular gold is 
retained in the body to a greater degree than oral gold. Approximately 40 
percent of the dose of intramuscular gold is eliminated, either in the urine 
(70 percent) or in the feces (30 percent). As an example, about 300 mg of 
elemental gold is retained following 20 weekly injections of 50 mg, while 
only 73 mg of gold is retained after 20 weeks of oral gold doses of 6 mg 
per day. The kidneys, adrenals, and reticuloendothelial system achieve the 
highest gold concentrations. Intracellularly, gold attaches to organelle 
membranes in the nuclear, mitochondrial, and lysosomal fractions. 
 
Auranofin is less bioavailable than injectable gold salts with about 15-25% 
absorbed and with less whole body retention at six months. The serum half-lives 
are similar and the total body half- life or auranofin is about 69 days, while it is 
three times longer for injectable ATM. Auranofin is excreted primarily by the 
fecal route {Furst, Dromgoole, 1984}. Oral administration is well tolerated and 
produces serum levels in the effective range based on both arthritis treatment and 
on our preclinical assessments of PKCiota inhibition. 
 
Mammalian Target of Rapamycin (mTOR) 
mTOR is a member of a family of protein kinases called phosphoinositide 
3-kinase (PI3-K)-related kinases, which is involved in the regulation of 
many intracellular functions such as the control of G1 cell cycle protein 
synthesis. The main upstream regulator of mTOR is the 
phosphatidylinositol 3-kinase (PI3K) /protein kinase B (Akt) (PI3K/Akt), 
which activates mTOR in response to growth factor stimuli. PI3K seems 
to play a central role in cellular proliferation and is clearly upregulated in 
cancer cells. Phosphorylation of mTOR, in response to the activation of a 
growth receptor by its ligand, leads to the modulation of 2 different 
pathways: the eukaryotic initiation factor 4E binding protein-1 (4E-BP1) 
and the 40S ribosomal protein S6 kinase (p70s6k) {Sabatini, 2006 #55}. 
4E-BP1 inhibits the initiation of translation through its binding with eIF- 
4E, the mRNA cap-binding sub-unit of the eukaryotic initiation factor-4 
(eIF-4F) complex. The phosphorylated form of 4E-BP1 induced by mTOR 
has a lower affinity for eIF-4E, which increases its availability and 
promotes the translation initiation of mRNA 5’ cap in the G1 phase. The 
second downstream target modulated by mTOR is p70s6k. The major 
function of this protein is the phosphorylation of 40S ribosomal protein 
S6, which finally leads to the translation of mRNA. 


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1.24 
Sirolimus 
Rapamycin is a macrolide fungicide isolated from the bacteria 
Streptomyces hygroscopicus and is a potent antimicrobial, 
immunosuppressant and anti-tumor agent {Huang, 2003 #81}. After 
binding intracellularly the immunophilin FK506 binding protein 12 
(FKBP12), rapamycin is capable of stopping cell proliferation and 
inducing apoptosis through the inhibition of mTOR and its downstream 
targets {Rao, 2004 #78}. This antiproliferative activity has been 
confirmed in preclinical experiments. mTOR inhibition has enhanced the 
efficacy of chemotherapy and radiation in preclinical models and early 
clinical trials in a variety of solid malignancies including NSCLC 
(reviewed in Pal S, et al Clinical Lung Cancer, Vol. 9, No. 6, 340-345, 
2008). 
 
Clinical trials of oral and IV inhibitors of mTOR have suggested an 
efficacy signal in lung cancers but have been disappointing as single 
agents with response endpoints. Their effects on relevant molecular 
pathways are clear from preclinical and animal models and their efficacy 
is likely to be more apparent to maintain responses initiated by cytotoxic 
agents than as primary therapy. A phase I study of everolimus suggested 
activity with disease stabilization in four of 14 heavily pretreated NSCLC 
pts treated with RAD001 {O’Donnell, 2003 #85}. A phase II study 
presented at ASCO in 2007 and subsequently published in 2009 in the 
Annals of Oncology showed PFS in the 3 month range in 85 advanced 
NSCLC patients treated in the second and third line settings with this 
agent {Soria, 2009 #86}. Most studies show stabilization of disease with 
mTOR inhibitors rather than measurable response, hence our interest in 
utilizing the drugs in studies in the maintenance or early second line 
setting as discussed below. 
 
Sirolimus, a structural analog of rapamycin, is converted in vivo to 
rapamycin and has antiproliferative effects in cell culture and animal 
models as well as having antitumor effects in several solid tumors 
including NSCLC. Some data suggest that sirolimus may reduce the risk 
of cancer in renal transplant recipients. Additionally, phase I studies of the 
drug in cancer patients have not shown significant immunosuppression. 
Sirolimus eluting stents have been used to reduce endothelial proliferation 
contributing to restenosis after angioplasty. Sirolimus has been combined 
safely with chemotherapy and radiation in a phase I trial in NSCLC 
patients with no evidence of immunosuppressive effects and with serum 
levels compatible with mTOR pathway inhibition (Sarkaria J et al, JTO 
2:751-7, 2007). 
 
Sirolimus is FDA approved for organ transplants to mediate rejection. 


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1.25 Rationale for the Clinical Trial 
 
PKC is required for cellular transformation mediated by oncogenic Ras, 
which is expressed in approximately 40% of all NSCLC, and up to 70% of 
NSCLC in smokers. PKCι is overexpressed in NSCLC and tumor PKC 
expression is predictive of poor clinical outcome independent of tumor 
stage. The PKC gene is a target of frequent, tumor-specific alteration by 
gene amplification in a significant subset of NSCLCs {Regala, 2009 #45}. 
Genetic disruption of PKC signaling blocks the transformed growth of 
NSCLC cells in vitro and in vivo {Stallings-Mann, 2006 #49}. Gold salts 
are potent inhibitors of oncogenic PKC signaling inhibiting transformed 
growth of NSCLC cells by binding to the PB1 domain of PKC, and 
blocking the interaction between PKC and downstream adaptor 
molecules {Regala, 2008 #46} {Erdogan, 2006 #52}. We have 
demonstrated a correlation between the sensitivity of NSCLC cells to the 
anti-tumor effects of ATM and auranofin and the level of expression of 
PKC. We hypothesize that auranofin will be an effective therapy for the 
treatment of NSCLC, especially those exhibiting elevated PKC 
expression by virtue of PKCι gene amplification. We conducted a phase I 
trial of ATM in patients with advanced NSCLC and ovarian and 
pancreatic cancers, both of which also express high PKC levels. The 
results of this trial demonstrated the safety of ATM and established a 
phase II dose of 50-75 mg IM weekly. No safety signals were identified in 
the first data analysis and the doses used mirror those used for the FDA 
approved indication of arthritis. There were no responses in the first 12 
patients on study in this heavily pretreated population and one patient had 
stable disease for one cycle. ATM has become unavailable. We tested the 
oral gold salt aurothiomalate and found that it is equal to or better than 
ATM in preclinical studies at inhibiting PKCiota and tumor growth. 
Serum levels in RA patients mirror effective concentrations in our 
preclinical studies. 
 
 
1.26 
Rationale for combination of auranofin with sirolimus for patients with 
progression of disease after standard chemotherapy: 
We were unable to obtain ATM for this study due to drug shortages. We 
have replicated the most important background data with ATM referenced 
above with auranofin in the laboratory and have demonstrated that 
auranofin shows highly synergistic anti-tumor activity with the mTOR 
inhibitor rapamycin in pre-clinical NSCLC models in vitro and in vivo as 
described in the translational research background below. Sirolimus is 
converted to rapamycin in vivo and is used clinically in transplant patients 
to manage organ rejection with overall good tolerance. Based on these 
data, we are pursuing a phase I/II trial to assess the efficacy of combined 
chemotherapy using auranofin and the mTOR inhibitor sirolimus in 


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advanced stage NSCLC patients and SCLC patients with residual or 
progressive disease after standard chemotherapy. 
 
Brief summary of scientific rationale: 
 
 Molecular targeted therapies have introduced clinically significant 
improvements in the therapeutic outcomes for NSCLC within the past 
5 years. Bevacizumab, an anti-angiogenesis monoclonal antibody that 
targets VEGF (vascular endothelial growth factor), is approved in 
combination with front-line therapy using paclitaxel and carboplatin in 
patients with non-squamous NSCLC, based on results of E4599 
(Sandler et al 2006). Inhibition of the epidermal growth factor pathway 
has also demonstrated clinical benefit particularly among patients with 
adenocarcinoma (Cappuzzo et al ASCO 2009 Abs). 
 More recently, the combination of pemetrexed with a platinum agent 
as first-line treatment for NSCLC has been compared with 
gemcitabine in combination with a platinum agent (Scagliotti et al 
2008). Pre-planned subset analysis in the phase III study reported by 
Scagliotti et al. suggested better survival with pemetrexed combination 
in patients with adenocarcinoma and in large cell histology and with 
gemcitabine for squamous NSCLC. 
 Currently, there exists an apparent preponderance of novel agents that 
seem to provide benefit favoring the non-squamous subset of NSCLC. 
 Patients with Ras mutated non-squamous NSCLC have worse 
prognosis and respond less well to chemotherapy than those with wild 
type Ras and present treatment challenges as a result. 
• Patients with Ras mutated non-squamous NSCLC frequently exhibit 
PKC gene and protein overexpression. 
 Patients with squamous histology and Ras mutated adenocarcinoma 
comprise approximately 40-45% of NSCLC in the United States and 
have similar treatment outcomes. While to this date there are no novel 
therapeutic combinations that clearly demonstrate improved outcomes 
over existing standard therapies in this patient population, emerging 
data suggest potential targeted therapeutic options that merit further 
investigation. 
• PKC is of particular relevance in squamous NSCLC as it is expressed 
strongly in this population. Auranofin inhibits PKC activity and slows 
the growth of squamous NSCLC in vitro and in vivo in animal models. 
 Preclinical results with Ras mutant non-squamous NSCLC and small 
cell lung cancer (SCLC) are similar to those for the squamous NSCLC 
cells. 
 Small cell lung cancer responds to first line therapy most of the time 
but relapses quickly and responds poorly to second line treatment. 


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• Small cell lung cancer overexpresses PKC and in the laboratory 
responds to auranofin with PKC inhibition and antiproliferative 
effects. 
• Synergy between inhibition of the PKC and mTOR pathways has 
been shown in recent laboratory studies in our and other laboratories. 
 A phase I clinical trial has demonstrated the safety of PKCiota 
inhibition with gold salts (ATM) in patients with pretreated advanced 
NSCLC. 
 A phase II study of mTOR inhibition in the second and third line 
setting in non-selected NSCLC showed a suggestion of activity, 
primarily stabilization of disease. 
 
Based on the above, we wish to test the hypothesis that the 
auranofin/sirolimus combination will be effective and well-tolerated in 
patients with NSCLC of squamous histology, Ras mutated lung cancer and 
relapsed small cell lung cancer with no standard treatment options. 
 
1.3 
Translational Research 
 
1.31 
Background: 
 
We have demonstrated that the atypical PKC (PKC) is an oncogene in 
lung cancer (Regala et al., 2005a; Regala et al., 2005b). PKC is 
overexpressed in a majority of non-small cell lung cancer (NSCLC) and 
small cell lung cancer (SCLC) tumors. PKC expression is driven in a 
significant subset of NSCLC tumors as a result of tumor-specific 
amplification of the PKC gene, which is part of the 3q26 amplicon. PKC 
gene amplification is most prominent in lung squamous cell carcinoma 
(LSCC) tumors, where it is present in ~70% of tumors (Regala et al., 
2005b). Functionally, PKC is required for NSCLC cell transformed 
growth and invasion in vitro and tumorigenicity in vivo (Regala et al., 
2005a). PKC drives transformed growth through activation of a PKC- 
Rac1-Pak-Mek-Erk proliferative signaling pathway. PKC activates this 
pathway by forming an oncogenic complex with the adaptor protein Par6, 
which serves to couple PKC to Rac1 (Frederick et al., 2008). The PKC- 
Par6 complex is required for oncogenic PKC signaling. Using a high 
throughput screen, we identified ATM and other gold salts such as 
auranofin as a potent and selective small molecule inhibitors of the PKC- 
Par6 interaction (Stallings-Mann et al., 2006). ATM inhibits the PKC- 
Par6 interaction in a dose dependent fashion, and exhibits potent anti- 
tumor activity against NSCLC cell proliferation in vitro and 
tumorigenicity in vivo (Erdogan et al., 2006; Stallings-Mann et al., 2006). 
Biochemical studies have demonstrated that the mechanism of action for 
the anti-tumor activity of ATM is to bind to a specific region of PKC 


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causing disruption of Par6 binding to PKC (Erdogan et al., 2006). ATM 
is currently unavailable due to drug shortages in the United States. 
Auranofin (Ridaura) is FDA-approved for the treatment of rheumatoid 
arthritis (RA). A phase I dose escalation study of ATM in advanced 
NSCLC has established a well-tolerated dosing regimen for ATM in the 
treatment of NSCLC patients. Auranafin also shows highly synergistic 
anti-tumor activity with the mTOR inhibitor rapamycin in pre-clinical 
NSCLC models. 
 
Auranofin is an FDA-approved anti-rheumatoid drug in the same 
chemical class as aurothiomalate (ATM) and aurothioglucose 
 
The original protocol proposed a phase I/II clinical trial of aurothiomalate 
(ATM) in combination with mTOR inhibitor rapamycin in the 
maintenance therapy of advanced lung cancer patients. Recent drug 
shortages of ATM have prompted us to assess the efficacy of auranofin, 
another gold compound in the same chemical class as ATM as a substitute 
for the proposed clinical trial. Auranofin (Ridaura) is FDA-approved for 
treatment of RA and has been in clinical testing for treatment of acute 
lymphocytic leukemia. The drug has not been a subject of drug shortages 
and is accessible for the trial. Figure 1 shows the chemical structure of the 
gold compounds ATM, ATG and auranofin. Note that all compounds 
belong to the same chemical class with the active pharmacophore being a 
gold thiolate moiety (Figure 1). 
Auranofin 
Aurothiomalate 
Aurothioglucose 
 
 
 
 
Figure 1: Structures of the major anti-rheumatoid gold compounds in 
clinical use. Note the presence of the same gold thiolate pharmacophore 
in each compound. 
 
In order to determine whether, like ATM, auranofin exhibits anti-tumor 
activity against NSCLC cell growth, we conducted a dose response 
experiment to assess the effect of auranofin on the growth of H1703 lung 
squamous cell carcinoma cell growth. As can be seen, auranofin exhibits 
good dose-dependent inhibition of the transformed growth of these cells 
with an apparent IC50 of ~0.3 < M (Figure 2). This IC50 is actually better 
than that of ATM against this cell line (~ 1< M). Therefore, these data 
indicate that auranofin is a suitable substitute for ATM in the proposed 
clinical trial. 


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Figure 2: Auranofin exhibits dose- 
dependent inhibition of growth of H1703 
human lung squamous cell carcinoma cells. 
Highly tumorigenic H1703 cancer stem cells 
were isolated from parental H1703 cell 
cultures, and assessed for transformed growth 
in the presence of the indicated concentrations 
of auranofin. Results are expressed as % 
growth relatively to DMSO negative control. 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: ATM and auranofin exhibit synergistic anti-tumor activity in 
combination with rapamycin. A. combination index of ATM with 
combination with the indicated targeted therapeutics. B. ATM and 
rapamycin show enhanced anti-tumor activity in vivo. C. Auranofin 
synergizes with rapamycin. 
 
We also demonstrated that ATM exhibits synergistic anti-tumor activity in 
vitro (Figure 3A) and in vivo (Figure 3B) when combined with the mTOR 
inhibitor rapamycin. Auranofin exhibits similar synergy when combined 
with rapamycin, indicating that these agents act similarly (Figure 3C). 
Based on these data and on existing safety data sirolimus and other mTOR 
inhibitors in human use, we propose this phase II trial to assess the 
efficacy of combined therapy with auranofin and the sirolimus in 
advanced stage NSCLC patients in the adjuvant setting. 


MC1125 
15 
MCCC Amendment 10 
 
 
Associated Laboratory Studies: 
 
Genetic and Molecular Markers of ATM Sensitivity: 
 
Our recent studies have demonstrated that the level of PKC  expression 
in NSCLC tumor cells correlates with response to the anti-tumor effects of 
ATM in vitro and in vivo (Regala et al., 2008). Furthermore, we 
demonstrated that tumor-specific PKC  gene amplification is a major 
mechanism driving PKC  expression in primary tumors (Regala et al., 
2005b). These preclinical data suggest that assessment of PKC  
expression and PKC  gene amplification in a patient’s tumor may be 
predictive of response to ATM or auranofin therapy. Therefore, we wish to 
assess whether there is a similar correlation between tumor PKC  
expression and auranofin response clinically. For this purpose, we propose 
to obtain pre- treatment biopsies of patients’ tumors prior to enrollment on 
the clinical trial. These biopsy samples will be used to extract genomic 
DNA for analysis of PKC  gene copy number (PKC  gene 
amplification) which is a major mechanism driving the overexpression of 
PKC  in NSCLC tumors, and for immunohistochemical analysis of tumor 
tissue for elevated PKC  protein expression within the tumor. In addition, 
we propose to assess whether levels of markers of PKC  and mTOR 
signaling activity correlate with subsequent response. The techniques for 
this analysis are well established in our laboratory. 
 
A gene panel to assess auranofin-mediated inhibition of 
PKC  signaling in vivo: 
 
 
 
 
2.0 
Goals 
We have conducted pre-clinical studies to identify genes that can be used as 
molecular markers for assessing auranofin mediated inhibition of PKC  
signaling. 
 
2.1 
Primary 
 
2.11 
Phase I: To establish the maximum tolerated dose of auranofin plus 
sirolimus after at least one line of platinum based chemotherapy for stage 
IV squamous histology NSCLC for lung cancer (squamous, Ras-mutated 
adenocarcinoma, or small cell lung cancer) patients with no acceptable 
standard treatment options. 
 
2.12 
Phase II: To assess the progression-free survival at four months of 
patients treated with auranofin after at least one line of platinum based 
chemotherapy for lung cancer (squamous, Ras-mutated adenocarcinoma, 
or small cell lung cancer) patients with no acceptable standard treatment 
options. 


MC1125 
16 
MCCC Amendment 10 
 
 
2.2 
Secondary 
2.21 
To assess the overall survival in this population in comparison to recent 
historical controls. 
 
2.22 
To determine the Adverse Events (AE) profile and safety of the regimen. 
 
2.23 
To determine the overall response rate, per RECIST criteria, and duration 
of tumor response in those patients with measurable disease. 
2.3 
Correlative Research 
2.31 
To assess the relationship between molecular correlates and PFS, OS, 
response and adverse events. 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥ 18 years. 
 
3.12 
Histologic or cytologic confirmation of lung cancer (squamous, Ras- 
mutated adenocarcinoma or small cell lung cancer). 
 
3.13 
Patients must have received at least one course of chemotherapy 
consisting of a platinum doublet and must have no acceptable standard 
treatment options. 
 
3.14 
Prior radiation therapy is permitted as long as: 
• Recovered from the toxic effects of radiation treatment before study 
entry, except for alopecia. 
 
3.15 
The following laboratory values obtained ≤ 14 days prior to registration: 
• ANC ≥1500 L 
• PLT ≥100,000 L 
• 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 
 
3.16 
ECOG performance status (PS) 0, 1, 2.  (Appendix I) 


 
 
 
 
3.17 
Negative serum pregnancy test done ≤7 days prior to registration, for 
women of childbearing potential only. 
 
3.18 
Ability to provide informed consent. 
3.19a   Life expectancy 12 weeks. 
3.19 b   Willing to return to Mayo Clinic enrolling institution for follow-up. 
3.19c Willing to provide tissue samples for correlative research purposes (see Sections 
6, 17). 
3.2 
Exclusion Criteria 
 
3.21 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects. 
 Pregnant women 
 Nursing women 
 Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.22 
Symptomatic, untreated, or uncontrolled CNS metastases or seizure disorder. 
NOTE: Patients with treated CNS metastases without evidence of progression 
and without uncontrolled symptoms or need for steroids may enroll. 
 
3.23 
HIV-positive patients receiving combination anti-retroviral therapy are 
excluded because of possible pharmacokinetic interactions with oral 
investigational agents. 
 
3.24 
Unwilling or unable to, comply with the protocol. 
 
3.25 
Any of the following prior therapies: 
 Radiation to ≥25% of bone marrow (see appendix III) 
 
 Major surgery (i.e., laparotomy), open biopsy, or significant traumatic 
injury ≤4 weeks prior to registration. Minor surgery ≤2 weeks prior to 
registration. Insertion of a vascular access device is not considered major 
or minor surgery in this regard. 
 
3.26 
Any of the following concurrent severe and/or uncontrolled medical 
conditions: 
 Hypertension, labile hypertension, or history of poor compliance with 
antihypertensive medication 
 Angina pectoris 
 History of congestive heart failure ≤3 months, unless ejection fraction 
>40% 
 Myocardial infarction ≤6 months prior to registration 
 Cardiac arrhythmia 
 Poorly controlled diabetes 
 Interstitial pneumonia or extensive and symptomatic interstitial 


 
fibrosis of the lung 
 Active or recent history of hemoptysis. If hemoptysis has resolved with 
measures such as palliative radiation therapy (e.g. 3000 cGy over 10 
fractions), arteriographic embolization or endobronchial interventions (e.g. 
photodynamic therapy, brachytherapy), etc. for >14 days, patients may be 
considered for participation in this study. 
 ≥ Grade 2 hypertriglyceridemia 
 ≥ Grade 2 hypercholesterolemia 
 Any illness that in the opinion of the investigator would compromise the 
ability of the patient to participate safely in the clinical trial. 
 
3.27 
Use of St. John’s Wort because of its effects on hepatic drug metabolism. 
3.28 
Other active malignancy. 
EXCEPTIONS: Non-melanoma skin cancer, localized prostate cancer, or 
carcinoma-in-situ of the cervix. NOTE: If there is a history or prior 
malignancy, patient must not be receiving other cytotoxic or molecularly 
targeted therapeutics treatment for their cancer. Patients receiving certain 
hormonal manipulations as part of their treatment may be allowed to continue 
at the discretion of the PI (e.g. LHRH analogs for prostate cancer). 
3.29 Unable to discontinue use of potent CYP3A4 inhibitors/inducers (see 
appendix IV). 
 
 
4.0 
Test Schedule 
 
Tests and procedures 
≤14 days 
prior to 
registration 
Weekly 
(± 2 days) 
Cycle 1 
Prior to subsequent 
cycles 
(± 2 days) 
History and exam, wt, PS 
X 
X 
X 
Height 
X 
Adverse event assessment 
X 
X 
Tumor measurement (CT, PET/CT) 
X1 
X2 
Hematology group 
WBC, ANC, Hgb, PLT 
X 
X4 
X 
X 
Chemistry group 
Na, K, chloride, glucose, creatinine, 
total bilirubin, albumin, alkaline 
phosphatase, SGOT (AST), SGPT 
(ALT) 
X 
X4 
X 
X 
Lipid Panel 
XR 
X8 
Urinalysis/urine protein dipstick 
X 
X4 
X 
X 
Pregnancy Test 
X3 
Patient Medication Diary for Sirolimus 
and Auranofin (Appendix II)5 
X 
X 
Mandatory research tissue (see Section 
17)6,7 
XR 
1. 
Imaging studies such as chest x-ray, CT scans, and MRIs can be performed 
≤30 days prior to registration. Use same imaging throughout the study. The CT 
portion of a PET CT can be considered interchangeable with a CT scan. 
2. 
Tumor assessment must be performed at least every other cycle after completing Cycle 


 
2; 
i.e. after Cycles 2, 4, 6, etc. Tumor assessment should be performed at any time 
during the treatment cycle that disease progression is clinically suspected so that 
patient can go off treatment and receive other therapy. 
3. 
Women of childbearing potential only.  Must be done ≤7 days prior to registration. 
4. 
Weekly during cycle 1 only. 
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. 
Tissue specimens must be collected and submitted once at baseline. 
7. 
Optional repeat biopsy of accessible tumor at response and/or disease 
progression.  
8. 
Lipid panel is performed at baseline, prior to cycle 2, every other cycle 
through cycle 6, and then as clinically indicated (per Standard of Care) 
thereafter.  
9. 
R 
Research funded (see Section 19.0). 
 
 
5.0 
Grouping Factor: 
 
5.1 
Phase:  Phase I vs Phase II. 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Phase I 
 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office (507-284-2753) for dose level and to insure that a place on the protocol is 
open to the patient. 
 
6.11 Registration Procedures 
 
6.111 To register a patient, fax (507-284-0885) a completed eligibility 
checklist to the Mayo Clinic Cancer Center (MCCC) Registration 
Office between 8 a.m. and 4:30 p.m. central time Monday through 
Friday. 
 
6.2 
Phase II 
 
6.21 
Registration Procedures 
 
6.211 To register a patient, 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 (507) 284-2753 between the hours of 8 
a.m. and 5:00 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 (507) 284-2753. If the 
patient was fully registered, the MCCC Registration Office 
staff can access the information from the centralized database 
and confirm the registration. 
• Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.3 
Phase I and II 
 
6.31 Correlative Research 
Mandatory 
A mandatory correlative research component is part of this study, the patient 
will be automatically registered onto this component (see Sections 3.19c and 
17.0). 
 
Optional 
 
An optional correlative research component is part of this study: there will be 
an option to select if the patient is to be registered onto this component (see 
Section 17.0). 
 
• Patient has/has not given permission to give his/her tissue sample for 
research testing as a part of this study (see section 17.0). 
 
6.32 
Prior to accepting the registration, registration/randomization 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 
 
6.33 
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: 507-284-0885).  If the necessary documentation is 


 
not submitted in advance of attempting patient registration, the registration 
will not be accepted and the patient may not be enrolled in the protocol until 
the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission 
of annual IRB approvals to the Registration Office is no longer necessary. 
 
6.34 
At the time of registration, the following will be recorded: 
• Patient has/has not given permission to store and use his/her sample(s) 
for future research of Non-small cell lung 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. 
 
6.35 
Treatment on this protocol must commence at Mayo Clinic Arizona 
institution under the supervision of a medical oncologist. 
 
6.36 
Treatment cannot begin prior to registration and must begin  14 
days after registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within 
the guidelines specified on the test schedule. 
 
6.38 
All required baseline symptoms (see Section 10.3) must be documented 
and graded. 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule 
 
7.11 
Phase I Cohort: 
 
Agent 
Dose Level 
Route Day 
ReRx 
Auranofin As assigned by 
Registration office 
PO 
Daily 
Q28 
days 
Sirolimus 
5 mg 
PO 
Daily (cycle 1 only, begin day 8, 
subsequent cycles begin day 1) 
Q28 
days 
 
7.12 
Phase 2 Cohort (at MTD from Phase I): 
 
Agent 
Dose Level 
Route Day 
ReRx 
Auranofin As determined by 
studies in Phase I 
PO 
Daily 
Q28 
Sirolimus 
5 mg 
PO 
Daily (cycle 1 only, begin day 8, 
subsequent cycles begin day 1) 
Q28 
days 


 
 
 
7.2 
Phase I Dose Escalation and Determination of MTD 
7.21 
Dose Escalation Guidelines 
 
 
Dose Level 
Auranofin 
0* 
3 mg daily 
1 
6 mg daily 
* 
Starting dose level. 
 
7.211 Three patients will be treated at each dose level and observed for a 
minimum of 1 cycle, to assess toxicities, before new patients are 
treated. 
 
7.212 Investigators are to contact the Study Chair as soon as any dose- 
limiting toxicity occurs. 
 
7.213 For this protocol, dose-limiting toxicity (DLT) will be defined as 
an adverse event attributed (definitely, probably, possibly) in the 
first cycle to the study treatment and meeting the following 
criteria: 
 
Toxicity 
DLT Definition 
Hematologic 
Grade 4 Neutropenia 
Grade 4 Thrombocytopenia 
Non- 
hematologic 
≥Grade 3 Anaphylaxis 
≥Grade 3 Proteinuria 
≥Grade 3 Hematuria 
≥Grade 3 Rash acneiform 
≥Grade 3 Diarrhea 
≥Grade 3 Mucositis oral 
 
7.22 
MTD Determination 
 
MTD is defined as the dose level below the lowest dose that induces dose- 
limiting toxicity in at least one-third of patients (at least 2 of a maximum 
of 6 new patients). 
 
7.221 Three patients will be treated at a given dose level combination 
and observed for at least 1 cycle to assess toxicity (accrual will be 
suspended while the 3 patients are treated and observed). 


 
 
 
 
 
7.222 If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, 
3 new patients will be accrued and treated at the next higher dose 
level. If DLT is seen in 2 or 3 of 3 patients treated at a given dose 
level, then the next 3 patients will be treated at the next lower dose 
level, if only 3 patients were enrolled and treated at this lower dose 
level. 
 
7.223 If DLT is seen in 1 of 3 patients treated at a given dose level, up to 
3 additional patients will be enrolled and treated at the same dose 
level (accrual will be suspended while the 3 patients are treated 
and observed). If DLT is seen in at least one of these additional 
three patients (≥2 of 6), the MTD will have been exceeded and 
further accrual will cease to this cohort. If DLT is not seen in any 
of the three additional patients, 3 new patients will be accrued and 
treated at the next higher dose level. 
 
7.224 After enrolling 6 patients on a specific dose level, if DLT is 
observed in at least 2 of 6 patients, then the MTD will have been 
exceeded and defined as the previous dose unless only 3 patients 
were treated at the lower dose level. In that case, 3 additional 
patients will be treated at this lower dose level. 
 
7.23 
Dose Escalation:  Doses will not be escalated in any individual patient. 
 
7.24 
If a patient fails to complete Cycle 1 for reasons other than toxicity, the 
patient will be regarded as treatment intolerant and an additional patient 
will be treated at the current dose level. 
 
7.3 
Patients can be instructed in administration techniques for both sirolimus and 
auranofin and granted treatment independence. 
 
7.4 
Patient must return to Mayo Clinic for evaluation at least every week during the 
first cycle of treatment and then at least every 4 weeks. 
 
7.5 
Study treatment by a local medical doctor (LMD) is not allowed. 
 
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 
 
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2) 
 
Dose 
Level 
Auranofin 
Sirolimus 
+1 
6 mg po daily 
Not applicable 
0 
3 mg po daily 
5 mg po daily 
-1 
3 mg po qOd 
3  mg po daily 
-2 
None 
2 mg po daily 
 
 
8.2 
Dose modification Table 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
BASED ON INTERVAL ADVERSE EVENT 


 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
Investigations 
Neutrophil count 
Auranofin 
Delay therapy until ANC ≥ 1500 
decreased Grade 4 
Sirolimus 
and/or 
PLT ≥ 100,000, and decrease by 1 
Platelet count 
dose level; discontinue treatment if 
decreased Grade 4 
toxicity persists beyond 14 days or if 
subject is already at dose level -2 and 
go to event monitoring phase per 
Section 18. 
 
 
_ 
Neutrophil count 
Delay therapy until ANC ≥ 1500 
decreased Grade 3 
and/or PLT ≥ 100,000. If delay is 1 
week or less, resume at prior dose. If 
Platelet count 
delay exceeds 7 days but is not more 
decreased Grade 3 
than 14 days, decrease by 1 dose 
level; discontinue treatment if 
toxicity persists beyond 14 days or if 
subject is already at dose level -2 and 
go to event monitoring phase per 
 
Section 18. 
Cholesterol High 
Grade 2 
 
Institute appropriate lipid/cholesterol 
lowering therapy. Hold treatment 
until levels return to Grade 1. If 
unresolved by four weeks, 
discontinue auranofin  and sirolimus 
therapy and go to event monitoring. 
Grade 3-4 
Discontinue auranofin and sirolimus 
and go to event monitoring. 
Respiratory, 
Interstitial 
Auranofin 
thoracic and 
pneumonitis any 
Sirolimus 
Discontinue and go to event 
mediastinal 
grade 
monitoring 
disorders 


 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
Metabolism 
and nutrition 
disorders 
Hypertriglyceridemia 
Grade 2 
Grade 3-4 
Auranofin 
Sirolimus 
Institute appropriate lipid/cholesterol 
lowering therapy. Hold treatment 
until levels return to Grade 1. If 
unresolved by four weeks, 
discontinue auranofin and sirolimus 
therapy and go to event monitoring. 
Discontinue auranofin and sirolimus 
and go to event monitoring. 
Other non- 
hematologic 
adverse events 
Non-hematologic 
Grade 3 or 4 
Auranofin 
Sirolimus 
Delay therapy until severity 
decreases to 
grade 0-1 and decrease dose by one 
level; 
discontinue treatment if toxicity 
persists 
beyond 14 days or if subject is 
already at 
dose level -2 and go to event 
monitoring 
phase per Section 18.. 
 
* Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the 
two dose-reduction steps (levels –1 and –2) will result in the patient coming off study. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Radiation therapy for symptom palliation is allowed. Radiation should be to non- 
target sites (i.e. painful pre-existing bony metastasis) in patients who are 
benefiting from therapy. 
 
9.3 
Corticosteroids for treatment of adrenal insufficiency or severe nausea 
and vomiting are permitted. 
 
9.4 
Blood products should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors is not 
permitted during study treatment. 


 
 
 
9.5 
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, and/or antiemetics 
received from the first day of study treatment administration until 30 days after 
the final dose will be recorded in the medical records. 
 
9.6 
Bisphosphonates: Patients with lytic metastatic bone disease may receive 
bisphosphonates at the discretion of the treating physician. 
 
9.7 
Rash: The use of corticosteroid creams, and/or antihistamines are allowed at 
physician discretion. 
 
9.8 
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 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/forms/default.htm). 
 
10.11 Adverse event monitoring and reporting is a routine part of every 
clinical trial.  First, identify and grade the severity of the event using 
the CTCAE v4.0. Next, determine whether the event is expected or 
unexpected (refer to Sections 10.12 and 15.0) and if the adverse event 
is related to the medical treatment or procedure (see Section 10.13). 
With this information, determine whether an adverse event should be 
reported to the NCI as an expedited report (see Section 10.2) or as part 
of the routinely reported clinical data.  Important: All AEs reported via 


 
 
 
expedited mechanisms must also be reported via the routine data 
reporting mechanisms defined by the protocol (see Section 10.3 and 
18.0). 
 
Expedited and/or routine reports are to be completed within the 
timeframes and via the mechanisms specified in Sections 10.2 and 10.3. 
All expedited AE reports must also be sent to the local Institutional 
Review Board (IRB) according to local IRB’s policies and procedures. 
 
10.12 Expected vs. Unexpected 
• The determination of whether an AE is expected is based on agent- 
specific adverse event information provided in Section 15.0 of the 
protocol. 
• Unexpected AEs are those not listed in the agent-specific adverse 
event information provided in Section 15.0 of the protocol. 
 
10.13 Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical 
treatment or procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the investigational agent(s). 
Probable - The adverse event is likely related to the investigational 
agent(s). 
Possible - The adverse event may be related to the investigational 
agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational 
agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s) 
 
 
10.2 
Expedited Adverse Event Reporting Requirements 
 
10.21 Paper reporting will be done via the AdEERS form found at Adverse 
Event Expedited Report – Single Agent or Multiple Agents 


 
 
 
 
Grade 4 or 51 
Unexpected/ 
Expected Regardless 
of Attribution 
Grade 3 
Unexpected/ 
Expected 
Regardless of 
Attribution 
Other Grade 4 or 5 
Events and/or any 
Hospitalization 
During Treatment 
Not Otherwise 
Warranting an 
Expedited Report 
Submit written 
report within 5 
working days2 
X 
X 
Submit Grade 4 or 5 
Non-AER 
Reportable 
Events/Hospitalization 
in EDC within 5 
working days.3 
X3 
 
1. Includes all deaths within 30 days of the last dose of agent regardless of attribution or any 
death attributed to the agent(s) (possible, probable, or definite) regardless of timeframe. 
2. Use paper Adverse Event Expedited Report – Single Agent or Multiple Agents report 
available within the study forms packet 
 
. 
 
Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies, along with the 
UPIRTSO cover sheet, by fax (507-538-7164) to the MCCC Regulatory Affairs Unit 
(RAU) Risk Information Specialist who will determine and complete IRB reporting. 
The RAU will submit to the MCCC SAE Coordinator and the MCCC IND 
Coordinator to determine if FDA submission is needed.  
 
3. Complete a Notification Form: Grade 4 or 5 Non-AER Reportable Events/Hospitalization Form 
electronically via the Data Entry System within 5 working days of the date the clinical research 
associate (CRA) is aware of the event(s) necessitating the form. If expedited written report was 
submitted, this form does not need to be completed. 


 
 
 
 
10.3 
Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
 
System Organ 
Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
General 
disorders and 
administration 
site conditions 
Fever 
X 
X 
Blood and 
lymphatics 
system 
disorders 
Anemia 
X 
X 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
Creatinine increased 
X 
X 
X 
X 
Cholesterol high 
X 
X 
Blood bilirubin increased 
Vascular 
disorders 
Hypotension 
Flushing 
X 
X 
X 
X 
Skin and 
Subcutaneous 
tissue orders 
Rash Acneiform 
X 
X 
Gastrointestinal 
disorders 
# of stools 
Diarrhea 
X 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Mucositis, oral 
X 
X 


 
 
 
Infections and 
Bladder Infection 
X 
X 
Infestations 
Bronchial Infection 
X 
X 
Skin Infection 
X 
X 
Lung Infection 
X 
X 
Renal and 
urinary 
disorders 
Proteinuria 
X 
X 
Metabolism and 
Nutrition 
disorders 
Hyperglycemia 
Hypertriglyceridemia 
X 
X 
X 
X 
Musculoskeletal 
and connective 
tissue disorders 
Myalgia 
Arthralgia 
X 
X 
X 
X 
Nervous system 
disorders 
Dizziness 
X 
X 
Immune system 
disorders 
Allergic Reaction 
X 
X 
 
10.31 Submit via appropriate MCCC Case Report Forms (i.e., paper or 
electronic, as applicable) the following AEs experienced by a patient and 
not specified in Section 10.3: 
 
10.311 Grade 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
10.312 Grade 3 and 4 AEs regardless of attribution to the study treatment 
or procedure. 
 
10.313 Grade 5 AEs (Deaths) 
 
10.3131 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure.


 
 
 
 
10.3132 
 Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.32 Refer to the instructions in the Forms Packet (or electronic data entry 
screens, as applicable) regarding the submission of late occurring AEs 
following completion of the Active Monitoring Phase (i.e., compliance 
with Test Schedule in Section 4.0). 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the 
footnote for the table regarding measureable disease in Section 11.44, as it pertains to 
data collection and analysis. 
 
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) 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. 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be 
reevaluated every 8 weeks. 
 
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 2.0 cm with chest x-ray, or as ≥1.0 
cm with CT scan, CT component of a PET/CT, or MRI. 
Tumor lesions in a previously irradiated area are considered 
measurable disease under the following conditions: 
a. The radiation completion date is ≥ 90 days from the 
registration date. 
b. There is objective evidence of disease progression after 
completion of the radiation therapy. 
 
11.212 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. 


 
 
 
 
11.213 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). 
 
11.214 Clinical Lesions: Clinical lesions will only be considered 
measurable when they are superficial (e.g. skin nodules and 
palpable lymph nodes) and >1.0 cm diameter as assessed using 
calipers (e.g. skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
 
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, 
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. 
 
11.3 
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. 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. 


 
 
 
 
11.32 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: 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. 
 
 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: FDG-PET scanning is allowed to complement CT scanning 
in assessment of progressive disease [PD] and particularly possible 
'new' disease. A ‘positive’ FDG-PET 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 scanned lesion is considered ‘negative.’ New lesions on the 
basis of FDG-PET imaging can be identified according to the following 
algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow- 
up is a sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
 
i. If the positive FDG-PET at follow-up corresponds to a new site 
of disease confirmed by CT, this is PD. 


 
 
 
ii. If the positive FDG-PET 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 scan. 
 
iii If the positive FDG-PET 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. 
 
11.33 Measurement at Follow-up Evaluation: 
 
 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 8 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 tumor types 
such as germ cell tumors, where known residual benign tumors can 
remain.) 
 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
 All measurable lesions (as defined in Section 11.21-11.22) up to a 
maximum of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs, should be identified as target lesions and recorded 
and measured at baseline. If the protocol specified studies are 
performed, and there are fewer than 5 lesions 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 should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected. 
 
Baseline Sum of Diameters (BSD): A sum of the diameters [longest 
for non-nodal target lesions (see Section 11.211), short axis for target 
lymph nodes see Section 11.212)] for all target lesions will be 
calculated and reported as the baseline sum of diameters. 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 Diameters (PBSD): A sum of the diameters 
[longest for non-nodal target lesions (see Section 11.211), short axis for 
target lymph noted (see Section 11.212)] for all target lesions will be 
calculated and reported as the post-baseline sum of diameters. If the 
radiologist is able to provide an actual measure for the target lesion, that 
should be recorded, even if it is below 0.5 cm. If the target lesion 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 diameters (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/physical examination must be measured on re- 
evaluation at evaluation times specified in Section 11.1. 
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. 
 
11.432 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. 


 
 
 
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
• 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. 
 
• 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 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 


 
 
 
11.44 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: 
 
For Patients with Measurable Disease 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
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 Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
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 Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the 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 MCCC 
protocol RECIST v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 


 
 
 
 
For Patients with Non-Measurable Disease Only: 
 
Non-Target Lesions & 
Non-Target Lymph Nodes 
New 
Sites of Disease 
Overall 
Objective Status 
CR 
Non-CR/Non-PD 
Not Evaluated (NE) 
PD 
PD 
CR 
No 
Non-CR/Non-PD 
No 
Not All Evaluated* 
No 
Unequivocal PD 
Yes or No 
Any 
Yes 
*See Section 11.431 
 
11.45 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 
Brain metastasis at on-study:  Yes vs. no. 
 
12.2 
Prior palliative radiation:  Yes vs. no. 
 
12.3 
Phase I dose level:  0 vs. 1 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring 
phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the 
event-monitoring phase per Section 18.0. 


 
 
 
 
13.4 
Patients who develop PD in the CNS only should receive resection and/or brain 
radiationand continue treatment on study after completion of CNS treatment. 
 
13.5 
Patients who develop non-CNS PD at any time should go to event monitoring. 
These patients should be treated with alternative chemotherapy if their clinical 
status is good enough to allow further therapy. 
 
13.6 A patient is deemed ineligible if after registration, it is determined that at the 
time of registration, the patient did not satisfy each and every eligibility criteria 
for study entry. The patient may continue treatment off-protocol at the discretion 
of the physician as long as there are no safety concerns, and the patient was 
properly registered. The patient will go directly to the event-monitoring phase of 
the study (or off study, if applicable). 
• If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per 
Section 
18.0 of the protocol. 
• If the patient never received treatment, on-study material must be 
submitted. Event monitoring will be required per Section 18.0 of the 
protocol. 
 
13.7 
A patient is deemed a major violation, if protocol requirements regarding 
treatment in cycle 1 of the initial therapy are severely violated that evaluability  
for primary end point is questionable.  All data up until the point of confirmation 
of a major violation must be submitted. The patient will go directly to the event- 
monitoring phase of the study. The patient may continue treatment off-protocol at 
the discretion of the physician as long as there are no safety concerns, and the 
patient was properly registered.  Event monitoring will be required per Section 
18.0 of the protocol. 
 
13. 8 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 
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: Dermatitis (aggravated by sunlight), pruritus, actinic 
rash, hair loss, urticaria 
Gastrointestinal: Nausea, vomiting, abdominal cramps, diarrhea, 
loose stools, constipation, dysgeusia, stomatitis, glossitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, Eosinophilia 
Hepatic: Elevated liver enzymes 
Renal: Hematuria 
 
Less common known potential toxicities, 1% - 10%: 
Gastrointestinal: Anorexia, flatulence, dyspepsia 
Ocular: Conjunctivitis 
Renal: Proteinuria 
 
Rare known potential toxicities, <1% (Limited to important 
or life-threatening): 
Dermatologic: Generalized exfoliative dermatitis, angioedema 


 
Gastrointestinal: Dysphagia, gastrointestinal bleeding, 
melena, positive stool for occult blood, ulcerative enterocolitis  
Mucous membrane: Gingivitis 
Hematologic: Aplastic anemia, neutropenia, agranulocytosis, pure 
red cell aplasia, pancytopenia 
Hepatic: Jaundice 
Neurologic: Peripheral neuropathy 
Respiratory: Interstitial pneumonitis 
 
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 Auranofin is contraindicated in patients with history of gold- 
induced disorders (see section 15.17). 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 LFT’s 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. 
 
15.24 Administration: Refer to the treatment section for specific administration 
instructions. 
Tablet: Do not crush, split or chew. 
Solution: Mix with at least 2 ounces 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 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 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. 
Common or severe toxicity: Hypertension, edema, capillary leak syndrome, 
poor wound healing, hypertriglyceridemia, hypercholesterolemia, 
hypokalemia, constipation, diarrhea, dyspepsia, nausea and vomiting, deep 
venous and arterial thrombosis, abnormal liver function tests, 
hypersensitivity reaction, infection, sepsis, lymphoma, arthralgia, headache, 
renal failure, interstitial pneumonitis, pulmonary hemorrhage, 
thrombocytopenia and leukopenia. 
 
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 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 bee 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 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. 
 
15.299 a 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. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Overview: This protocol will assess the efficacy of maintenance auranofin plus 
sirolimus after at least one line of platinum based chemotherapy for lung cancer 
(squamous, Ras-mutated adenocarcinoma, or small cell lung cancer) patients with 
no acceptable standard treatment options , using a one-stage phase II study 
design. A run-in phase I study (described in Section 7.0) will be conducted to 
determine the MTD for the phase II portion. 
 
16.11 Phase I Study 
 
This run-in phase I study is a cohorts of 3 design. For a subject to be 
considered evaluable for dose-limiting toxicity (DLT) the subject must 
have received at least one dose of each drug in Cycle 1. If a subject 
withdraws from the study within the first cycle of treatment for reasons 
other than adverse events, the subject will be replaced; and only DLTs 
occurring in Cycle 1 will be used for establishing safety during the run-in 
phase I study. However, all adverse event data will be summarized in the 
final analysis. For this run-in phase I study, DLT the study design is 
defined in Section 7.0. The patients treated at the MTD within the phase I 
will be included in the phase II efficacy analysis. Safety for all patients 
(including the patients in the run-in phase I study) will continue to be 
monitored via the Adverse Event Stopping Rule. 
 
16.12 Sample Size: Phase I: The study may involve a maximum of 12 patients 
(6 for each of 2 dose levels).  Phase II: This study will accrue an 
additional 35 patients to have a total of 41 patients accrued to the efficacy 
portion of this study (6 patients at the MTD in the phase I portion plus 35 
patients accrued during the phase II portion). This includes 10% 
overaccrual of patients during the phase II portion to allow for 
cancellation, ineligibility, and major treatment violations (i.e., accrual of 
41 patients to have 37 evaluable patients as required in 16.41). Overall: 
Therefore, overall, the study will accrue a maximum of 47 patients. 
 
16.13 Accrual Time and Study Duration: The anticipated accrual rate is 
approximately 2 patients per month, based on physician estimate. This 
corresponds to a requirement of approximately 17 weeks to enroll (12 
weeks), treat (4 weeks), and evaluate (1 week to submit data) 6 patients. 
Therefore, the accrual time for the phase I portion will be a maximum of 
34 weeks. The overall study duration will be 34 weeks (phase I 
component) + 70 weeks (accrual of an additional 35 patients) + 16 weeks 
(4 months to evaluate the primary endpoint) = 120 weeks (about 28 
months). The final analysis can begin approximately 28 months after 
activation, i.e., as soon as the last patient has been observed for 4 months 
and data have been submitted. 


 
 
 
 
16.14 Operating Characteristics: The following table gives the probability of 
dose escalation at a single dose level as a function of the true probability 
of DLT at that level using the cohorts of 3 design described in Section 
7.0. 
 
True Rate 
of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
16.2 
Phase I Analysis Plans: All the relevant phase I results pertaining to adverse 
events, MTD, clinical endpoints, and laboratory correlates will be examined in 
an exploratory and hypothesis generating fashion. 
 
16.21 Adverse Events Profile 
 
The number and severity of all adverse events (overall and by dose level) 
will be tabulated and summarized. 
 
16.22 Clinical Endpoints 
 
Overall survival, progression-free survival, and response will be 
summarized descriptively (overall and by dose level). 
 
16.3 
Phase II Design and Analysis 
 
16.31 Primary Endpoint: The primary endpoint of this trial is the 4-month 
progression-free survival rate. Throughout Section 16.0, “4-month 
progression-free survivor” will be considered synonymous with 
“success”, unless otherwise specified. A patient is considered to be a 4-
month progression-free survivor if the patient is 4 months from 
registration without a documentation of disease progression (note, the 
patient need not be on study treatment at 4 months to be considered a 
success).  All patients meeting the eligibility criteria who have signed a 
consent form and have initiated treatment will be evaluable for the 
primary endpoint. 
 
16.4 
Statistical Design 
16.41 Decision Rule:  The largest success proportion where the proposed 
treatment regimen would be considered ineffective in this population is 
35%, and the smallest success proportion that would warrant subsequent 
studies with the proposed regimen in this patient population is 55%. The 
following one-stage design based on properties of the binomial 
distribution uses 37 patients to test the null hypothesis that the true 
success proportion in a given patient population is at most 35%. 
The null 4-month progression-free survival rate of 35% is based on Figure 


 
2 of Scagliotti et al (2008). In the subgroup of patients with squamous cell 
carcinoma on the cisplatin / gemcitabine arm, approximately 65% of 
patients were progression-free 4 months after randomization (i.e., at or 
near completion of first-line therapy). Four months subsequent to this time 
point, the PFS rate was approximately 25%. Thus, among those who were 
progression-free at or near completion of first-line therapy, the subsequent 
4-month PFS rate for patients receiving no maintenance therapy 
following first-line cisplatin / gemcitabine is approximately 35% 
(≈0.25/0.65). 
Enter 37 patients into the study. If 16 or fewer successes are observed in 
the first 37 evaluable patients, we may consider this regimen ineffective in 
this patient population. If 17 or more successes are observed in the first 37 
evaluable patients, we may recommend further testing of this regimen in 
subsequent studies in this population. 
 
16.411 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 16.34. 
 
16.42 Power and Significance Level: Assuming that the number of successes 
is binomially distributed, the significance level is ≤0.12 and the 
probability of declaring that this regimen warrants further studies (i.e., 
statistical power) under various success proportions can be tabulated as 
a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is . . . . . . 
0.35 
0.40 
0.45 
0.50 
0.55 
then the probability of declaring that the 
regimen warrants further studies is . . . . . . 
0.11 
0.28 
0.52 
0.74 
0.90 
 
16.43 Other Considerations: Adverse events, quality/duration of response, 
and patterns of treatment failure observed in this study, as well as 
scientific discoveries or changes in standard care will be taken into 
account in any decision to terminate the study. 
 
16.5 
Analysis Plan: The analysis for this trial will commence at planned timepoints 
and at the time the patients have become evaluable for the primary endpoint. 
Such a decision will be made by the Statistician and Study Chair, in 
accordance with Mayo Clinic Cancer Center (MCCC) Standard Operating 
Proceedures, availability of data for secondary endpoints (e.g., laboratory 
correlates), and the level of data maturity. 
 
16.51 Primary Endpoint 
 
16.511 Definition: The primary endpoint of this trial is the proportion of 
4-month progression-free survivors as defined in Section 16.31. 
 
16.512 Estimation: The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable 
patients. Confidence intervals for the true success proportion will 


 
be calculated using the properties of the binomial distribution. 
Additionally, if some patients are lost to follow-up not having been 
observed for at least 4 months, an estimate and confidence interval 
for the 4-month progression-free survival rate incorporating 
censoring will be computed using the method of Kaplan-Meier 
(1958). 
 
16.52 Definitions and Analyses of Secondary, Exploratory, and 
Correlative Endpoints 
 
 
Survival time is defined as the time from registration to death due to any cause. 
The distribution of survival time will be estimated using the method of Kaplan-
Meier (1958). 
 
Progression-free survival time is defined as the time from registration to the 
earliest date of documentation of disease progression. If a patient dies without a 
documentation of disease progression the patient will be considered to have had 
disease progression at the time of their death. In the case of a patient starting 
treatment and then never returning for any evaluations, the patient will be 
censored for progression 1 day post-registration. The distribution of progression-
free survival time will be estimated using the method of Kaplan-Meier (1958). 
 
 
A response is defined to be either a CR or PR noted as the objective status. As 
response rate is a secondary endpoint, confirmation is no longer required per 
RECIST v1.1. The overall response rate will be estimated in the subset of 
patients with measureable disease by the number of responses in evaluable 
patients with measurable disease divided by the total number of evaluable 
patients with measureable disease. The appropriate confidence interval will be 
calculated based on the binomial distribution. 
 
 
Duration of response is defined for all evaluable patients with measurable 
disease who have achieved a response as the date at which the patient’s earliest 
best objective status is first noted to be either a CR or PR to the earliest date 
progression is documented. If a patient dies subsequent to the response without a 
documentation of disease progression, the patient will be considered to have had 
disease progression at the time of their death. In the case of a patient failing to 
return for evaluations before a documentation of disease progression, the patient 
will be censored for progression on day 1 post response or the date of last 
evaluation (whichever one occurs later).  The distribution of 
duration of response will be estimated using the method of Kaplan- 
Meier (1958). 
 
 
Translational analyses: Given the small sample size, all translational analyses 
are considered exploratory and no adjustment for multiplicity will be employed.  
One-sided p-values 
≤0.10 are considered statistically significant throughout. Results 
will be used to design subsequent confirmatory studies (likely as 
translational components within the subsequent phase III study 
should this phase II study support the use of this combination in a 
phase III study). 
 
We consider the analysis of baseline PKCι gene amplification to 
be the primary analysis (though still exploratory) among the 


 
various translational anlayses. PKCι gene amplification will be 
evaluated at baseline using the baseline tissue specimen and 
explored in relation to 4-month progression-free survival and 
subsequently in relation to other clinical outcomes such as tumor 
response and adverse event incidence using two-way tables and 
analyzed using Fisher’s exact tests. To estimate power for this 
primary analysis, we assume that 90% of patients (N=33) will 
provide a usable sample (i.e., will have gene amplification status 
for this tissue study). We also assume that 70% of patients (N=23) 
will have PKCι gene amplification (Regala et al., 2005b) and that 
55% of patients overall will have 4-month PFS.  The proportion of 
patients with 4-month PFS will be compared between patients with 
tumors with PKCι gene amplification to patients with tumors 
without PKCι gene amplification using a 1-sided α=0.10 Fisher’s 
exact test. We have 86% power to detect a 50% difference in the 
4-month PFS rates (70% vs 20%) between gene amplified and 
gene not amplified groups (calculated using nQuery Advisor 6.01 
with the following parameters: α=0.10 1-sided, π1=0.70, π2=0.20, 
n1=23, n2=10). 
 
PKCι protein expression (using the baseline tissue specimen) will 
be evaluated at baseline and explored in relation to clinical 
outcomes such as 4-month progression-free survival, tumor 
response, and adverse event incidence using two-way tables and 
box plots and analyzed using Fisher’s exact tests or logistic 
regression methods, as appropriate. Further, the relationship 
among PKCι gene amplification and PKCι protein expression will 
be investigated using box plots and scatter plots and analyzed 
using Wilcoxon rank sum tests and Spearman correlation 
coefficients, as appropriate. 
 
 
Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum grade for 
each type of adverse event will be recorded for each patient, and frequency tables 
will be reviewed to determine patterns. Additionally, the relationship of the 
adverse event(s) to the study treatment will be taken into consideration. 
 
16.53 Data & Safety Monitoring 
 
16.531 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 Mayo 
Clinic Cancer Center (MCCC) Data Safety Monitoring Board 
(DSMB) is responsible for reviewing accrual and safety data for 
this trial at least twice a year, based on reports provided by the 
MCCC Statistical Office. 
 
16.532 Adverse Event Stopping Rule (PHASE II ONLY): The stopping 
rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may 
be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in 


 
consideration of newly acquired information regarding the adverse 
event profile of the treatment(s) under investigation. The study 
team may choose to suspend accrual because of unexpected 


 
 
 
adverse event profiles that have not crossed the specified rule 
below. 
 
Accrual will be temporarily suspended to this study if at any time 
we observe events considered at least possibly related to study 
treatment (ie, an adverse event with attribute specified as 
“possible”, “probable”, or “definite”) that satisfy the following: 
 
• 
if 3 or more patients in the first 20 treated patients (or 10% 
after 20 patients have been accrued) experience a Grade 4 
or higher non-hematologic adverse event. 
 
We note that we will review Grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution 
and to monitor the emergence of a previously unrecognized 
treatment-related adverse event. 
 
16.6 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have 
been registered within the “ClincialTrails.gov” website. The Primary and 
Secondary Endpoints (i.e., “Outcome Measures”) along with other required 
information for this study will be reported on ClinicalTrials.gov. For purposes of 
timing of the Results Reporting, the initial estimated completion date for the 
Primary Endpoint of this study is 32 months after the study opens to accrual. The 
definition of “Primary Endpoint Completion Date” (PECD) for this study is at the 
time the last patient registered has been followed for at least 4 months. 
 
16.7 
Inclusion of Women and Minorities 
 
16.71 This study will be available to all eligible patients, regardless of race, 
gender, or ethnic origin. 
 
16.72 There is no information currently available regarding differential effects of 
this treatment regimen in subsets defined by race, gender, 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 and gender groupings, the sample size is not 
increased in order to provide additional power for subset analyses. 
 
16.73 Based on prior MCCC studies involving similar disease sites, we expect 
about 4% of patients will be classified as minorities by race and 40% of 
patients will be women. Expected sizes of racial by gender subsets are 
shown in the following table: 


 
 
 
Accrual Estimates by Gender/Ethnicity/Race for All Phase 2 and 3 Studies 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
18 
26 
44 
Ethnic Category: Total of all subjects* 
19 
28 
47 
Racial Category 
American Indian or Alaska Native 
0 
1 
1 
Asian 
0 
0 
0 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
White 
18 
26 
44 
Racial Category: Total of all subjects* 
19 
28 
47 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
 
Racial 
Categories: 
American Indian or Alaska 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 
 
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
Correlative Study 
(Section for more 
information) 
Mandator 
y or 
Optional 
Block, 
Slides, 
Core, etc. 
(# of each 
to submit) 
Baseline 
At 
disease 
progres 
sion 
Process 
at site? 
(Yes or 
No) 
Temperatur 
e 
Conditions 
for Storage 
/Shipping 
Archival Tissue - 
Mandatory 
FFPE 
Blocks or 
Slides1 
X2 
No 
Ambient/ 
Ambient 
Tissue - 
Optional 
FFPE 
Blocks or 
Slides1 
X3 
No 
Ambient/ 
Ambient 
 
1. Formalin Fixed Paraffin Embedded (FFPE). If a block is not available, then please submit 1 
H&E and 10 unstained slides 
2. Submit Pathology report with archival tissue sent to the MCF Biospecimen Facility. 
3. For those subjects in Event Monitoring for reasons other than PD (e.g. adverse event, refusal), 
optional tissue will not be collected 
 
17.2 
Tissue Collection and Processing 
Tissue will be obtained from previous biopsy material or from biopsy of 
accessible tumor sites at protocol entry, along with pathology report. Patients 
who consent and who have accessible disease will have tissue samples 
obtained by standard needle core biopsy at the time of disease progression as 
well. These samples will be analyzed by Dr. Alan Fields as described in 
Section 17.3. 
 
Forward FFPE tissue to the following laboratory: 
Laura Pacheco-Spann 
Pathology Research Core 
Mayo Biorepositories 
4500 San Pablo Road S. 
Jacksonville, FL 32224 
 
For quality assurance purposes, biopsy tissues will be fixed immediately in 10% 
phosphate-buffered formalin and fixed tissues will be embedded in paraffin. 
Tissue processing will occur at the BAP/PRC Laboratory, which is a College of 
American Pathologists (CAP) certified 
This laboratory follows the NCI guidelines (National Cancer Institute Best 
Practices for Biospecimen Resources, 2007) and develops customized Quality 
Assurance/Quality Control (QA/QC) policies and procedures for each study. In 


 
 
 
this particular study, the quality of biopsy tissues will be assessed by the study 
pathologist (Dr. Andras Khoor) on an H&E slide. For patients who have 
previously undergone biopsy, existing biopsy tissue may be used. 
 
Samples upon arrival will be accessioned into the biorepository through the 
Research Laboratory Information Management System (RLIMS), samples are 
to be forwarded to Dr. Alan Fields laboratory in Griffin Building in MCF. 
 
17.3 
Background 
 
Genomic DNA will be extracted from 5-3μm sections from the biopsy and 
subjected to PRKCI gene copy number analysis as described previously. Sections 
(3μm) from the biopsy will be processed for IHC using established protocols as 
described previously. 
Tissue sections will be stained with antibodies specific to PKCι, phospho-Ser298- 
Mek, phospho-Thr202/Tyr204-Erk, phospho-Ser473-Akt, phospho-Thr70-4E- 
BP1 and phospho-Ser240/244-S6 (Cell Signaling Technology Inc.) as previously 
described. 
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 our board certified lung pathologist, Dr. 
Andras Khoor. 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 
(Dr. Cherise Cortese). 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 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. Diagnostic Slides 
from Original and /or Recurrent Tissue. 
 
18.0 
Records and Data Collection Procedures 
Submission Timetable 
 
Initial Material(s) - 
 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
2 weeks after registration 
Baseline Adverse Event Form 
Pretreatment Measurement Form 
 
Baseline Research Tissue Submission 
Form (see Section 17.0) 
Baseline Concomitant Medication Form 
End of Active Treatment/Cancel 
Notification Form 
Submit 2 weeks after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
 
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 Form 
X2 
X 
Adverse Event Form 
X 
X 
Measurement Form 
X1 
X1 
 
Research Tissue Submission Form 
X (see Section 17.0) 
Concomitant Medication Form 
X 
X 
End of Active Treatment/Cancel 
X 


 
 
 
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Notification Form 
Notification Form – Grade 4 or 5 Non- 
AER Reportable Events/Hospitalization 
Form 
At each occurrence 
(see Section 10.0) 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
1. Submit supporting documentation of response or progression to the MCCC operations office 
via RAVE. 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
 
Follow-up Material(s) - 
 
 
CRF 
Event Monitoring Phase1 
q. 3 
months 
until PD2 
At PD2 
After 
PD q. 6 
mos. 
Death 
New Primary 
Event Monitoring Form 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
2. Submit supporting documentation of response or progression to the MCCC 
operations office via RAVE. 
 
 
19.0 
Budget 
 
19.1 
Costs charged to patient: Routine clinical care will be the responsibility of the 
patient and or their insurance carrier. 
 
19.2 
Items to be research funded: Serum gold levels; Sirolimus; Auranofin; Lipid 
Panel at Baseline, C2, C3, and C4; Research blood draw and tissue collection 
and processing. 
 
19.3 
Other budget concerns: None 


 
 
 
 
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Reck, M., J. von Pawel, et al. (2009). "Phase III trial of cisplatin plus gemcitabine with 
either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung 
cancer: AVAil." J Clin Oncol 27(8): 1227-34. 
 
Regala, R. P. et al. Atypical protein kinase C iota is an oncogene in human non-small cell 
lung cancer. Cancer Res 65, 8905-11 (2005). 
 
Regala, R. P. et al. Atypical protein kinase Ciota plays a critical role in human lung 
cancer cell growth and tumorigenicity. J Biol Chem 280, 31109-15 (2005). 
 
Regala, R. P., Thompson, E. A. & Fields, A. P. Atypical protein kinase C iota expression 
and aurothiomalate sensitivity in human lung cancer cells. Cancer Res 68, 5888-95 
(2008). 


 
 
 
Regala, R. P., Thompson, E. A. & Fields, A. P. Atypical Protein Kinase C{iota} 
Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells. Cancer Res 68, 
5888-5895 (2008). 
 
Regala RP, T., EA, Fields, AP. Atypical protein kinase Cι expression and aurothiomalate 
sensitivity in human lung cancer cells.  . Cancer Res. In press, July 15 (2008). 
 
Regala, R. P. et al. Atypical Protein Kinase C{iota} Is Required for Bronchioalveolar 
Stem Cell Expansion and Lung Tumorigenesis. Cancer Res (2009). 
 
Sabatini, D. M. (2006). "mTOR and cancer: insights into a complex relationship." Nat 
Rev Cancer 6(9): 729-34. 
 
  
Sandler, A., R. Gray, et al. (2006). "Paclitaxel-carboplatin alone or with bevacizumab for 
  
non- small-cell lung cancer." N Engl J Med 355(24): 2542-50. Erratum in N Engl J Med. 
  
2007 Jan 18;356(3):318 
 
Scagliotti, G. V., P. Parikh, et al. (2008). "Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with 
advanced-stage non-small-cell lung cancer." J Clin Oncol 26(21): 3543-51. 
 
Scagliotti, G., N. Hanna, et al. (2009). "The differential efficacy of pemetrexed according 
to NSCLC histology: a review of two Phase III studies." Oncologist 14(3): 253-63. 
 
Schiller, J. H. Current standards of care in small-cell and non-small-cell lung cancer. 
Oncology 61 Suppl 1, 3-13 (2001). 
 
Schiller, J. H., D. Harrington, et al. (2002). "Comparison of four chemotherapy regimens 
for advanced non-small-cell lung cancer." N Engl J Med 346(2): 92-8. 
 
Soria, J. C., F. A. Shepherd, et al. (2009). "Efficacy of everolimus (RAD001) in patients 
with advanced NSCLC previously treated with chemotherapy alone or with 
chemotherapy and EGFR inhibitors." Ann Oncol 20(10): 1674-81. 
 
Stallings-Mann, M. et al. A novel small-molecule inhibitor of protein kinase Ciota blocks 
transformed growth of non-small-cell lung cancer cells. Cancer Res 66, 1767-74 (2006). 


 
 
 
 
 
Appendix I: ECOG PERFORMANCE STATUS 
 
 
Grade 
 
0 
Fully active, able to carry on all pre-disease activities without restriction (Karnofsky 90 
100). 
 
1 
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 (Karnofsky 70-80). 
 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up 
and about more than 50 percent of waking hours   (Karnofsky 50-60). 
 
3 
Capable of only limited self-care, confined to bed or chair 50 percent or more of waking 
hours (Karnofsky 30-40). 
 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
(Karnofsky 10-20). 
 
5 
Dead 


 
 
 
Appendix II: PATIENT’S MEDICATION DIARY 
 
Today’s date   
 
Patient Name   
 
(initials acceptable) 
 
Patient Study ID   
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month. 
2. You will take 
pills each day.  You may take the pill(s) one hour before or 2 hours after eating, as you 
prefer. 
3. Record the date, the number of pills you took, and when you took them. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
3. 
Please bring your pill bottle and this form to your physician when you go for your next appointment. 
Date 
Day 
# pills and 
when 
taken 
Comments 
Date 
Day 
# pills and 
when 
taken 
Comments 
1 
17 
2 
18 
3 
19 
4 
20 
5 
21 
6 
22 
7 
23 
8 
24 
9 
25 
10 
26 
11 
27 
12 
28 
13 
29 
14 
30 
15 
31 
16 
Patient’s Signature: 
Date: 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
Date patient was removed from study 
 
2. Patient’s planned daily dose  
 Total number of pills taken this month 
Physician/Nurse/Data Manager’s Signature   
  
 
 


 
 
 
 
 
Appendix III: Percent of Normal Bone Marrow Irradiated 
using Standard Radiation Ports* 
 
 
Marrow Volume 
At Risk 
 
Skull (not including mandible) 
12% 
Upper limb girdle (unilateral) 
4% 
(humeral head, scapulae, clavicle) 
Sternum 
2% 
Ribs (all) 
8% 
Ribs (hemithorax) 
4% 
Cervical vertebrae (all) 
3% 
Thoracic vertebrae (all) 
14% 
Lumbar vertebrae (all) 
11% 
Sacrum 
14% 
Pelvis (including both innominates and both femoral 
26% 
heads and necks) 
Mantle (approximate) 
25% 
Upper para aortic nodes (approximate) 
11% 
Inverted Y (approximate) 
45% 
 
*Based on Ellis RE: Phys Med Biol 5:255, 1961 


63 
MC102A 
 
 
 
Appendix IV: 
Selected  drugs known to be metabolized  by CYP3A4 
 
 
When drugs classified as 'substrates' are co-administered with (Study Agent). there is the potential for higher concentrations of the 'substrate'. 
When {Study Agent) is co-administered with compounds classified as 'inhibitors', increased plasma concentrations of (Study Agent/ is the 
potential outcome. The co-administration of'inducers'  would  potentially lower plasma   (Study Agent) concentrations. 
CYP3A4 
 
Generic Name 
Anti-neoplastics: e.g. 
Docetaxel 
Gefitinib 
Irlnotecan 
Anti-virals: e.g. 
Amprenivir 
Rifampin 
I Trade Name 
 
Rifadin 
Anxio\ytics: e.g. 
Diazepam 
Sertraline 
 
 
Generic Name 
Anti-arrhythmics: e.g. 
Amlodarone 
Diltiazem 
 
Anti-virals: e.g. 
Amprenavir 
Indinavir 
Nelfinavir 
Ritonavir 
Cimetadine 
Trade Name 
 
 
 
Trade Name 
Cytadren 
Taxotere 
Iressa 
 
Cordarone, Pacerone 
Cardizem, Dilacor XR 
Cardioauin 
Crixivan 
Viracept 
Norvir 
Tagamet 
Antibiotics: e.g. 
 
Rifadin 
 
 
 
Cyc\osporine 
Anti-infectives: e.g. 
Erythromycin 
Tetracycline 
 
Sandimmune 
Sandimmune 
 
Carbamazapine 
Tegretol 
Phenytoin 
DHantin 
 
Phenobarbital 
Luminal 
 
Erythrocin 
Sumycin 
Steroids: e.g. 
Estrogens, conjugated 
Estradiol 
Progesterone 
Antibiotics: e.g. 
Ciprofloxacin 
Clarithromycin 
Doxycycline 
Enoxacin 
Isoniazid 
Telithromvcin 
Imatinib 
Cipro, Ciloxan 
Biaxin 
Adoxa, Periostat 
Penetrex 
Nydrazid, INH 
Ketek 
Gleevec 
C!imara 
Crinone 
 
 
 
Digitoxin 
Quinidine 
 i  Haldol 
Ji. _l_ p r.!9£1" --·· 
Diclofenac 
Haldol 
 
 
 
Crystodigin 
 
 
Anti-hypertensives: e.g. 
Nicardipine 
Verapamil 
Anesthetics: e.g. 
Ketamine 
Lidocaine 
Nefazodone 
 Cardene 
Calan. Chronovera 
j Xylocaine 
Ketoconazole 
Sildenafil 
Albuterol 
Carbamazapine 
Lovastatin 
 
 
 
 
 
Vasodi\ators: e.g. 
Nlcard_ipine 
yera12:amil 
Anesthetics: e.i: 
Lidocaine 
 
Anti-depressants: e.g. 
Sertraline 
 
Itraconazole 
Miconazole 
 
   
 
Cardene 
Calan, Chronovera 
 
 
 
Serzone 
 
Serzone 
 
I Xylocaine 
Cocaine 
Sporanox 
Nizoral 
Lotrimin, Monistat 
Caffeine 
 
 
  
 
 
 
 


64 
MC102A 
 
 
Comprehensive list of drngs that may have potential interactions with CYP3A4 
CYP3A4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP3A4 
Inhibitors 
Acetaminophen 
Diltiazem 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazo!e 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldioine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacro!imus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Acetazolamide 
Amioderone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithrornycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffiene 
Cerivastatin 
Chloramphcnico! 
Chlorzoxazone 
Cimetadine 
Ciorofloxacin 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamnrcnavir 
Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodiplne 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Cita\opram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disoovramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterlfied 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fu\vestrant 
Gefitinib 
Halofantrine 
Haloperido\ 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
ltraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl  acetate 
hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Monte!ukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardlpine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Pac!itax.e\ 
Pergolide 
Phencyclidine 
Pimozide 
Piog\itazone 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafi! 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
To\terodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamidc 
Zopic!one 


65 
MC102A 
 
 
 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Glyburide 
Grapefruit juice 
I-Ialoperidol 
Hydralazine 
Ifosfamide 
Nitrendipine 
Nizatidine 
Nortloxacin 
O!anzapine 
Omeprazo\e 
Tetracycline 
Ticlopidine 
Trany\cypromine 
Trazodone 
Troleandomycin 
Clozapine 
Imatinib 
Orphenadrine 
Valproic acid 
Cocaine 
Indinavir 
Oxybutynin 
Venlafaxine 
Cyclophosphamide 
Irbesartan 
Paroxetine 
Verapimil 
Cyclosporine 
Danazol 
Delavirdine 
lsoniazid 
Isradapine 
Itraconazole 
Pentamidine 
Pergolide 
Phencyclidine 
Vinb!astine 
Vincristine 
Vinorelbine 
Desipramine 
Ketoconazole 
Pilocarpine 
Zafirlukast 
Dexmedetomidinc 
Lansoprazole 
Pimozide 
Ziprasidone 
Diazepam 
Lidocaine 
Pravastatin 
Diclofenac 
Lomustine 
Prednisolone 
Dihydroergotamine 
Losartan 
Primaquine 
 
Inducers 
Aminoglutethimide 
Nevirapine 
Phenytoin 
Rifapentine 
Carbamazapine 
Oxcarbazepine 
Primidone 
Fosphenytoin 
Pentobarbital 
Rifabutin 
St. John's wort 
Phenobarbital 
Rifampin 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Annstrong LL, Goldman MP, Lance LL eds. Drug Infonnation 
Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
 
Potential  Drug Interactions: 
In vitro data indicate that sirolimus is an inhibitor for CYP2C9, CYP1A2, CYP2B6, 
CYP2C8, CYP2C19, CYP2D6, CYP2El, and CYP3A4. In animal studies, there were no 
GW786034-related effects on the activities ofCYPlA, CYP2B, CYP2E, CYP3A, and 
CYP4A. 
 
In vitro, the most potent inhibition was seen for the isoenzyme CYP2C9. Accordingly, the 
following medications which are substrates for CYP2C9 are PROHIBITED in subjects 
receiving sirolimus (the washout period is at the discretion of the clinician based on the 
pharmacokinetic properties of each individual agent): 
 
• 
Anticoagulants: warfarin  (therapeutic doses only) 
• 
Oral hypoglycemics: glipizide,  glyburide, tolbutamide,  glimepiride, nateglinide 
• 
Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine,  methylergonovine 
• 
Neuroleptic: pimozide 
• 
Erectile dysfunction  agents: sildenafil, tadalafil, vardenafil 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexilitine, amiodarone, quinidine, 
propafenone 
• 
Immune modulators:  cyclosporine,  tacrolimus, sirolimus 
• 
Miscellaneous: theophylline,  quetiapine,  risperidone, tacrine, cloazapine, atomoxetine 
 
Certain medications should be used with CAUTION due to the potential for alterations in the 
pharmacologic  effects or increased  adverse events secondary to the inhibition  of multiple 
CYP enzymes by sirolimus. These medications  include (but are not limited to): 
 
• 
Antidepressants: amitriptyline, buproprion,  fluoxetine,  fluvoxamine, imipramine 


66 
MC102A 
 
 
• 
HMG co-reductase  inhibitors: atorvastatin,  fluvastatin, lovastatin, simvastatin 
• 
Benzodiazepines: alprazolam,  midazolam, triazolam, clorazepate, diazepam,  flurazepam 
• 
Calcium channel blockers: diltiazem, felodipine, nifedipine, nicardipine, nimodipine, 
nitrendipine,  verapamil, amlodipine,  nisoldipine, isradipine 
• 
Angiotensin II blockers: losartan, irbesartan 
• 
Beta blockers: carvedilol,  metoprolol,  propanolol, timolol 
• 
Anticonvulsants:  phenobarbital, phenytoin,  primadone, carbamazepine 
• 
Miscellaneous: codeine, methadone, mifepristone, estrogens and progestins (including 
oral contraceptives) 
• 
Oral  hypoglycemics: pioglitazone, rosigitazone 
 
In vitro data also suggest that sirolimus is a substrate for CYP3A4. Therefore, substances that 
induce or inhibit CYP3A4  may alter the pharmacologic  effects of sirolimus and should  be 
used with CAUTION. These medications  include (but are not limited  to): 
 
Inhibitors of CYP3A4: 
• 
Antibiotics:  clarithromycin, erythromycin, troleandomycin 
• 
HIV: anti-retrovirals (delaviridine), protease inhibitors (ritonavir, indinavir, saquinavir, 
nelfinavir, amprenavir, lopinavir) 
• 
Antifungals:  itraconazole, ketoconazole,  voriconazole, fluconazole 
• 
Antidepressants: nefazodone,  fluvoxaine 
• 
Calcium channel blockers: verapamil,  diltiazem 
• 
GI: cimetidine, aprepitant 
• 
Miscellaneous: grapefruit  or its juice 
 
Inducers  of CYP3A4: 
• 
Glucocorticoids: cortisone (> 50 mg), hydrocortisone (> 40 mg), prednisone (>10 mg), 
methylprednisolone (> 8 mg), dexamethasone (> 1.5 mg)Anticonvulsants: phenytoin, 
carbamazepine,  Phenobarbital, oxcarbazepine 
• 
HIV: efavirenz, nevirapine 
• 
Antibiotics: rifampin, rifabutin,  rifapentine 
• 
Miscellaneous: St. John's wort, modafinil 

ICF_001.pdf: 
 
 
 
 
 
MC1125 / 11-001987 
 
 
A Phase I-II Trial of Combined PKCι and mTOR Inhibition for 
Patients with Advanced or Recurrent Lung Cancer (NSCLC and 
SCLC) without Standard Treatment Options 
 
 
NCT01737502 
 
 
Document Date: 09/28/2022 


  
  
 
IRB 11-001987 00  
Page 1 of 15 
MC1552rev0803 
 
Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
 
 
Name and Clinic Number 
 
IRB # 11-001987 00 
Consent form approved   September 28, 2022; 
This consent valid through   September 27, 2023; 
 
1. General Information About This Research 
Study  
 
Study Title:   MC1125, A Phase I-II trial of combined PKCι and mTOR inhibition for 
patients with advanced or recurrent lung cancer (NSCLC and SCLC) 
without standard treatment options  
 
Name of Principal Investigator on this Study: Dr. Yanyan Lou and Colleagues 
 
A.  Study Eligibility and Purpose 
 
You are being asked to take part in this research study because you have advanced or 
recurrent lung cancer (non-small cell lung cancer (NSCLC) or small cell lung cancer 
(SCLC)).  The primary purpose of your participation in this study is to help answer the 
following research questions: 
• To find out what effects (good or bad) the drugs Auranofin and sirolimus have on 
you and your lung cancer;  
• To find out if Auranofin and sirolimus can stop or slow the growth of your lung 
cancer;  
• To learn more about how Auranofin and sirolimus work against lung cancer by 
testing blood and tissue samples. 
 
The drugs used in this study are considered investigational for lung cancer. Both study 
drugs are approved for other diseases.  
 
As you read this form describing the study, ask any questions you have. Take your time 
to decide. Feel free to discuss the study with your family, friends, and healthcare provider 
before you decide. If you decide to participate, you may stop participating at any time 
during the study. You may decide not to participate. If so, none of your current benefits 
or normal health care will be affected in any way.  When you feel comfortable that all 
your questions have been answered, and you wish to take part in this study, sign this form 
in order to begin your participation. Your signature means you have been told about the 
study and what the risks are. Your signature on this form also means that you want to 
take part in this study.  
 
 


  
  
 
IRB 11-001987 00  
Page 2 of 15 
MC1552rev0803 
 
Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
B.  Number of Participants 
 
The plan is to have 47 people take part in this study at Mayo Clinic.  
 
C.  Additional Information You Should Know 
 
A grant from the National Cancer Institute is funding the study. This grant will pay Mayo 
Clinic to cover costs related to running the study.  
 
2. What Will Happen To You While You 
Are In This Research Study? 
 
If you agree to be in the study, you will be asked to participate in the following:  
 
Before you start any study treatment, you will have certain tests and procedures to 
determine if you can take part in this study. The researcher will look at your medical 
history, you will have a physical exam, and you will have standard blood tests and a urine 
test done. If you are a woman who can become pregnant, you will also have a pregnancy 
test. 
 
Treatment on this study will follow a 4-week schedule, and each 4-week period is known 
as a “cycle.” You will take auranofin and sirolimus by mouth every day. During your first 
week of medication you will only take the auranofin and will start the sirolimus on day 8. 
Every cycle of treatment thereafter you will take both drugs by mouth every day. Before 
the 8th week, your doctors will do tests to see how your cancer is responding to the study 
treatment. If it stays the same or is helped you will continue to get study treatment but if 
your cancer gets worse you will be taken off study treatment. If you are responding and 
stay on the study, you will have tests to see whether your cancer is growing about every 8 
weeks. If you come off study treatment, your cancer doctor will talk to you about other 
treatment options.  
 
Each week during the first cycle of treatment, you will have a blood test (approximately 1 
tablespoon of blood) and urine test completed. These tests are needed to measure your 
blood cell counts and blood chemistries and the protein in your urine. These tests will be 
repeated about every four weeks while you continue to participate in the study. 
 
You will continue to receive oral auranofin and sirolimus treatment until your disease 
gets worse and then the treatment will be stopped. 
 
You will be given a diary to record when you take auranofin and sirolimus study drug. 
While you are on this study you should avoid food and beverages containing grapefruit. 
Your study doctor can discuss this with you.  
 


  
  
 
IRB 11-001987 00  
Page 3 of 15 
MC1552rev0803 
 
Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
3. How Long Will You Be in This Research 
Study? 
 
You may remain in this study as long as you wish if you are not experiencing serious side 
effects and your cancer does not get worse. Your health status will be evaluated regularly 
and the results will be shared with you. 
 
4. Why You Might Want To Take Part In 
This Research Study 
 
This study may not make your health better. However, your participation in this research 
study may help develop a new medication for the treatment of Non-Small Cell Lung 
cancer that might benefit other cancer patients in the future. 
 
5. What Are the Risks Of This Research 
Study? 
 
Sirolimus 
 
Likely risks of sirolimus (events occurring greater than 20% of the time) 
 
• High blood pressure (Hypertension) 
• Headache 
• Pain 
• Insomnia 
• Acne 
• Increased fats in blood stream (Hypertriglyceridemia) 
• High blood cholesterol (Hypercholesterolemia) 
• Low blood potassium levels (Hypokalemia) 
• Low blood phosphorous levels 
• Trouble passing stools (Constipation) 
• Loose stools (Diarrhea) 
• Indigestion or heartburn (Dyspepsia) 
• Feeling sick to your stomach (Nausea) 
• Throwing up (Vomiting) 
• Infection 
• Decreased number of blood cells (platelets) that help to clot the blood which 
could increase risk of bleeding (Thrombocytopenia) 


  
  
 
IRB 11-001987 00  
Page 4 of 15 
MC1552rev0803 
 
Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
• Decrease in red blood cells, which are the oxygen carrying cells, which could 
make you feel tired (Anemia) 
• Joint pain (Arthralgia) 
• Shortness of breath (Dyspnea) 
• Weakness 
• Tremor 
• Reduced kidney function or Increased blood level of creatinine (a substance 
normally eliminated by the kidneys into the urine) 
 
Less likely risks of sirolimus (events occurring less than or equal to 20% of the time) 
 
• Poor wound healing 
• Pale or reddened irregular, elevated patches of skin and severe itching, hives 
• Wide-spreading inflammation and/or rash that goes deep into the skin. 
• Collection of fluid in the body overall, and/or in the facial area (edema or 
swelling of the face, hands or feet) 
• Collection of fluid or blood in the lungs 
• Catheter infection 
• Infection in the bloodstream 
• Fungal yeast infection 
• Urinary tract infection 
• Conjunctivitis (infection around the eye, also called pink eye) 
• Recurrence of herpes simplex infection, which may cause sores in the mouth or 
on the lips, inflammation of the gums and throat, and recurrence of genital herpes 
• Inflammation of the tongue 
• Mouth pain 
• Low calcium in the blood that can result in muscle cramps, abdominal cramps, 
spasms 
• Elevated levels of phosphorus in the blood 
• Confusion 
• Dizziness 
• Inability to sleep, or abnormal wakefulness 
• Depression 
• Dehydration 
• Distention/bloating of the belly 
• Weight loss 
• Anxiety (nervousness) 
• Fast heart rate 
• Tingling in fingers and toes 
• Chest pain not heart-related 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Abnormal control of blood sugar level 
• Sleepiness 


  
  
 
IRB 11-001987 00  
Page 5 of 15 
MC1552rev0803 
 
Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
• Problem of the sinuses 
• Dry Skin 
 
Rare but serious risks of sirolimus (events occurring less than 2-3% of the time 
 
• A condition in which fluid and proteins leak out of tiny blood vessels and flow 
into 
• surrounding tissues, resulting in dangerously low blood pressure which may lead 
to multiple organ failure and shock 
• Blood clot in vein or artery (Deep venous and arterial thrombosis) 
• Abnormal liver function tests/Liver failure 
• Hypersensitivity reaction 
• Infection that has spread to the bloodstream and can cause low blood pressure, 
fever, and/or death (Sepsis) 
• Cancer of lymph nodes (Lymphoma) 
• Kidney failure (Renal failure) 
• Inflammation of the tissue and space around the air sacs of the lungs (Interstitial 
pneumonitis) 
• Bleeding from the lungs or respiratory tract (Pulmonary hemorrhage) 
• Exfoliative Dermatitis 
 
Sirolimus may cause active immunizations to be less effective. Thus, the use of live 
vaccines should be avoided while taking sirolimus. 
 
Auranofin 
 
Likely risks of Auranofin (events occurring greater than 20% of the time) 
 
• Rash 
• Loose stools or diarrhea 
 
Less likely risks of Auranofin (events occurring less than or equal to 20% of the time) 
 
• Abdominal pain 
• Weight loss due to reduction of appetite (Anorexia) 
• Flatulence 
• Indigestion or heartburn (Dyspepsia) 
• Nausea with or without vomiting 
• Unpleasant sensation that causes the need to scratch (Pruritis) 
• Inflammation of the stomach (Stomatitis) 
• Inflammation or infection of the lining of the eyelids (Conjunctivitis) 
• Excess serum proteins in the urine (Proteinuria) 
 


  
  
 
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This Consent Valid Through: September 27, 2023 
Rare but serious risks of Auranofin (events occurring less than 2-3% of the time) 
 
• Constipation 
• Alteration in the sense of taste (Dysgeusia) 
• Hives (Urticaria) 
• Hair Loss 
• Inflammation of the tongue (Glossitis) 
• Decrease in number of red blood cells (Anemia) 
• Decrease in the number of white blood cells (Leukopenia) 
• Decrease of platelets in blood (Thrombocytopenia) 
• Higher than normal level of white blood cells (Eosinophilia) 
• Presence of red blood cells in the urine (Hematuria) 
• Elevated liver enzymes 
• Rapid swelling of the tissues just below the surface of the skin (Angioedema) 
• Inflammation of the gums (Gingivitis) 
• Bone marrow does not produce enough new cells to replenish blood cells 
(Aplastic anemia) 
• Low number of neutrophils (Neutropenia) 
• An acute disease characterized by high fever, lesions of the mucous membranes 
and skin, and a sharp drop in circulating granular white blood cells 
(Agranulocytosis) 
• A type of anemia caused by selective depletion of erythroid cells (Pure red cell 
aplasia) 
• Abnormal depression of all the cellular elements of the blood (Pancytopenia) 
• Skin and the whites of the eyes are discolored yellow due to an increased level of 
bile pigments in the blood (Jaundice) 
• Inflammation of the tissue and space around the air sacs of the lungs (Interstitial 
Pneumonitis) 
• Damage to nerves of the peripheral nervous system (Peripheral Neuropathy) 
• Gold deposits in the lens or cornea unassociated clinically with eye disorders or 
visual impairment 
 
As with any medication, allergic reactions are a possibility.   
 
The risks of drawing blood include pain, bruising, and rarely, infection at the site of the 
needle stick. 
 
Risks of Biopsy: The risks of biopsies include, pain, bruising, bleeding and infection at 
the biopsy site. 
 
Standard of care risks 
 
Your doctor will discuss the risks of radiographic imaging (CT scans, MRIs, X-rays and 
standard blood tests) as these tests and procedures are part of your standard clinical care. 


  
  
 
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Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
 
Pregnancy and Birth Control:  
 
1)  Will women of child-bearing-potential be allowed to participate in this study? 
 
Yes: Women of child-bearing-potential will be able to participate in this study if they 
have a negative pregnancy test and agree to use acceptable birth control (see #5) since 
the risks to an unborn child are either unknown or potentially serious. 
 
2)  Will pregnant and/or nursing women be allowed to participate in this study?  
 
No:  There is not enough medical information to know what the risks might be to a 
breast-fed infant or to an unborn child carried by a woman who takes part in this 
study.  Breast-feeding mothers must stop breast-feeding to take part in this study. 
 
3)  Do you need to have a pregnancy test done to be part of the study?  
 
Yes: As part of this study a pregnancy test is required for all women who are able to 
become pregnant. 
 
A blood pregnancy test will be done by taking blood from your arm.  
 
 
You will be told the results of the pregnancy test. If the pregnancy test is positive, you 
will not be able to take part in the study. 
 
4)  Will men who are able to father a child be allowed to participate in this study? 
 
Yes:  Men who are able to father a child will be able to participate in this study if they 
agree to use acceptable birth control (see #5) since the risks to an unborn child are 
either unknown or potentially serious. 
 
5)  What types of birth control are acceptable?  
 
Surgical sterilization 
Approved hormonal contraceptives (such as birth control pills, Depo-Provera) 
Barrier methods (such as a condom or diaphragm) used with a spermicide 
An intrauterine device (IUD) 
Abstinence 
 
Risk summary  
 
Many side effects go away shortly after sirolimus and/or auranofin are stopped, but in 
some cases side effects can be serious, long lasting, or may never go away. There may be 
a risk of death. 
 


  
  
 
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This Consent Valid Through: September 27, 2023 
Some side effects may not be known. Side effects may range from mild to life-
threatening. Other drugs may be given to make side effects less serious and less 
uncomfortable. Talk to the researcher and/or your healthcare provider about side effects 
and ask any other questions. 
 
6. What Other Choices Do You Have If You 
Don’t Take Part In This Research Study? 
 
You do not have to be in this study to receive treatment for your condition. Your other 
choices may include: 
• Another chemotherapy 
• Other investigational drugs 
• No anti-cancer therapy with full supportive care for your symptoms (sometimes 
called comfort or palliative care) 
• Other care measures to manage your symptoms that may include pain, infection, 
nausea, vomiting, etc., will be offered to you, as needed, regardless of whether 
you participate in this trial. 
 
You should talk to the researcher and your regular physician about each of your choices 
before you decide if you will take part in this study. 
 
7. Are There Reasons You Might Leave 
This Research Study Early? 
 
Taking part in this research study is voluntary. You may decide to stop at any time. You 
should tell the researcher if you decide to stop and you will be advised whether any 
additional tests may need to be done for your safety.  
 
In addition, the researchers or Mayo may stop you from taking part in this study at any 
time: 
• If it is in your best clinical interest,  
• If you do not follow the study procedures,  
• If the study is stopped.  
 
 


  
  
 
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This Consent Valid Through: September 27, 2023 
8. Will You Need To Pay For Any Of The 
Tests And Procedures? 
 
You will not need to pay for tests and procedures which are done just for this research 
study.  These tests and procedures are: 
• Research tissue samples (baseline and end of treatment, if applicable) 
• Oral Sirolimus and Auranofin (daily) 
• Lipid panel at baseline, prior to cycle 2, and every other cycle through cycle 6 
 
However, you and/or your health plan will need to pay for all other tests and procedures 
that you would normally have as part of your regular medical care.  These tests and 
procedures are: 
• Physical exams (baseline and every 4 weeks and end of treatment) 
• Routine Blood Tests (baseline, weekly during cycle 1, every 4 weeks and end of 
treatment) 
• PET/CT or CT scans (baseline, every 8 weeks and end of treatment) 
• Urine tests (baseline and every 4 weeks and end of treatment) 
• Serum pregnancy test (baseline) 
• Tumor biopsy at the end of treatment if your disease progresses 
• Lipid panel as clinically indicated 
 
If you have study related questions regarding billing, insurance or reimbursement, 
stop by:  
 
Arizona:  The concourse level Patient Financial Services office or call this office at  
(800) 603-0558. 
 
9. Will You Be Paid For Participating In 
This Research Study? 
 
You will not be paid for taking part in this study. 
 


  
  
 
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Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
10. What Happens If You Are Injured Or Ill 
Because You Were In This Research 
Study? 
 
If you have side effects from the study treatment, you need to report them to the 
researcher and your regular physician, and you will be treated as needed. Mayo will bill 
you or your insurer for these services at the usual charge. Mayo will not offer free 
medical care or payment for any bad side effects from taking part in this study. 
 
11. What Are Your Rights If You Are In 
This Research Study? 
 
Taking part in this research study will not change your rights and benefits. Taking part in 
this research study does not give you any special privileges. If you decide to not 
participate in this study, or stop in the middle of the study, no benefits are taken away 
from you. You do not have to be in this research study to receive or continue to receive 
medical care from Mayo Clinic. 
 
You will be told of important new findings or any changes in the study or procedures that 
may affect you or your willingness to continue in the study. 
 
12. What About Your Privacy? 
 
Authorization To Use And Disclose Protected Health Information 
 
Your privacy is important to us, and we want to protect it as much as possible. By signing 
this form, you authorize Mayo Clinic and the investigators to use and disclose any 
information created or collected in the course of your participation in this research 
protocol. This information might be in different places, including your original medical 
record, but we will only disclose information that is related to this research protocol for 
the purposes listed below. 
 
This information will be given out for the proper monitoring of the study, checking the 
accuracy of study data, analyzing the study data, and other purposes necessary for the 
proper conduct and reporting of this study. If some of the information is reported in 
published medical journals or scientific discussions, it will be done in a way that does not 
directly identify you. 
 


  
  
 
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This Consent Valid Through: September 27, 2023 
This information may be given to other researchers in this study, including those at other 
institutions, or private, state or federal government parties or regulatory authorities in the 
USA and other countries responsible for overseeing this research. These may include the 
Food and Drug Administration, the Office for Human Research Protections, or other 
offices within the Department of Health and Human Services, and the Mayo Clinic Office 
for Human Research Protections or other Mayo groups involved in protecting research 
subjects. 
 
In addition, individuals involved in study oversight and not employed by Mayo Clinic 
may be allowed to review your health information included in past, present, and future 
medical and/or research records. This review may be done on-site at Mayo Clinic or 
remotely (from an off-site location). These records contain information that directly 
identifies you. However, the individuals will not be allowed to record, print, or copy 
(using paper, digital, photographic or other methods), or remove your identifying 
information from Mayo Clinic. 
 
This information may include information relating to sexually transmitted disease, 
acquired immunodeficiency syndrome (AIDS), or human immunodeficiency virus (HIV).  
It may also include information relating to behavioral or mental health services or 
treatment and treatment for substance abuse 
 
If this information is given out to anyone outside of Mayo, the information may no longer 
be protected by federal privacy regulations and may be given out by the person or entity 
that receives the information.  However, Mayo will take steps to help other parties 
understand the need to keep this information confidential. 
 
This authorization lasts forever. 
 
You may stop this authorization at any time by writing to the following address: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN:  Notice of Revocation of Authorization 
200 1st Street SW 
Rochester, MN  55905 
 
If you stop authorization, Mayo may continue to use your information already collected 
as part of this study, but will not collect any new information.  
 
If you do not sign this authorization, or later stop authorization, you may not be able to 
receive study treatment.  
 
 
 


  
  
 
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This Consent Valid Through: September 27, 2023 
13. What Will Happen to Your Samples? 
 
Your tissue sample will be kept at Mayo for use in this study. Researchers at Mayo who 
are not involved with this study may ask to use your sample for more research. You have 
a say in how your stored sample is used in future research. You can still take part in the 
study without giving your sample for future use.   
 
Identification information:  
If you agree to allow your sample to be used for further research, the sample may be 
stored forever. The sample will be stored at Mayo and would be given a code (instead of 
your name) while it is stored and when it is used in research. This code allows your 
sample to be used without anyone knowing that it is your sample just by looking at the 
label. 
 
There is a very small chance that some commercial value may result from the use of your 
donated sample.  If that happens, you will not be offered a share in any profits. 
 
Risks: 
Some future studies may be for testing the genes you inherited from your parents (also 
known as genetic testing). If a researcher finds that future test results may be useful for 
your health care, you will be contacted and given the choice to learn the test results. At 
that time, you will be given general information on the potential risks, benefits, and costs 
of choosing to learn the test results. The risks of learning genetic test results may include 
emotional upset, insurance or job discrimination, and/or family conflicts from learning 
unknown information about your parents or blood relatives. Test results will only be put 
into your medical record if you chose to learn the results.  Sometimes results should be 
released only through a genetic counselor, who can help explain the possible risks and 
benefits of learning the results. 
 
Exceptions when your samples may be used without your permission:  
1)  When government rules allow your sample to be used without identifying you, 
even with a code. 
2)  When use of the sample is not considered human subject research.   
 
At all other times:   
-You can let Mayo use your sample.  
-You can say NO to have your sample used by Mayo. 
 
Please read the following statements and mark your choice: 
1.  I permit my tissue sample to be stored and used in future research of lung cancer at 
Mayo: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 


  
  
 
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This Consent Valid Through: September 27, 2023 
2.  I permit my tissue sample to be stored and used in future research at Mayo to learn 
about, prevent, or treat any other health problems: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
Who will use your sample? 
If you agree to give your sample, it will be the property of Mayo and may be used for 
research by the investigators and other staff at Mayo Clinic. Researchers at other 
institutions may also ask for a part of your sample for future studies.  
 
If you want your sample destroyed at any time, write to:  
Yanyan Lou, MD 
Mayo Clinic in Florida 
4500 San Pablo Road 
Jacksonville, FL 32224 
 
If you move please send your new address to:  
Mayo Clinic in Arizona 
Section of Registration 
13400 East Shea Boulevard 
Scottsdale, AZ 85259 
 
 
 


  
  
 
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Consent Form Approved: September 28, 2022  
 
This Consent Valid Through: September 27, 2023 
14. Who Can Answer Your Questions? 
 
 
You can call … 
At … 
If you have questions concerns 
about … 
Principal Investigator: 
Dr. Panayiotis Savvides  
(Arizona) 
 
Yanyan Lou, M.D., PhD 
(Florida) 
 
 
 
Phone:  
(480) 301-8000 
 
Phone: 
(904) 953-2000 
Questions about the study tests 
and procedures 
 
Research-related injuries or 
emergencies 
 
Any research-related concerns or 
complaints 
Mayo Clinic IRB  
 
 
Research Subject 
Advocate  
 
Phone: 
(507) 266-4000 
 
Toll-Free: 
(866) 273-4681 
Rights of a research subject 
 
Use of Protected Health 
Information 
 
Any research-related concerns or 
complaints 
Patient Account 
Services  
Toll Free:  
(844) 217-9591  
Billing / Insurance 
Questions 
 
15. Summary and Enrollment Signatures 
 
You have been asked to take part in a research study at Mayo Clinic.  The information 
about this study has been provided to you to inform you about this study. 
 
• I have read the whole consent form, and all of my questions have been answered 
to my satisfaction. 
• I am satisfied that I have been given enough information about the purpose, 
methods, risks, and possible benefits of the study to decide if I want to join. 
• I know that joining the study is voluntary and I agree to join the study. 
• I know that I can call the investigator and research staff at any time with any 
questions or to tell them about side effects. 
• I know that I may withdraw from the study at any time. 
• A copy of this form will be put in my medical records and I will be given a copy 
of this completed form. 
 
 
 


  
  
 
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Please sign and date to show that you have read all of the above guidelines.  Please do not 
sign unless you have read this entire consent form.  If you do not want to sign, you don’t 
have to, but if you don’t you cannot participate in this research study.  
 
 
 
______________   
__________________________________________    ________________ 
(Date / Time) 
(Printed Name of Participant) 
(Clinic Number) 
 
 
_____________________________________________ 
(Signature of Participant) 
 
 
 
______________ 
_______________________________________________ 
(Date / Time) 
(Printed Name of Individual Obtaining Consent) 
 
 
 _______________________________________________ 
(Signature of Individual Obtaining Consent)