Phase II Trial of Exemestane in Previously Treated Post-Menopausal Women With Advanced Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Sponsor: Masonic Cancer Center, University of Minnesota

Masonic Cancer Center 
University of Minnesota 
 
 
 
Phase II Trial of Exemestane in Previously Treated Post-Menopausal 
Women with Advanced Non-Small Cell Lung Cancer 
CPRC# 2015LS095 
Pfizer Reference Number W1209610 
 
Principal Investigator: 
Manish R Patel, DO 
Hematology, Oncology and Transplantion 
 
 
Co-Investigators: 
Jill M Siegfried, PhD* 
Department of Pharmacology 
*non-clinical co-investigator 
 
Robert A Kratzke, MD 
Naomi Fujioka, MD 
Hematology, Oncology and Transplantation 
 
 
Biostatistician: 
Todd E. DeFor, MS 
 
 
Version Date: 
July 17, 2020 
 
 
 
Confidential 
 
 

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Revision History 
Version 
# 
Version 
Date 
Summary of Changes 
Consent 
Revision? 
 
08/18/2015 
original to CPRC 
n/a 
 
10/05/2015 
In response to CPRC review minor stipulations: 
 Section 6.3 – patients experiencing a Grade 4 treatment related 
toxicity will be permanently discontinued from exemestane 
therapy; 
 Synopsis, Sections 1.2, 8, 9, 12.2 and Appendix VI – add 
completion of the quality of life questionnaire (PROMIS-29 Profile) 
before beginning exemestane, every 3 weeks while on study drug, 
and at the final treatment visit. 
 Section 13.3 – expand description of biomarker analysis and 
indicate they will not be a surrogate 
Additional changes: 
 Synopsis, Section 4.1.2 and Eligibility Checklist –Require archived 
tumor tissue to be available at study enrollment for research 
related analysis  
 Clarify enrollment will be 56 patients over 2 years 
n/a 
 
01/07/2016 
Initial version to the IRB 
 Add Pfizer related information regarding drug ordering (section 7) 
and SAE reporting (section 10.3) 
 Other minor clarifications through-out  
 
 
02/29/2016 
In response AURPAC stipulations (interim version – not submitted to 
IRB) 
 Sections 6.2 and 9.1 – change Dexa scan to every 12 months 
while receiving exemestane (previously every 3 months)  
yes 
 
04/05/2016 
In response to IRB and AURPAC stips (incorporates 2/29/2016 
version provided to AURPAC only) 
Two minor updates to the protocol: 
 Section 4.1.2 - change the number of unstained pathology slides 
from archived tumor tissue required for eligibility from 3 to 5 
 Section 9.1 – research related blood collection: replace a 10 ml 
red top tube with a 10 ml Cell-Free DNA BCT tube  
yes 
1 
05/26/2016 
Eligibility criteria – Synopsis, Sections 3 and 4 – simplify eligibility 
criteria 
 make less restrictive by removing upper limit of previous 
treatments permitted (previously limited to no more than 3 prior 
treatments) and simplify text in Section 4.1.3 by deleting 
definitions of treatment types (adjuvant vs maintenance etc.);  
 lower required hemoglobin count to 8 g/dL (from 9) at enrollment 
as exemestane does not affect blood counts; 
 simplify time from previous treatment requirements 
Synopsis, Sections 4.2.2 and 6.2 - delete exclusion of women 
diagnosed with osteoporosis; add in Section 6.4 that women with 
osteoporosis should be on treatment with calcium/vitamin D and/or 
bisphosphonates 
Section 9 – Schedule of Activities  
 add row for disease re-assessment (previously missing)  
 add an X to the CT of chest/abd/pelvis box under every 6 weeks 
for disease re-assessment, add a comment no need to repeat at 
final study visit if done in previous 6 weeks 
other clarifications and edits including: 
Section 1.2 add follow-up for survival is for up to 1 year 
Section 9 - add a row to monitor for stopping rules; require DEXA at 
baseline only if not done in previous 12 months; change blood 
yes 

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Version 
# 
Version 
Date 
Summary of Changes 
Consent 
Revision? 
volumes for research tubes but total volume unchanged, delete the 
cycle 12 research sample 
Section 9. 2 – add a statement regarding testing of tumor tissue 
Section 13.1 – edit follow-up for response and survival as 12 months 
from enrollment not through 12 months post-treatment to match rest 
of protocol 
Appendix I – update to reflect changes to Section 4 
2 
04/17/2018 
 Update protocol through-out to enroll post-menopausal women 
who are progressing on FDA approved immune checkpoint 
blockade (e.g. pembrolizumab, atezolizumab, or nivolumab) with 
exemestane being an add on therapy 
 Updated protocol to current template language 
 
yes 
3 
09/05/2019 
 Sections 4.1 and 9.1 – remove PT/INR criteria as prolonged INR 
or PTT due to anticoagulation should not be exclusionary 
 Sections 6.2. and 9 - Remove references to every 2 week 
nivolumab as now may be given less frequently per current 
package insert 
 Update to current template including deleting eligibility checklist as 
Appendix I and renumbering all appendices, and other edits 
 Update for future MNCCTN participation 
 
yes 
4 
02/21/2020 
 Section 4.1.1 – - Patients with EGFR/ALK/ROS1 rearrangements 
should have received an FDA-approved TKI prior to enrollment on 
this trial 
 Section 6.1.1 Exemestane Expected Toxicity – change risk section 
to table format based on NCI risk formatting – change common 
risk from 10% to 20% of patients potentially experiencing, reword 
and reorganize some of the risks, add possible liver damage, 
allergic reaction, and vaginal bleeding under rare occurrence and 
hair thinning or changes under occasional  
 Section 6.4 – Duration of Treatment – permit up to a 6 week break 
from exemestane Section 9.1 – currently up to 3 weeks 
 Section 9.1 – Add footnote #4 in the table, clarify that 
questionnaire completion, like research blood collection is tied to 
the clinical calendar. 
 Update the term Primary Clinical Research Coordinator to the 
more general term Study Coordinator 
 
yes 
5 
07/17/2020 
Revert back to the September 2019 risk profile (current IRB 
approved protocol) with updated risks based on Micromedex: 
Section 2.3 – state Micromedex is the source of the toxicity profile 
Section 6.1.1 – revert back to the September 2019 version with new 
risks tracked (gastric ulcer, cholestatic hepatitis, hair loss or 
thinning, increased alk phos 
yes 
 
PI Contact Information: 
Manish R Patel, DO 
Department of Medicine 
Division of Hematology, Oncology and Transplantation 
MMC 480 Mayo 8480A 
420 Delaware Street SE 
Minneapolis, MN 55455 
Phone:  612-624-6490   Email:  patel1069@umn.edu 
 

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Table of Contents 
 
Abbreviations ................................................................................................................................................ 6 
Synopsis ........................................................................................................................................................ 7 
Treatment Schema ........................................................................................................................................ 8 
1 
Objectives .............................................................................................................................................. 9 
1.1 
Primary Objective .......................................................................................................................... 9 
1.2 
Secondary Objectives ................................................................................................................... 9 
2 
Background and Rationale .................................................................................................................... 9 
2.1 
Advanced Non-Small Cell Lung Cancer ....................................................................................... 9 
2.2 
Therapeutic Potential of Targeting the Estrogen Receptor Pathway in NSCLC ......................... 10 
2.3 
Exemestane ................................................................................................................................ 13 
2.4 
Anti-PD-1/Anti-PDL-1 Therapy for NSCLC ................................................................................. 14 
2.5 
Rationale ..................................................................................................................................... 14 
3 
Study Design ....................................................................................................................................... 15 
4 
Patient Selection ................................................................................................................................. 15 
4.1 
Inclusion Criteria ......................................................................................................................... 15 
4.2 
Exclusion Criteria ........................................................................................................................ 17 
5 
Patient Registration and Study Enrollment ......................................................................................... 18 
5.1 
Registration with the Masonic Cancer Center Clinical Trials Office............................................ 18 
5.2 
Study Enrollment with the Masonic Cancer Center Clinical Trials Office ................................... 18 
5.3 
Patients Who Are Enrolled and Do Not Receive Study Treatment ............................................. 18 
6 
Treatment Plan .................................................................................................................................... 18 
6.1 
Exemestane Dosing Plan ............................................................................................................ 18 
6.1.1 
Exemestane Expected Toxicity ............................................................................................... 19 
6.1.2 
Exemestane Dose Interruptions and Modifications ................................................................. 20 
6.2 
Immune Checkpoint Blockade Therapy ...................................................................................... 20 
6.3 
Supportive Care and Prohibited Medications .............................................................................. 21 
6.4 
Duration of Study Treatment ....................................................................................................... 21 
6.5 
Duration of Study Participation .................................................................................................... 22 
7 
Exemestane Drug Information ............................................................................................................ 22 
8 
Measurement of Effect ........................................................................................................................ 24 
9 
Schedule of Activities .......................................................................................................................... 24 
9.1 
Schedule of Patient Tests and Procedures ................................................................................. 25 
9.2 
Research Related Tests and Procedures ................................................................................... 26 
10 
Adverse Event Monitoring, Recording and Reporting ......................................................................... 27 

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10.1 
Definitions .................................................................................................................................... 27 
10.2 
Adverse Event Monitoring and Documentation ........................................................................... 28 
10.3 
Stopping Rule Events .................................................................................................................. 29 
10.4 
SAE and Death Documentation .................................................................................................. 29 
10.5 
MNCCTN Required Reporting To the MCC CTO ....................................................................... 30 
10.6 
Required Reporting By the CTO to UMN IRB, Pfizer, and MCC SAE Coordinator .................... 30 
11 
Study Data Collection and Monitoring ................................................................................................. 31 
11.1 
Data Management ....................................................................................................................... 31 
11.2 
Case Report Forms ..................................................................................................................... 31 
11.3 
Data and Safety Monitoring Plan (DSMP) .................................................................................. 32 
11.4 
Investigational New Drug (IND) Assessment .............................................................................. 32 
11.5 
Monitoring .................................................................................................................................... 32 
11.6 
Record Retention ........................................................................................................................ 32 
12 
Study Endpoints .................................................................................................................................. 33 
12.1 
Primary Endpoint ......................................................................................................................... 33 
12.2 
Secondary Endpoints .................................................................................................................. 33 
13 
Statistical Considerations .................................................................................................................... 33 
13.1 
Study Design, Objectives and Endpoints .................................................................................... 33 
13.2 
Sample Size ................................................................................................................................ 34 
13.3 
Statistical Analysis ...................................................................................................................... 34 
13.4 
Monitoring Guidelines ................................................................................................................. 34 
14 
Conduct of the Study ........................................................................................................................... 35 
14.1 
Good Clinical Practice ................................................................................................................. 35 
14.2 
Ethical Considerations ................................................................................................................ 35 
14.3 
Informed Consent ........................................................................................................................ 35 
15 
References .......................................................................................................................................... 36 
Appendix I – ECOG Performance Status .................................................................................................... 39 
Appendix II - Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) ................. 40 
Methods for Evaluation of Measurable Disease ..................................................................................... 41 
Appendix III– Strong CYP3A4 Inducers ...................................................................................................... 46 
Appendix IV – Potential Risks of Standard of Care Anti-PD1/PDL-1 Therapy ........................................... 47 
Appendix V - Daily Drug Log ....................................................................................................................... 50 
Appendix VI - PROMIS -29 Profile .............................................................................................................. 52 
 
 

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Abbreviations 
 
 
 
AI 
aromatase inhibitor 
BMD 
bone mineral density 
CPRC 
Cancer Protocol Review Committee 
CNS 
central nervous system 
CR 
complete response 
CTO  
Clinical Trials Office 
ECOG 
Eastern Cooperative Oncology Group 
e-CRF 
electronic case report form 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
ICB 
immune checkpoint blockade 
IRB 
Institutional Review Board 
MCC 
Masonic Cancer Center 
MDSC 
myeloid derived suppressor cells 
MNCCTN 
Minnesota Cancer Clinical Trials Network 
NSCLC 
non-small cell lung cancer 
OnCore 
Online Enterprise Research Management Environment 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
standard of care 
 
 
 

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Synopsis 
Phase II Trial of Exemestane in Previously Treated Post-Menopausal Women with 
Advanced Non-Small Cell Lung Cancer 
Study Design: 
This is a phase II therapeutic study of adding exemestane therapy in post-menopausal women 
with advanced non-small cell lung cancer (NSCLC) who are progressing while on treatment with 
an immune checkpoint blockade antibody (pembrolizumab, atezolizumab, or nivolumab). 
 
Enrollment will use a two-stage design. Stage 1 will enroll 10 patients. If at least 2 objective 
responses are observed at the first disease re-evaluation after beginning oral exemestane, Stage 
2 will be activated. In Stage 2, an additional 19 patients will be enrolled for a total of 29 patients. If 
4 or more objective responses are observed in the 29 patients, exemestane will be deemed worthy 
of further investigation in this population. 
 
Primary 
Objective: 
To determine a preliminary estimate of response of daily oral exemestane for the treatment of 
previously treated, advanced non-small cell lung cancer (NSCLC) in post-menopausal women 
receiving and progressing on immune checkpoint blockade (ICB) therapy. 
 
Secondary 
Objectives: 
 To determine the toxicity profile of daily exemestane in combination with immune checkpoint 
blockade therapy in this patient population. 
 To estimate the disease control rate, progression-free survival (PFS), and overall survival (OS) 
of exemestane in this patient population through 1 year from study enrollment.  
 To estimate quality of life during treatment and for 1 month after discontinuation. 
 
Correlative 
Objectives:  
 To conduct an exploratory biomarker correlative study of clinical outcome utilizing archived 
tumor tissue and serum collected at baseline and serially during therapy.  
 To examine biomarkers in tissue post-treatment at the time of re-biopsy, if performed. 
 To examine serum biomarkers of the peripheral immune response after aromatase inhibition. 
 
 
Treatment Plan 
Eligible, consenting patients will take exemestane 25 mg once daily by mouth after a meal for a 
minimum of 6 weeks (2 treatment courses) while continuing on treatment with an FDA-approved 
anti-PD1 or anti-PD1 antibody. A disease re-evaluation will be performed at 6 weeks and those 
experiencing a complete response (CR), partial response (PR) or stable disease (SD) based on 
the Response Evaluation Criteria in Solid Tumors (RECIST) may continue exemestane daily with 
standard of care ICB until disease progression, unacceptable side effects, or patient refusal/non-
compliance. Patients are seen in clinic every 3 weeks with a disease re-evaluation every 6 weeks.  
 
An end of treatment visit occurs 4 weeks after the last dose of exemestane or the start of a new 
therapy, whichever is earlier. All patients are followed for response until disease progression or the 
start of a new treatment, then for survival through 1 year from study enrollment. 
 
Key Inclusion 
Criteria 
 Advanced stage non-small cell lung cancer (NSCLC) currently receiving an FDA approved anti-
PD1 or anti-PDL1 therapy with progressive disease 
 Sufficient tumor tissue from the diagnostic or subsequent biopsy either as a block or a 
minimum of 5 slides for estrogen receptor and aromatase analysis 
 Failed at least 1 prior FDA approved treatment regimen for advanced NSCLC - Patients with 
EGFR/ALK/ROS1 rearrangements should have received an FDA-approved TKI prior to 
enrollment on this trial. 
 Measureable disease per RECIST 
 Post-menopausal defined as 1 year or more of amenorrhea and if < 55 years of age estradiol 
assay < 20 pg/mL 
 ECOG performance status 0, 1, or 2 
 
Key Exclusion 
Criteria 
 Untreated or unstable CNS disease 
 Inability or unwillingness to swallow tablets 
 Currently using hormone replacement therapy (oral or patch) or/and phytoestrogen 
supplements (i.e. black cohosh) 
 
Enrollment: 
Stage 1: 10 patients, Stage 2 if activated, 19 additional patients 
 
 

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Treatment Schema 
 
 
 
* or unacceptable toxicity, patient refusal/noncompliance/> 3 week break from therapy, or, in the opinion 
of the treating physician stopping therapy is in the best interest of the patient 
 
- Clinic visit every 3 weeks during treatment 
- Maintain SOC ICB specific dosing schedule  
- Disease reassessment every 6 weeks during exemestane treatment 
- Follow for disease response until disease progression or start of a new therapy, then 
survival only for 1 year from study enrollment 
 
Patients who are discontinued from standard of care ICB therapy due to toxicity may 
continue exemestane as single agent provided disease response criteria is met. 
 
 
 

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1 Objectives 
1.1 Primary Objective 
The primary objective is to determine a preliminary estimate of response of daily 
oral exemestane for the treatment of previously treated, advanced non-small cell 
lung cancer (NSCLC) in post-menopausal women receiving and progressing on 
immune checkpoint blockade (ICB) therapy. 
1.2 Secondary Objectives 
 To determine the toxicity profile of daily exemestane in combination with 
immune checkpoint blockade therapy in this patient population. 
 To estimate the disease control rate, progression-free survival (PFS), and 
overall survival (OS) of exemestane for up to 1 year from study enrollment in 
post-menopausal women with previously treated advanced NSCLC. 
 To estimate quality of life during study treatment and for one month following 
discontinuation of study treatment. 
 
1.3 Correlative Objectives 
 To conduct an exploratory biomarker correlative study of clinical outcome 
utilizing archival tumor tissue and serum collected at baseline and serially 
during therapy  
 To examine biomarkers in tissue post-treatment at the time of re-biopsy, if 
performed 
 To examine serum biomarkers of the peripheral immune response after 
aromatase inhibition 
2 Background and Rationale 
2.1 Advanced Non-Small Cell Lung Cancer 
The standard of care for first-line treatment of advanced non-small cell lung 
cancer (NSCLC) includes platinum based-doublets, such as combinations of 
cisplatin or carboplatin with either paclitaxel, docetaxel, and vinorelbine or 
gemcitabine. In patients with advanced NSCLC and good performance status, 
these doublets lead to predictable response rates of approximately 30%, median 
survival of 8-9 months and 1-year survival of 30-40%1. Alternatives to 
chemotherapy are also now approved for first line therapy of NSCLC based on 
molecular biomarkers. Patients whose tumors harbor genetic mutations in 
epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or 
ROS1 have superior response rates, progression free survival and overall survival 
when treated with a targeted oral tyrosine kinase inhibitor. Moreover, patients 

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whose tumors have >50% expression of programmed death ligand (PDL-1), a 
marker of immune activation within the tumor microenvironment, have improved 
outcomes when treated with an immune checkpoint antibody, pembrolizumab. 
FDA approved agents for the second and third line therapy of NSCLC includes 
docetaxel, pemetrexed, and erlotinib2. These include two chemotherapeutic 
agents that are currently approved and in use for second line therapy: docetaxel 
(75 mg/m2) (response rates of 6.7% - 8.8%; Median survival of 5.7 months to 7.9 
months and 1 year survivals of about 30%); and pemetrexed (response rate of 
9.1%, median survival of 8.3 months and 1 year survival of 29.7%)3-5. In several 
randomized controlled trials, immune checkpoint antibodies, have now been 
approved in the 2nd or 3rd line setting based on improved overall survival compared 
to docetaxel. Thus, pembrolizumab, nivolumab, and atezolizumab are now 
commonly used 2nd line agents for the treatment of NSCLC. The major advance 
of immune checkpoint blockade is that in patients who respond, the duration of 
response is quite long and some patients (~15%) remain in remission for several 
years after the initiation of treatment. Unfortunately, the objective response rate 
remains relatively low in the range of 20-30%. Thus, the majority of patients will 
not respond to such therapy. While modest improvements have been made in 
survival and quality of life in patients with advanced NSCLC there is a need to 
explore new agents with novel mechanisms of action in this patient population. 
Moreover, novel combination therapies with immune checkpoint blockade are 
actively sought to improve upon the low response rates with this therapy. 
2.2 Therapeutic Potential of Targeting the Estrogen Receptor Pathway 
in NSCLC 
Over the last decade, increasing evidence from multiple disciplines have 
demonstrated that the estrogen signaling pathway plays an important role in 
lung tumorigenesis6 Furthermore, recent data has suggested that anti-estrogen 
therapy may be an effective therapeutic strategy for advanced stage non-small 
cell lung cancer (NSCLC)6,7. Several large cohort studies have implicated the 
estrogen receptor pathway in lung tumorigenesis8,9 and have demonstrated a 
protective effect of anti-estrogen therapy in the prevention of NSCLC9,10. 
Furthermore, in vitro and in vivo studies have shown estrogen can modulate 
expression of genes that are important for cell proliferation in NSCLC1 1. We and 
others have previously demonstrated that estrogen receptor beta (ER) is 
expressed in the vast majority of NSCLC, including in post-menopausal 
women6,12. This is in contrast to the predominant expression of ER alpha (ER) 
protein in breast cancer12. Furthermore, the aromatase enzyme is expressed in 
86% of NSCLC and high expression of aromatase is a poor prognostic marker in 
post-menopausal women with NSCLC13. Over the last decade, increasing 

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evidence from multiple disciplines has demonstrated that the estrogen signaling 
pathway plays an important role in lung tumorigenesis14,15. Recent data has 
suggested that anti-estrogen therapy may be an effective therapeutic strategy for 
advanced stage non-small cell lung cancer (NSCLC)16-18. 
Preclinical and early clinical studies on anti-estrogen therapy appear promising. 
Aromatase inhibitors (AI) suppressed cell proliferation in vitro as well as in lung 
tumor xenografts13. Furthermore, treatment with an AI significantly inhibited lung 
tumor formation in a carcinogen induced model of lung cancer15. In addition, we 
have previously demonstrated that significant crosstalk exists between the 
estrogen and EGFR signaling pathways16. We have validated this preclinical 
observation in a recent phase II clinical trial, combining fulvestrant and erlotinib, 
an EGFR tyrosine kinase inhibitor, which demonstrated that the combination was 
well-tolerated and had a significant clinical benefit rate in patients with EGFR 
wild type tumors18. Recent data suggest that hormonal therapy can have 
significant impact upon the immune microenvironment of tumors19. Oopherectomy 
of female mice improved the survival of mice bearing lung cancer in a syngeneic 
mouse model. Likewise, estrogen supplementation led to enhanced tumor growth. 
This effect was associated with increased myeloid derived suppressor cells 
(MDSC) in the tumor microenvironment which was reversed upon oophorectomy. 
These effects were tumor independent as knockout of ER on hematopoietic cells 
resulted in improved survival of tumor bearing mice and resulted in reduced 
MDSCs and enhanced CD8 and CD4+ T cells in the tumor microenvironment. 
Finally, in human squamous cell NSCLC, the expression of PDL-1 is highly 
correlated to ER expression providing a further link between ER signaling and 
immune regulation in the tumor microenvironment (unpublished data).  
Estrogen Receptors are also expressed by T cells20,21, myeloid-derived suppressor 
cells (MDSC)22 and macrophages23. E2 promotes human epidermal growth factor 
receptors (HERs) ligand release, including amphiregulin (AREG), and AREG has 
been shown to suppress T cell response and promote T regulatory function24. Both 
macrophages and T cells express EGFR receptor that promotes their tumorigenic 
phenotypes (5). A recent report suggests that E2 increases the mobilization of pro-
tumor 
immune 
cells 
and 
promotes 
an 
immunosuppressive 
tumor 
microenvironment (TME)25. 
 

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Our recent unpublished data also show that E2 at 10nM induces PD-L1 expression 
in two NSCLC cell lines (201T, A549) (Figure 1), suggesting that an aromatase 
inhibitor could reverse immunosuppression mediated through PD-L1.  
These observations suggest that E2 can suppress T cells cytotoxic activity against 
lung cancer cells, stimulate M2 macrophages, increase activity of myeloid derived 
suppressor cells, and enhance activity of Treg cells (shown in Figure 2), as well as 
stimulate NSCLC cells directly. Since exemestane will reduce E2 levels in the 
tumor microenvironment, immunosuppression should be reversed, and adding 
exemestane to an immune checkpoint blocker should be beneficial. 
Given these promising preclinical and clinical studies, it is imperative to evaluate 
anti- estrogen therapy in NSCLC.   
Based on work in breast cancer, aromatase inhibitors are very effective in blocking 
estrogen-driven pro-cancer effects by inhibit production of the hormone estrogen, 
and have shown superior efficacy against breast cancer progression than agents 
such as tamoxifen or fulvestrant that block the estrogen receptor26. Aromatase 
 
Figure 1: Immunoblots of whole cell lysates from two NSCLC cell lines treated with E2 at 10nM or 
ethanol as a vehicle for 24 hr. 30μg of each sample were analyzed by western blotting using rabbit 
monoclonal anti-PD-L1 antibody and rabbit β-actin antibody. 
 
Figure 2: Summary of the expected immunosuppressive effects of E2. E2 will enhance the activation of 
MDSC leading to more suppression of T cell cytotoxic activity. E2 will also promote the conversion of T 
cell to Treg state. Macrophages will be polarized toward M2 phenotype with less phagocytic activity. 
Lastly, E2 will enhance NSCLC proliferation and immune-escape through upregulation of PD-L1 
expression.    

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inhibitors (AIs) have a good safety profile and have been given to post-menopausal 
women for up to 5 years27. AIs are contraindicated in men due to a buildup of 
testosterone when aromatase is inhibited28. AIs are administered orally on a daily 
regimen, while fulvestrant is only available as a depot IM injection. We are 
proposing to use the AI exemestane in the female post-menopausal population 
with advanced lung cancer that has failed prior chemotherapy.  
2.3 Exemestane 
Exemestane (AROMASIN®) is an aromatase inhibitor initially approved by the FDA 
in 1999 for the treatment of advanced breast cancer in postmenopausal women 
whose disease has progressed following tamoxifen therapy. On October 5, 2005 
it was approved by the FDA for the adjuvant treatment of postmenopausal women 
with estrogen-receptor positive early breast cancer who have received two to three 
years of tamoxifen and are switched to exemestane for completion of a total of five 
consecutive years of adjuvant hormonal therapy. Standard approved dosing is 25 
mg PO per day continuously. 
Safety and efficacy were evaluated in the Intergroup Exemestane Study (IES), a 
double-blind, multicenter, international clinical trial in postmenopausal women with 
early stage breast cancer who had received two to three years of adjuvant 
tamoxifen. Four thousand seven hundred and twenty four patients in the intention-
to-treat population were randomized to either continue tamoxifen (20-30 mg/day) 
or switch to exemestane (25 mg/day) to complete a total of five years of adjuvant 
hormonal therapy. In the hormone receptor-positive subpopulation representing 
about 85 percent of the trial patients, disease free survival (DFS) was significantly 
improved (HR=0.65, 95 percent CI: 0.53-0.79, p=0.00001) in the exemestane arm 
compared to the tamoxifen arm.   
Adverse Reactions:  Early breast cancer: Adverse events occurring in ≥10% of 
patients in any treatment group (AROMASIN vs. tamoxifen) were hot flushes 
(21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), 
headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating 
(11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between 
AROMASIN and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events 
(myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, 
tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 0.4%, tamoxifen 0.3%. 
Advanced breast cancer: Most common adverse events were mild to moderate 
and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), 
increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for 
AROMASIN and megestrol acetate, respectively. 

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As this study is directed at post-menopausal women with advanced lung cancer, 
IBM Micromedex® available through the University of Minnesota Libraries is being 
used as the source of risks in this protocol assessed on July 17, 2020. This closely 
aligns to the toxicity profile found in the September 2019 protocol version with a 
few updates. 
Refer to the AROMASIN prescribing information for additional information at 
http://www.pfizer.com/products/product-detail/aromasin.   
2.4 Anti-PD-1/Anti-PDL-1 Therapy for NSCLC  
There are currently 3 FDA-approved antibodies for the treatment of metastatic 
NSCLC in the 2nd or 3rd line setting, pembrolizumab, nivolumab, and atezolizumab. 
These are all based on randomized controlled trials showing an improved 
progression free survival and overall survival comparing immune checkpoint 
blockade to docetaxel chemotherapy29. Across all of the trials, the objective 
response rate to immune checkpoint blockade is approximately 20-30% in 
unselected patients. In each of these trials the response rate was improved in 
patients whose tumors expressed a high level of PDL-1 on the cell surface. In 
previously untreated patients with PDL-1 expression on >50% of tumor cells, the 
response rate to pembrolizumab was improved to 55% and PFS and OS were 
improved compared to standard first-line chemotherapy in the Keynote-024 trial 
leading to FDA approval of pembrolizumab in the first line setting for NSCLC30. 
Thus at this time, the majority of patients are being treated with immune therapy 
at some point in their treatment course. While immune checkpoint blockade 
response can be quite durable, the vast majority of patients with a response will 
ultimately become resistant to therapy or be primarily resistant. Thus, novel 
strategies to overcome resistance are needed. 
2.5 Rationale 
While modest improvements have been made in survival and quality of life in 
patients with advanced non-small cell lung cancer (NSCLC) there is a need to 
explore new agents and combinations with novel mechanisms of action in an effort 
to improve clinical outcomes in this patient population. With the introduction of 
immune checkpoint blockade and the durability of response, the vast majority of 
patients with NSCLC are receiving immune checkpoint blockade at some point in 
there therapy. However, response rate is relatively low spawning interest in 
developing novel combination therapies that can improve upon the response or 
generate responses in patients who are failing therapy. It is generally accepted 
that the aromatase inhibitor (AI) exemestane is less toxic then chemotherapy, yet 
potentially it can provide equal or greater benefit. In hormone receptor positive 
breast cancer, anti-estrogen therapy is a first-line treatment for metastatic disease, 

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and is given as adjuvant therapy for 5 years in earlier stage disease. Exemestane 
has been used in tens of thousands of women and its efficacy and side effect 
profile has been well established. Furthermore, preclinical and clinical data 
suggest that there might be a role of estrogen receptor signaling in maintaining 
immune suppression in the tumor microenvironment. Therefore, we propose a 2-
stage phase II trial of exemestane in previously treated postmenopausal women 
with metastatic NSCLC who are progressing on anti-PD1 or anti-PDL1 therapy to 
determine if aromatase inhibition will result in treatment responses in this patient 
population and to determine whether ER-related biomarkers can identify patients 
likely to receive clinical benefit. 
The estrogen pathway inhibition is a promising novel target in NSCLC. Preclinical 
evidence support targeting the synthesis of estrogen in NSCLC as a strategy that 
may result in enhanced antitumor activity.  
3 
Study Design 
This is a phase II study of daily oral exemestane for the treatment of advanced 
non-small cell lung cancer in post-menopausal women who are progressing on an 
FDA approved immune checkpoint blockade therapy. The study will be conducted 
using Simon's two-stage design. 30 Stage 1 will enroll 10 patients. If at least 2 
objective responses are observed at the first disease re-evaluation at 6 weeks after 
beginning oral exemestane, Stage 2 will be activated. In Stage 2, an additional 19 
patients will be enrolled for a total of 29 patients. If 4 or more objective responses 
are observed in the 29 patients, exemestane will be deemed worthy of further 
investigation in this patient population.   
4 
Patient Selection 
Study entry is open to post-menopausal women regardless of race or ethnic 
background. While there will be every effort to seek out and include minority women, 
the patient population is expected to be similar to that of advanced non-small cell 
cancer lung studies at the University Of Minnesota. Men are not eligible for this study 
as exemestane works by suppressing estrogen production. Women of child-bearing 
potential are not eligible as exemestane is FDA pregnancy category X – known harm 
to the unborn. 
4.1 Inclusion Criteria 
4.1.1 Recurrent or progressive advanced stage non-small cell lung cancer (no 
small cell component) with most recent treatment being an FDA approved 
immune checkpoint inhibitor (pembrolizumab, atezolizumab, or nivolumab)  

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NOTE: Pathology reports documenting the diagnosis of NSCLC are required 
to be reviewed to confirm outside diagnosis 
4.1.2 Sufficient tumor tissue available from original diagnosis or subsequent 
biopsy for analysis of estrogen receptor and aromatase – tumor block or a 
minimum of 5 unstained slides  
4.1.3 Failed at least 1 prior FDA approved treatment for advanced NSCLC. 
Patients with EGFR/ALK/ROS1 rearrangements should have received an 
FDA-approved TKI prior to enrollment on this trial.  
4.1.4 Measureable disease by RECIST version 1.1 (Appendix II) 
4.1.5 Post-menopausal defined as  
 Age ≥ 55 years and 1 year or more of amenorrhea 
 Age < 55 years and 1 year or more of amenorrhea with an estradiol assay 
< 20 pg/mL 
 Surgical menopause with bilateral oophorectomy 
4.1.6 ECOG performance status 0, 1 or 2 (Appendix I) 
4.1.7 Life expectancy of 3 months or more in the opinion of the enrolling 
investigator and documented in the medical record 
4.1.8 Adequate organ function within 14 days of study enrollment defined as: 
Hematology: 
Absolute neutrophil count (ANC)  1500/mm³, Platelets  100,000/mm³, 
Hemoglobin ≥ 8 g/dL 
Biochemistry: 
Total Bilirubin within normal institutional limits 
AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN), except if 
there is known hepatic metastasis, wherein transaminases may be ≤ 5 x 
institutional ULN. 
Serum creatinine ≤ 1.5 mg/dl or glomerular filtration rate > 50 ml/min 
4.1.9 Must have recovered to CTCAE v 4 Grade 1 or better from the acute effects 
of any prior surgery, chemotherapy or radiation therapy. Chronic residual 
toxicity (i.e. peripheral neuropathy) is permitted 
4.1.10 A minimum time period must elapse between the end of a previous 
treatment and start of study therapy: 
 1 week from the completion of radiation therapy for brain metastases 
 4 weeks from the completion of chemotherapy or any experimental 
therapy  
 4 weeks from prior major surgery (such as open biopsy or significant 
traumatic injury)  

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4.1.11 Voluntary written consent before any research related procedures or 
therapy 
4.2 Exclusion Criteria 
4.2.1 Known active CNS disease - If patient has history of brain metastases, the 
brain lesions must have been treated with radiation and/or surgery - patients 
should be neurologically stable and requiring ≤10mg oral prednisone 
equivalence of steroids per day 
4.2.2 Any toxicity from immune-related toxicity from prior immune therapy that 
would preclude further treatment with anti-PD-1/PDL-1 inhibitor or ongoing 
IR toxicity ≥ Grade 2 
4.2.3 Requiring > 10 mg prednisone equivalence of steroids per day for immune-
related toxicity 
4.2.4 Inability or unwilling to swallow study drug 
4.2.5 Any gastrointestinal condition causing malabsorption or obstruction (eg, 
celiac sprue, gastric bypass surgery, strictures, adhesions, history of small 
bowel resection, blind loop syndrome) 
4.2.6 Currently using hormone replacement therapy (oral or patch) or/and 
phytoestrogen supplements (i.e. black cohosh)   
4.2.7 Known hypersensitivity to exemestane or its excipients 
4.2.8 Any serious underlying medical condition that, in the opinion of the enrolling 
physician, would impair the ability of the patient to receive protocol 
treatment 
4.2.9 Prior malignancy, with the exception of curatively treated squamous cell or 
basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-
year disease-free interval 
4.2.10 Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, 
carbamazepine, phenobarbital, or St. John’s wort as these may significantly 
reduce the availability of exemestane  
 
 

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5 
Patient Registration and Study Enrollment 
Written consent must be obtained prior to the performance of any research related 
tests or procedures. Consent is usually obtained before final eligibility is determined. 
5.1 Registration with the Masonic Cancer Center Clinical Trials Office 
Any patient who has been consented is to be registered in OnCore by the Study 
Coordinator or designee. If a patient is consented, but not enrolled, the patient’s 
record is updated in OnCore as a screen failure and reason for exclusion recorded.   
5.2 Study Enrollment with the Masonic Cancer Center Clinical Trials Office 
To be eligible for study enrollment, the patient must sign the treatment consent 
and meet each of the inclusion criteria and none of the exclusion on the eligibility 
checklist based on the eligibility assessment documented in the patient’s medical 
record. 
The Study Coordinator or designee will assign the study treatment arm to complete 
enrollment. 
5.3 Patients Who Are Enrolled and Do Not Receive Study Treatment 
If a patient is enrolled in the study and is later found not able to begin exemestane, 
for whatever reason, the patient will be removed from study and treated at the 
physician’s discretion. The PCRC or designee will update OnCore of the patient’s 
non-treatment status. The reason for removal from study prior to starting study 
treatment will be clearly indicated in OnCore. The patient will be replaced to 
complete enrollment. 
6 Treatment Plan 
In order to provide optimal patient care and to account for individual medical 
conditions, investigator discretion may be used in the prescribing of all supportive care 
drug therapy. Refer to Section 6.3 for prohibited medications during exemestane 
therapy. 
6.1 Exemestane Dosing Plan 
Exemestane is self-administered as a single, 25 mg tablet by mouth following a 
meal once daily at approximately the same time each day.  If the dose is missed 
by more than 8 hours, the patient will skip that dose and take the next scheduled 
dose at the usual time.   
 
Exemestane will continue once daily until disease progression, unacceptable side 
effects, patient refusal/non-compliance, or the treating physician feels 
discontinuing therapy is in the best interest of the patient. 

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The patient will be provided with a daily drug log to record the time of 
administration, side effects, and any missed doses. The patient will be instructed 
to bring the drug log and study drug bottles (including any empties) to each 
appointment for reconcilement.   
During the first treatment cycle only, the patient will be contacted by a member of 
the research staff 8 to 12 days after dosing was started to inquire “how things are 
going” and to see if she has any questions or concerns. 
For the purpose of this study each 3 week (21 day) dosing period will be considered 
a treatment course. A disease re-assessment will be done after every 2 treatment 
courses.   
 
Participants who do not undergo the 1st disease re-evaluation will be considered 
unevaluable and replaced. 
6.1.1 Exemestane Expected Toxicity  
Based on extensive use in post-menopausal women with breast cancer as 
sourced through IBM Micromedex® available through the University of Minnesota 
Libraries: 
In general, exemestane is well tolerated at this dose when given long term to post-
menopausal women with breast cancer. It is thought that adding exemestane to 
ongoing immune checkpoint blockade the risks profile for neither drug will be 
different.   
 
Rare, but potentially serious side effects 
Bone loss.  Exemestane lowers the level of estrogen in the body and may reduce 
bone mineral density (BMD) over time, possibly increasing the risk of bone 
fracture. A DEXA scan will be done at baseline, if none performed in the previous 
12 months and every 12 months while receiving exemestane.  
Chest pain, heart failure, or stroke.  A small number of women had chest pain, 
heart failure, or a stroke while taking exemestane 
Occurring in less than 1 out of 100 women 
Gastric ulcer  
Cholestatic hepatitis, hepatitis 
 
 
 

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Common side effects (occurring in 10 or more out of 100 women) 
 hot flashes 
 fatigue 
 joint pain 
 headache 
 insomnia  
 increased sweating 
 depression 
 feeling anxious 
 upset stomach 
 difficulty breathing 
 hair loss or thinning 
 an increase by a blood test of a liver enzyme (alkaline phosphatase) that may 
indicate a bone disorder or liver disease 
Use of estrogens (such as hormone replacement therapy or HRT) and 
phytoestrogen supplements (such as black cohosh) to relieve the menopausal like 
side effects are prohibited during exemestane treatment. 
 
Only post-menopausal women are enrolled in this study as taking exemestane 
during pregnancy is known to cause birth defects and/or miscarriages. 
Refer to the prescribing information for additional details. 
We do not expect any difference in the toxicity profile of exemestane when it is 
added to an ongoing treatment with anti-PD1 or anti-PDL1 antibody treatment. 
There are ongoing clinical trials in breast cancer using the combination of hormone 
therapy and an immune checkpoint blockade.  
6.1.2 Exemestane Dose Interruptions and Modifications 
There are no dose reductions/modifications recommended for exemestane related 
toxicities; however patients should be treated according to Institutional practices. 
If a patient experiences a Grade 4 toxicity felt at least possibly related to 
exemestane, the study drug will be discontinued per Section 6.4. Patients will not 
make up missed or vomited doses of exemestane. 
6.2 Immune Checkpoint Blockade Therapy 
All patients will continue treatment with their prior anti-PD1 or anti-PDL1 antibody 
treatment as per standard of care.  
Dose delays or modifications for the ICB agent will be per standard of care and 
independent of exemestane therapy. A summary of the expected toxicity for each 
of the three possible ICB agents is provided in Appendix IV.  

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ICB therapy will be obtained through the same mechanism and will continue to be 
charged to the patient and her third party payer as before study enrollment. 
If the ICB therapy is delayed, exemestane therapy should continue as medically 
appropriate.  
Exemestane may be continued at the discretion of the treating investigator if the 
ICB therapy is permanently discontinued. 
6.3 Supportive Care and Prohibited Medications 
Commercially available palliative and supportive care for disease-related 
symptoms should be offered to all treated patients.   
Patients 
with 
pre-existing 
osteoporosis 
should be 
on 
treatment 
with 
calcium/vitamin D and/or bisphosphonates.   
Patients must be instructed not to take any additional medications (including over-
the-counter products) during the study without prior consultation with her study 
doctor. Use of estrogens (i.e. hormone replacement therapy) and phytoestrogen 
supplements (i.e. black cohosh) are prohibited during exemestane treatment.  
Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure 
therefore their use will be prohibited. For a list of CYP34A inducers refer to 
Appendix III. 
No chemotherapy, hormonal anticancer therapy, or experimental anticancer 
medications other than those study related will be permitted while the patient is on 
study. Any disease progression requiring other forms of specific anti-tumor therapy 
will be cause for discontinuation from the study. 
6.4 Duration of Study Treatment 
Treatment continues for a minimum of 2 cycles (6 weeks) and then until disease 
progression unless one of the following occurs: 
 Patient experiences unacceptable side effects exemestane 
 Patient refuses further treatment or is non-compliant 
 Patient requires other anti-cancer therapy 
 A greater than 6 week break from exemestane therapy occurs, regardless of 
cause 
 In the opinion of the treating investigator, continuing on study therapy is not in 
the best interest of the patient 
Exemestane may be continued as a single agent at the discretion treating 
investigator in the event the ICB therapy is permanently discontinued due to 

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unacceptable toxicity (refer to Appendix IV for potential risks of ICB therapy) as 
long as none of the above criteria is not met. 
An end of treatment visit occurs 4 weeks (± 1 week) after the last dose of 
exemestane or prior to the start of a new therapy, whichever is shorter, to assess 
for ongoing toxicity and for the patient to return their study drug supply and daily 
drug log. 
6.5 Duration of Study Participation 
Direct study participation stops with the end of treatment visit; however all patients 
are followed for 1 year from the start of study treatment or until death, whichever 
is shorter. 
Patients who discontinue treatment due to disease progression are followed for 
survival only (medical record review, local MD or patient contact) for 1 year from 
study treatment start. 
Patients who discontinue treatment in the absence of disease progression are 
followed for disease response per standard of care until disease progression or 
the start of a new treatment, whichever is shorter and then for survival only for 1 
year from study treatment start. 
By 1 year from treatment start, all patients should have a last known date alive or 
a death date with cause recorded in OnCore, as well as, an initial date for disease 
progression in association with exemestane treatment.  
7 Exemestane Drug Information  
Names: exemestane, AROMASIN®, 6-Methyleneandrosta-1,4-diene-3,17-dione 
Category:  Aromatase Inhibitors 
Indications:  1) For the treatment of advanced breast cancer in postmenopausal 
women whose disease has progressed following tamoxifen therapy and 2) adjuvant 
treatment of postmenopausal women with estrogen-receptor positive early breast 
cancer who have received two to three years of tamoxifen and are switched to 
exemestane for completion of a total of five consecutive years of adjuvant hormonal 
therapy.  
Pharmacology:  Aromatase is an enzyme that converts hormones to estrogen in the 
body's adrenal glands. The aromatase inhibitors (AIs) are drugs that reduce estrogen 
levels by blocking the action of aromatase in the adrenal glands. The selective AIs 
(SAIs) selectively reduce levels of estrogen without interfering with levels of other 

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steroid hormones that are produced by the adrenal gland. Drugs in this class include 
anastrozole (Arimidex ™), letrozole (Femara ™) and exemestane (Aromasin ™) 
Availability:  For the purposes of this study a commercial formulation of Aromasin will 
be provided by the manufacturer, Pfizer.  The study specific drug reorder form is 
attached in OnCore under this study.  It is recommended that a drug inventory 
sufficient to treat study subjects for approximately four (4) weeks be maintained while 
waiting for additional ordered supplies. 
Drug Accountability:  The study drug supply will be stored and dispensed by the 
University of Minnesota Medical Center, Fairview Investigational Drug Services (IDS) 
Pharmacy. IDS will be responsible for drug accountability through the study. IDS will 
provide study drug to participating MNCCTN sites. 
Dosage and Administration Schedule:  One 25 mg tablet once daily after a meal 
Dose Forms and Strengths:  Aromasin Tablets are round, biconvex, and off-white 
to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on 
one side with the number “7663” in black. 
Storage and Stability:  Store at 25°C (77ºF); excursions permitted to 15°–30°C (59°–
86°F). 
Drug Return/Destruction:  At the end of the study and after final reconciliation, IDS 
will destroy any remaining drug according to their current SOP. 
 
Expected Side Effects:  refer to Section 6.1.1. 
 
FDA Pregnancy Category X 
 
Contraindications and Counseling:  
Patients with a known hypersensitivity to the drug or to any of the excipients 
 
Women of premenopausal endocrine status, including pregnant women 
 
Patients should be informed that they should not take estrogen-containing agents 
while they are taking exemestane as these could interfere with its pharmacologic 
action. 
 
Patients should be informed that AROMASIN lowers the level of estrogen in the body. 
This may lead to reduction in bone mineral density (BMD) over time.  The lower the 
BMD, the greater the risk of osteoporosis and fracture. 
 

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Refer 
to 
the 
Aromasin 
Prescribing 
Information 
(https://www.pfizer.com/products/product-detail/aromasin) for additional information 
8 Measurement of Effect  
For the purposes of this study’s primary endpoint, patients should be re-evaluated for 
response every 6 weeks.  
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009]. Refer to Appendix II for the complete RECIST guidelines. 
Quality of life scores, as measured by PROMIS, will be evaluated descriptively at 
baseline, every 3 weeks during and at the end of treatment visit using medians, 
ranges, interquartile ranges and boxplots to look for trends in various areas measured 
by PROMIS. 
9 Schedule of Activities 
Note: Study visits are scheduled every 3 weeks independent of the immune 
checkpoint blockade therapy administration per standard of care. During exemestane 
a ±2 day window is permitted for every 3 week visits (start of new treatment cycle) and 
a ±7 day window is permitted for the every 6 week disease reassessment. The end of 
treatment (EOT) visit 30 days after the last dose of study drug may be performed with 
a ±7 day window. Follow-up visits are per standard of care with disease status and 
survival status abstracted from the medical record. 
 
 

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9.1 
Schedule of Patient Tests and Procedures 
 
Baseline 
(within 14 
days of 
enrollment) 
During Exemestane 
Therapy 
End of 
Treatment Visit 
4 weeks ±1 
week) after 
final dose of 
exemestane 
Follow-up  
Every 3 
weeks 
(± 2 days) 
Every 6 
weeks 
(± 1 week) 
disease 
response (until 
PD or start of 
new therapy) 
survival at 
1 year (all 
patients) 
ASSESSMENTS 
Witten consent 
X 
 
 
 
 
 
Medical history 
X 
X 
 
X 
 
 
Review of prior anti-cancer 
therapy 
X 
 
 
 
 
 
Concomitant meds 
X 
X 
 
 
 
 
Physical exam  
X 
X 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
Weight 
X 
X 
 
 
 
 
ECOG Performance status  
X 
X 
 
 
 
 
Disease re-assessment 
 
 
X 
 
X 
 
Symptom and toxicity notation 
(pt diary) 
X 
X 
 
X 
 
 
LABORATORY EVALUATIONS 
CBC/diff, plts 
X 
X 
 
 
 
 
Comprehensive Metabolic 
Profile (CMP) 
X 
X 
 
 
 
 
Estradiol assay2 
X 
 
 
 
 
 
SCANS AND PROCEDURES 
CT of chest/abd/pelvis 
X1 
 
X 
X  
(if not done in 
previous 6 weeks) 
X4 
 
MRI or CT of brain if previous 
hx of CNS dz or as clinically 
indicated 
X1 
 
 
 
 
 
DEXA scan  
X1 
(perform only  if 
none in previous 
12 months) 
repeat every 12 months  
 
 
 
CONTINUATION OF STANDARD OF CARE IMMUNE CHECKPOINT INHIBITOR THERAPY 
Nivolumab pembrolizumab, or 
atezolizumab  
Continue per SOC while maintaining every 3 week visits 
for exemestane 
 
 
RESEARCH RELATED  
Exemestane 
 
25 mg po once a day 
every day 
 
 
 
Research staff “check-in”3 
 
Cycle 1 only between Day 
8 and 12 
 
 
 
Reconciling of Exemestane 
tablets  
 
X 
 
X 
 
 
Quality of Life Questionnaire 
(PROMIS–29 Profile) 
X 
X 
 
X 
 
 
Monitoring for stopping rule 
events 
 
Refer to Section 10.3 
 
 
Blood Samples 
30 ml serum (red top) 
20 ml EDTA (purple top) 
20 ml cell-free DNA BCT tube 
X 
X 
prior to cycle 
2, 3, and 5 
 
X 
 
 
Blood Samples 
10 mL green top tube for PBMC  
X 
X 
prior to Cycle 
2 and 3 
 
 
 
 
biopsy material5  
X 
at the time of biopsy for clinical reasons 
 
1 
Within 4 weeks of study enrollment 
2 
For women < 55 years of age 

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3 
A member of the research staff will contact the patient to see how things are going (screen for toxicity) and if 
they have any questions 
4 
Per standard of care for patients who discontinued exemestane for reasons other than disease progression 
– abstract results from medical record  
5 
At enrollment archived from original diagnosis will request 15 unstained slides but require a minimum of 5 
unstained slides for eligibility or resection and fresh at any time tissue is obtained for clinical reasons (i.e. 
SOC)  - consent for tissue is embedded in the treatment consent 
 
All research blood samples go to the Masonic Cancer Center’s Translational 
Therapy Lab (TTL).  
 
Research sample collection and questionnaire completion is tied to the clinical care 
schedule of events and their associated window for performance. Therefore, if a 
clinical time point does not occur or is altered, the research related time point will 
be adjusted (or eliminated) as appropriate.  
9.2 
Research Related Tests and Procedures 
The PROMIS-29 Profile (Appendix VI) will be completed before starting 
exemestane, every 3 weeks while taking the study drug, and at the end of 
treatment visit.   
Correlative studies will examine biomarkers in the Estrogen Receptor (ER) 
pathway including circulating levels of hormones and products of ER response 
genes. DNA will be extracted from blood collected at baseline, during treatment, 
and at progression and sent for sequencing using the Guardant360 assay to 
determine if mutations are present that are correlated with resistance to an 
aromatase inhibitor. Three hundred sixty (360) common mutations will be analyzed 
that have been used to monitor breast cancer patents on aromatase inhibitor 
therapy. Additionally, since cigarette smoking is associated with increased ER 
expression29, we will measure serum cotinine in patients at baseline as a measure 
of recent tobacco smoke exposure. 
Tumor tissue will be analyzed ERβ receptor expression and aromatase at baseline 
using immunohistochemistry (IHC). Additionally, we will analyze PDL-1 expression 
if not already done for clinical reasons. Finally, we will evaluate tumor sections for 
CD8 T cell staining and MDSC on archival tissue as well as any post-treatment 
tissue obtained.   
Finally, peripheral blood mononuclear cells (PBMCs) will be obtained at baseline 
and prior to Cycle 2 and 3 to evaluate the peripheral immunophenotype prior to 
and after initiation of exemestane. 
 

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10 Adverse Event Monitoring, Recording and Reporting 
Toxicity and adverse events will be classified according to NCI’s Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE).  
A copy of the CTCAE can be downloaded from the CTEP home page 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
10.1 Definitions 
Note:  throughout this section the generic term “drug” refers to the exemestane. 
The following definitions are based on the Code of Federal Regulations Title 21 
Part 312.32 (21CFR312.32(a)). 
Adverse Event:  Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
Suspected Adverse Reaction:  Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse 
Reaction: An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. 
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An adverse 
event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
Unexpected Event: An adverse event or suspected adverse reaction is 
considered “unexpected” if it is not listed in protocol-related documents (e.g. 
protocol, consent documents, investigator brochure, package insert), or is not 

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listed at the specificity or severity that has been observed or given the 
characteristics of the subject population being studied.   
 
Attribution: is the relationship between an adverse event or serious adverse event 
and the study drug. Attribution is assigned as follows: 
 
Definite – The AE is clearly related to the study drug 
 
Probable – the AE is likely related to the study drug 
 
Possible – the AE may be related to the study drug 
 
Unlikely – the AE is doubtfully related to the study drug 
 
Unrelated – the AE is clearly not related to the study drug 
Attribution must be assigned by the treating physician or the PI. 
 
The following definitions are from the Masonic Cancer Center’s Data and Safety 
Monitoring Plan (http://z.umn.edu/dmsp) 
 
Major Deviation: A deviation or violation that impacts the risks and benefits of the 
research; may impact subject safety, affect the integrity of research data and/or 
affect a subject’s willingness to participate in the research. Deviations that place a 
subject at risk, but do not result in harm are considered to be major deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, 
compromise the integrity of research data and/or affect a subject’s willingness to 
participate in the research.   
10.2 Adverse Event Monitoring and Documentation 
10.2.1 Event Monitoring  
Monitoring for adverse events will begin with the start of the exemestane and 
continue through and including 28 calendar days after the last dose of 
exemestane.    
10.2.2 Event Documentation 
Adverse events occurring after the initiation of exemestane treatment through and 
including 28 calendar days after the last dose must be documented. Refer to 
Section 6.1.1 for a list of expected toxicities of exemestane and Appendix IV for a 
list of expected toxicities for the ICB therapy. 
Since a key outcome parameter of this study is to characterize the toxicities of 
exemestane in combination with an FDA approved immune checkpoint inhibitor in 
this patient population, adverse event documentation requirements will be 

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determined based on grade, expectedness and relationship to study therapy as 
follows: 
 
CTCAE 
Grade 1 
CTCAE Grade 2 
CTCAE Grade 3 
CTCAE Grade 4 
and 5 
Expected or 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
Not 
required 
Required 
Required 
Possible 
Probable 
Definite 
Not required 
Not 
required 
Required 
Required 
Required 
Required 
In addition any event meeting the definition of a serious adverse event (SAE) 
regardless of attribution that occurs during this period will be documented in the 
source document and recorded in OnCore.  
After the end of treatment visit, monitoring for adverse event will become less 
frequent based on the schedule in Section 9 and only events at least possibly 
related to study treatment (based on the table above) will be documented upon 
knowledge. 
10.3 Stopping Rule Events 
For the purpose of this protocol any Grade 4 or 5 treatment related event and any 
Grade 3, 4, or 5 immune related adverse event (pneumonitis, colitis, nephritis, 
myocarditis or hepatitis) will be considered excess toxicity per Section 13.4 and be 
reported as a stopping rule event using the Event Form found in OnCore.   
Events that count toward an early study stopping rule do not necessarily constitute 
an event requiring expedited reporting and should only be reported as such if they 
meet the criteria found in Section 10.5. 
10.4 SAE and Death Documentation  
The reporting period for this study is from initiation of study treatment 
(exemestane) through and including 28 days after the last dose of exemestane. 
However, after this time point, the investigator must report upon knowledge any 
study treatment related meeting the definition of a serious adverse event (SAE) 
using the MCC SAE Report Form in OnCore.  
Deaths, including due to disease, within the follow-up period will be recorded as 
an SAE. Deaths due to disease should be recorded as a Grade 5 “Neoplasms 
benign, malignant and unspecified (including cysts and polyps) – Other 
(Progressive Disease).  

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In addition, upon knowledge, the death date and cause must be reported in the 
patient follow-up tab in OnCore using the comment field in the survival status 
section to record the cause.  
10.5 MNCCTN Required Reporting To the MCC CTO  
The following events are to be reported to the Masonic Cancer Center Clinical 
Trials Office in an expedited manner based on the table below. In addition, the 
Network site is responsible for reporting to their local IRB as required.  
Event Type 
Reporting Timeframe 
Form in OnCore to Use 
Any event meeting the definition of serious 
and all patient deaths 
Within 24 hours of 
knowledge 
SAE Report Form 
 
Stopping Rule Events 
Within 24 hours of 
knowledge 
Stopping Rule Event Form 
Major Deviations, as defined in Section 10.1. 
Within 5 working days of 
knowledge 
Deviation Report Form 
The MCC CTO is responsible for reporting qualifying events to the UMN IRB, 
Pfizer and the MMC SAE coordinator per Section 10.6. 
10.6 Required Reporting By the CTO to UMN IRB, Pfizer, and MCC SAE 
Coordinator 
 
 
Agency 
reporting to 
Criteria for reporting 
Timeframe 
Form to Use 
Submission 
address/ fax 
numbers 
U of MN 
IRB 
Unexpected Death, Information that indicates a 
new or increased risk, or a safety issue. 
5 Business Days 
Ethos Reportable New 
Information (RNI) 
 Via Ethos 
and/or Oncore 
Deviations that occur at MCC  
5 Business Days 
OnCore Deviation 
Form and Ethos RNI 
Pfizer 
 
Abstracted from Pfizer’s Safety Reporting 
Reference Manual for Investigator-Initiated 
Research (IIR) Interventional Studies 
Using the criteria for Mature Anti-Cancer 
Products- SAEs are reported only if they are: 
 Deaths that occur during the study reporting 
period 
 SAE’s that occur during the study period and 
are assessed by the investigator as both related 
to exemestane and unexpected 
 Any related SAE that occur after the study 
reporting period that the investigator becomes 
aware of 
Refer to the Safety Reporting Manual found as an 
attachment under this study in OnCore 
immediately 
upon awareness, 
if the SAE is fatal 
or life-
threatening – 
regardless of the 
extent of 
available 
information or 
within 24 hours 
of first 
awareness of the 
SAE, if the SAE 
is not fatal or life-
threatening 
Attached in OnCore 
under this study 
Refer to 
Reportable 
Event Fax 
Cover Sheet – 
attached in 
OnCore under 
this study 
Masonic 
Cancer 
Center SAE 
Coordinator 
Events that meet the criteria of an early study 
stopping rule 
At time of 
reporting 
Event Form 
SAE 
Coordinator 
mcc-
saes@umn.edu 

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11 
Study Data Collection and Monitoring 
11.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota 
CTSI’s instance of OnCore® (Online Enterprise Research Management 
Environment). 
 
The Oncore database resides on dedicated secure and PHI compliant hardware 
located in the University of Minnesota (UMN) datacenter (WBOB) All the data 
servers are managed by the Academic Health Center – Information Systems 
(AHC-IS) virtual servers which utilize clustered infrastructure to provide real-time 
failover of virtual servers. All relevant AHC IS procedures related for PHI compliant 
servers (as required by the Center of Excellence for HIPAA Data) apply to Oncore 
databases. 
 
The integrated data will be stored in PHI compliant servers managed by AHC IS 
with access given to those authorized users in the Clinical and Translation Science 
Institute Informatics team (CTSI BPIC and MCC CISS). The informatics team will 
grant the IRB approved study team members access to data. 
 
Additional data about correlative laboratory samples generated by the Masonic 
Cancer Center Translational Therapy Laboratory (TTL) from the protocol-directed 
correlative research samples is stored in their Laboratory Information Management 
System (LIMS).The LIMS database application is also stored on a production 
server located in the UMN datacenter (WBOB) and is managed by the Academic 
Health Center 
 
Key study personnel are trained on the use of OnCore and will comply with protocol 
specific instructions embedded within the OnCore. 
11.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRF) developed within OnCore based on its library of standardized forms. 
The e-CRF will be approved by study’s Principal Investigator and the Biostatistician 
prior to release for use. The Study Coordinator or designee will be responsible for 
registering the patient into OnCore at time of study entry, completing e-CRF based 
on the patient specific calendar, and updating the patient record until patient death 
or end of required study participation.   
 
 

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11.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at http://z.umn.edu/dmsp 
For the purposes of data and safety monitoring, this study is classified as 
moderate-risk (Phase II). Therefore the following requirements will be fulfilled: 
 Twice yearly review by the Masonic Cancer Center Data and Safety Monitoring 
Council (DSMC) with the understanding the Cancer Protocol Review 
Committee (CPRC) may require more frequent reporting. 
 The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in Section 10.6 to the Masonic Cancer Center’s SAE 
Coordinator, the University of Minnesota IRB and Pfizer.   
11.4 Investigational New Drug (IND) Assessment 
A commercial formulation of Exemestane will be provided by Pfizer for the 
purposes of this study. In addition was determined that this study meets all 
conditions of the exemption criteria found in 21 CFR 312.2. No IND application is 
required for this study.  
11.5 
Monitoring 
The investigator will permit study-related monitoring, audits, and inspections by 
IRB, government regulatory bodies, and University of Minnesota compliance 
groups. The investigator will make available all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data, 
etc.). The investigator will ensure the capability for inspections of applicable study-
related facilities (e.g. pharmacy, diagnostic laboratory, etc.) will be available for 
trial related monitoring, audits, or regulatory inspections. 
11.6 
Record Retention 
The investigator will retain study records including source data, copies of case 
report form, consent forms, HIPAA authorizations, and all study correspondence 
in a secured facility for at 6 years after the study file is closed with the IRB.   
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the medical 
records for that patient.  
Please contact the CTO before destroying any study related records. 

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12 
Study Endpoints 
12.1 Primary Endpoint 
Initial disease response will be assessed 6 weeks after the start of exemestane 
using the Response Criteria in Solid Tumors (RECIST). Refer to Appendix II. 
12.2 Secondary Endpoints 
Toxicity will be assessed from the 1st dose of exemestane through 30 days after 
the last dose, or the start of a new anti-cancer treatment, whichever is earlier. 
Toxicity severity will be graded using the Common Toxicity Criteria for Adverse 
Events (CTCAE) version 4. Attribution and expectedness will be assigned per the 
definitions found in Section 10.1. 
Response duration, progression-free survival and survival will be assessed until 1 
year after study enrollment based on the definitions found in RECIST 1.1 
(Appendix II). 
Quality of life will be assessed by use of PROMIS-29 at baseline, every 3 weeks 
while on study drug and at the end of treatment visit. 
13 Statistical Considerations 
13.1 Study Design, Objectives and Endpoints 
The goal of this phase II study is to estimate the probability of response after 
treatment of exemestane in post-menopausal women with advanced non-small 
cell lung cancer progressing while on immune checkpoint blockade. The primary 
endpoint of treatment response will be assessed at 6 weeks after the start of 
treatment using RECIST criteria. Secondary endpoints include the proportion of 
toxicities through 30 days after the last dose or start of new treatment as described 
in Section 10.2.2, disease-control as measured by response duration, progression-
free and overall survival through 12 months from study enrollment and quality of 
life scores as measured by PROMIS-29 at baseline, every 3 weeks during 
treatment and at the end of treatment visit. The primary endpoint of response will 
be evaluated using a two-stage design. 
Stage 1 will enroll 10 patients. If 2 or more patients have an objective response 
after completion of stage 1, an additional 19 patients will be enrolled in stage 2 for 
a total of 29 patients. If the total number of patients responding is 4 or greater, the 
treatment will be considered worthy of further investigation. 
 
 

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13.2 Sample Size 
Sample size is based on testing our primary endpoint using Simon’s optimal two 
stage design with a type I error of 5% and power of 80%.30 Our null hypothesis is 
that the response is ≤5% (as all will be progressing on anti-PD1 therapy) and our 
alternative hypothesis is that response is ≥20%. If the treatment is truly not 
effective, there is a 5% chance of concluding that the drug is effective while if the 
treatment is truly effective, there is a 20% chance of concluding that it is not 
effective. Up to 10 patients will be enrolled per year. 
13.3 Statistical Analysis 
The primary endpoint of response will be estimated with a simple proportion and a 
95% confidence interval. The secondary endpoints of survival and progression-
free survival will be estimated with Kaplan-Meier curves. Disease control will be 
assessed with descriptive statistics and plots such as medians, ranges, 
interquartile ranges and box-plots. Toxicities will be assessed with descriptive 
statistics and plots such as simple proportions and bar graphs. Quality of life 
scores, as measured by PROMIS, will be evaluated descriptively at baseline, every 
3 weeks during and at the final visit using medians, ranges, interquartile ranges 
and boxplots to look for trends in various areas measured by PROMIS. Analysis 
of correlative objectives will involve assessment of associations of baseline 
measurements of five biomarkers from tumor tissue and clinical outcome. 
Biomarkers will be evaluated by evaluation of quartiles with subsequent 
dichotomization and then comparison by response using a Chi-square test or 
Fisher’s exact test depending on sample size. Evaluation of biomarkers is primarily 
descriptive and will be used in the planning of future studies both for selection 
criteria and validation. Six biomarkers from blood will similarly be assessed; 
however, these measurements will be assessed at individual post-treatment time-
points as well. If warranted, repeated measures analyses may be used to look at 
measurements over time. There is currently no plan to demonstrate that the 
biomarkers could be used as surrogate endpoints but rather if associations exist 
for future evaluation. 
13.4 
Monitoring Guidelines 
Monitoring guidelines are developed to monitor excess toxicity using a continuous 
monitoring strategy based on an adaptation of Pocock stopping boundaries.31 In 
the event that a stopping rule is triggered, enrollment will be halted in the affected 
Treatment Plan. The Treatment Plan will be reviewed by the study committee (PI, 
co-I’s and Statistician) and a decision made about the future of the study. The IRB 
would be notified in the appropriate manner (expedited or at time of annual 
continuing review). 

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13.4.1 Grade 4/5 treatment Related Toxicity 
The goal is to construct a boundary based on toxicity such that the probability of 
early stopping is at most 10% if the toxicity rate is equal to 5% with a sample size 
of 29. Given these parameters, the upper stopping boundary for toxicity is 2 events 
out of 7 patients, 3 out of 16, 4 out of 28, or 5 at any time. If the true toxicity rate is 
as high as 20% then chance of early stopping is 87% and the expected sample 
size is 13.5. 
13.4.2 Grade 3/4/5 Pneumonitis, Colitis, Nephritis, Myocarditis or Hepatitis 
The goal is to construct a boundary based on toxicity such that the probability of 
early stopping is at most 10% if the toxicity rate is equal to 4% with a sample size 
of 29. Given these parameters, the upper stopping boundary for toxicity is 2 events 
out of 8 patients, 3 out of 19 or 4 at any time. If the true toxicity rate is as high as 
20% then chance of early stopping is 90% and the expected sample size is 11.5.  
Due to the addition of stopping rules, it is understood that the overall power may 
be slightly reduced for this study. 
14 
Conduct of the Study 
14.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be 
established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.   
14.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients. The study will 
only be conducted at sites where IRB approval has been obtained. The protocol, 
consent, written information given to the patients, safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB by the 
investigator.   
14.3 
Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent to 
review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant decides 
to participate in the study, he/she will be asked to sign and date the consent 

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document. Patients who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
15 
References  
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non-small-cell lung cancer. N. Engl J Med 355:2542-50, 2006 
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5. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed 
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6. Stabile LP, Davis AL, Gubish CT, Hopkins TM, Luketich JD, Christie N, et al. Human 
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7. Marquez-Garban DC, Chen HW, Fishbein MC, Goodglick L, Pietras RJ. Estrogen 
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8. Chlebowski RT, Schwartz AG, Wakelee H, et al. Estrogen plus progestin and lung 
cancer in postmenopausal women. Lancet 375:1243-51, 2009 
9. Bouchardy C, Benhamou S, Schaffar R, et al. Lung cancer mortality risk among breast 
cancer patients treated with anti-estrogens. Cancer 117:1288-95, 2011 
10. Lother SA, Harding GA, Musto G, et al. Antiestrogen use 
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13. Mah V, Seligson DB, Li A, Marquez DC, Wistuba II, Elshimali Y, et al. Aromatase 
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14. Marquez-Garban DC, Chen H-W, Fishbein MC, Goodglick L, Pietras RJ. Estrogen 
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15. Stabile LP, Rothstein ME, Cunningham DE, et al. Prevention of tobacco carcinogen-
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25. Hamilton DH, Griner LM, Keller JM, Hu X, Southall N, Marugan J, David JM, Ferrer M, 
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27. Zucchini G, Geuna E, Milani A, Aversa C, Martinello R, Montemurro F. Clinical utility of 
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29. Cheng TD, Darke AK, Redman MW, Smoking, Sex, and Non-Small Cell Lung Cancer: 
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Appendix I – ECOG Performance Status 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655. 
 
 
 
 
 

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Appendix II - Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) 
Definitions: 
Evaluable for Response:  Only those patients who have measurable disease present at baseline, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
Disease Parameters: 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.  If the investigator thinks it appropriate to include them, the conditions under which such 
lesions should be considered must be defined in the protocol. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘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. 
Target lesions.  All measurable lesions 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.  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 

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lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation 
by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and 10 mm 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.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable.  
 
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.  MRI is also acceptable 
in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  
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.  Furthermore, as with CT, the modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  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. 
 

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PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements.  However, 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.  Note, however, that the PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent review 
at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
(CR) or surgical resection is an endpoint. 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clinical response.  
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 
1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-
line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology  These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  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:  If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional follow-up CT  scans are 
needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 

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corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease-specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): 
 Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response. 
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion status.  
It must be representative of overall disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 

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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
 
 

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Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
 

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Appendix III– Strong CYP3A4 Inducers 
Most common strong CYP3A4 Inducers 
Carbamezepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
 
 

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Appendix IV – Potential Risks of Standard of Care Anti-PD1/PDL-1 
Therapy 
Source: Micromedex 
Pembrolizumab 
 
Common 
 
Dermatologic: Pruritus (11% to 28% ), Rash, Immune-mediated (17% to 42% ) 
 
Endocrine metabolic: Hypercholesterolemia (Non-small cell lung cancer, 20% ), Hyperglycemia 
(40% to 48% ), Hypertriglyceridemia (23% to 25% ), Hypoalbuminemia (32% to 34% ), Hyponatremia 
(10% to 38% ) 
 
Gastrointestinal: Constipation (15% to 51% ), Decrease in appetite (16% to 31% ), Diarrhea (14% to 
37% ), Nausea (13% to 68% ) 
 
Hepatic: Alkaline phosphatase raised (Non-small cell lung cancer, 26% ), AST/SGOT level raised 
(20% to 24% ) 
 
Musculoskeletal: Arthralgia (10% to 18% ), Musculoskeletal pain (21% to 32% ) 
 
Respiratory: Cough (15% to 24% ), Dyspnea (11% to 39% ) 
 
Other: Fatigue (20% to 71% ) 
 
Serious 
 
Cardiovascular: Vasculitis, Immune-mediated (Less than 1% ) 
 
Dermatologic: Bullous pemphigoid (Less than 1% ), Erythroderma (Less than 1% ) 
 
Endocrine metabolic: Hypophysitis, Immune-mediated (0.6% ) 
 
Hematologic: Anemia, Grade 3 or 4 (2% to 8% ), Hemolytic anemia, Immune-mediated (Less than 
1% ) 
 
Hepatic: Hepatitis, Immune-mediated (0.7% ), Pancreatitis, Immune-mediated (Less than 1% ), 
Veno-occlusive disease of the liver, Immune-mediated (9% ) 
 
Immunologic: Graft versus host disease, Immune-mediated (26% ) 
 
Musculoskeletal: Eaton-Lambert syndrome, Rhabdomyolysis 
 
Neurologic: Confusional state (Head and neck cancer, 2% or more ) 
 
Ophthalmic: Optic neuritis, Uveitis, Immune-mediated (Less than 1% ) 
 
Renal: Nephritis, Immune-mediated (0.3% ), Renal failure 
 
Respiratory: Pleural effusion (2% or more ), Pneumonia (2% or more ), Pneumonitis, Immune-
mediated (3.4%), Respiratory failure (Head and neck cancer, 2% or more ) 
 
Other: Infusion reaction (0.2% ), Sepsis (Up to 10% ) 
 
 

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Nivolumab 
Common 
 Dermatologic: Pruritus (10% to 28% ), Rash 
 Endocrine metabolic: Hyperglycemia (Urothelial carcinoma, 42% ), Hyperkalemia (15% to 30% ), 
Hypocalcemia (23% to 29% ), Hyponatremia (25% to 41% ), Serum cholesterol raised (Renal cell 
carcinoma, 21% ), Serum triglycerides raised (Renal cell carcinoma, 32% ) 
 Gastrointestinal: Abdominal pain, Constipation (10% to 23% ), Decrease in appetite (22% to 28% 
), Nausea (20% to 28% ), Vomiting (12% to 28% ) 
 Hematologic: Anemia, All Grades (39% to 40% ), Lymphocytopenia, All Grades (37% to 42% ) 
 Hepatic: Alkaline phosphatase raised (Urothelial carcinoma, 33% ), ALT/SGPT level raised 
(Urothelial carcinoma, 18%), AST/SGOT level raised (Urothelial carcinoma, 24% ) 
 Musculoskeletal: Arthralgia (10% to 21% ), Backache (Renal cell carcinoma, 21% ), 
Musculoskeletal pain 
 Neurologic: Asthenia, Headache (17% to 23% ), Peripheral neuropathy (Up to 12% ) 
 Renal: Serum creatinine raised (Urothelial carcinoma, 39% ) 
 Respiratory: Cough (10% to 36% ), Dyspnea (2% to 20% ), Upper respiratory infection 
 Other: Fatigue (49% ) 
 
Serious 
 Cardiovascular: Myocarditis, Immune-mediated (Less than 1% ), Vasculitis, Immune-mediated 
(Less than 1% ) 
 Dermatologic: Rash, Immune-mediated (9% to 22.6% ), Stevens-Johnson syndrome, Immune-
mediated, Toxic epidermal necrolysis, Immune-mediated 
 Endocrine metabolic: Adrenal insufficiency, Immune-mediated (1% to 5% ), Diabetic 
ketoacidosis, Hypercalcemia (Renal cell carcinoma, 19% ), Hyperthyroidism, Immune-mediated 
(2.7% to 8% ), Hypophysitis, Immune-mediated (0.6% to 9% ), Hypopituitarism, Immune-mediated 
(Less than 1% ), Hypothyroidism, Immune-mediated, Thyroiditis, Immune-mediated, Type 1 
diabetes mellitus, Immune-mediated (0.9% to 1.5% ) 
 Gastrointestinal: Colitis, Immune-mediated (Monotherapy, 2.9%; combined with ipilimumab, 26% 
), Diarrhea (17% to 52% ), Duodenitis, Immune-mediated (Less than 1% ), Gastritis, Immune-
mediated (Less than 1% ), Pancreatitis, Immune-mediated (Less than 1% ), Perforation of colon 
(Less than 10% ) 
 Hematologic: Anemia, Grade 3 or 4 (1.1% to 8% ), Lymphocytopenia, Grade 3 or 4 (4.3% to 9% 
), Neutropenia, Grade 3 or 4 (1.1% ) 
 Hepatic: Hepatitis, Immune-mediated (1.8% to 13% ) 
 Immunologic: Histiocytic necrotizing lymphadenitis, Immune-mediated (Less than 1% ), 
Sarcoidosis, Immune-mediated (Less than 1% ) 
 Musculoskeletal: Eaton-Lambert syndrome, Immune-mediated (Less than 1% ), Myositis, 
Immune-mediated (Less than 1% ), Rhabdomyolysis, Immune-mediated (Less than 1% ) 
 Neurologic: Demyelination of spinal cord, Immune-mediated (Less than 1% ), Encephalitis, 
Immune-mediated (0.2% ), Guillain-Barré syndrome, Immune-mediated (Less than 1% ), 
Neuropathy, Immune-mediated (Less than 1% ) 
 Ophthalmic: Uveitis, Immune-mediated (Less than 1% ) 
 Renal: Nephritis, Immune-mediated, Renal impairment, Immune-mediated, Urinary tract infectious 
disease (Urothelial carcinoma, 17% ) 
 Respiratory: Pleural effusion (2% or greater ), Pneumonitis, Immune-mediated (3.1% to 6%), 
Pulmonary embolism (Non-small cell lung cancer, 4.2% ), Respiratory failure (2% or greater), 
Respiratory tract infection (2% or greater ) 
 Other: Sepsis (2% or greater ) 
 

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Atezolizumab 
Common 
 Gastrointestinal: Constipation (15% to 21% ), Decrease in appetite (24% to 35% ), Diarrhea, 
Immune-mediated (18% to 24% ), Nausea (22% to 25% ) 
 Respiratory: Cough (14% to 30% ), Dyspnea (12% to 32% ) 
 Other: Fatigue (52% ) 
 
Serious 
 Cardiovascular: Myocarditis (Up to 1% ) 
 Endocrine metabolic: Adrenal insufficiency, Immune-mediated (0.4% ), Diabetes mellitus, Immune-
mediated (0.2% to 0.3% ), Hyperthyroidism (0.6% to 1.1% ), Hypophysitis, Immune-mediated (0.2% ), 
Hypothyroidism (2.5% to 4.2% ) 
 Gastrointestinal: Abdominal pain (15% to 17% ), Colitis, Immune-mediated, Pancreatitis, Immune-
mediated (0.1% ) 
 Hepatic: Hepatitis, Immune-mediated (0.9% to 1.3% ) 
 Musculoskeletal: Eaton-Lambert syndrome, Myasthenia gravis, Immune-mediated 
 Neurologic: Encephalitis, Guillain-Barré syndrome, Immune-mediated, Meningitis 
 Renal: Hematuria (14% ), Urinary tract infectious disease (17% to 22% ) 
 Respiratory: Interstitial lung disease, Pneumonitis, Immune-mediated 
 Other: Fever (14% to 21% ), Infectious disease (37.7% to 43% ), Infusion reaction (1.6% to 1.7% ) 
 
  
 
 

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Appendix V - Daily Drug Log 
Patient ID: _____________________ 
 
 
The study drug exemestane should be taken with a meal once a day, every day until you are 
told to stop.  If you forget to take a dose by more than 8 hour after the scheduled time or vomit 
after you take a dose, you should skip the dose and only take the next schedule dose.  If this 
occurs, record a “0” in the time taken column and indicate the reason the dose was missed 
under the notes column.   
Please bring this completed drug log and your study drug bottles (including any unused 
medication) with you to each appointment.  If you have any questions, please contact the study 
coordinator _________________ at ________________. 
date 
time of 
dose 
verify 1 tablet 
taken (if dose 
missed record 0) 
side effects and notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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date 
time of 
dose 
verify 1 tablet 
taken (if dose 
missed record 0) 
side effects and notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upon return of the completed log and drug reconciliation: 
Research Staff Signature:  
 
 
 
 
 
Date Reviewed:  
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix VI - PROMIS -29 Profile 
 
 

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e
 

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