Clinical trial NCT04037462
Conditions: Non-Small Cell Lung Cancer Immunotherapy
Sponsor: VA Office of Research and Development
Start date: 2021-07-07; Completion date: 2023-02-23
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Lung cancer accounts for 30% of all cancers among American war Veterans and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung cancer (NSCLC), with a 2-year survival rate of 10%. Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer. However, given the modest response rates of 20-25% to these immune checkpoint inhibitors, there is a greater desire to extend their benefits to more patients. Along with the desire to extend their benefits, there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses, prolonging survival from lung cancer. The investigators' studies show that extended dexamethasone (Dex) treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor (GR) overexpressing lung adenocarcinoma (AC) cell populations. Further, following withdrawal of Dexamethasone, proteins associated with the senescence associated secretory phenotype (SASP) strongly attracted and expanded T-cells, NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells. Therefore, dexamethasone may induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal.

Detailed description:
Lung cancer accounts for 30% of all cancers among American war Veterans and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung cancer (NSCLC), with a 2-year survival rate of 10%. Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer. However, given the modest response rates of 20-25% to these immune checkpoint inhibitors, there is a greater desire to extend their benefits to more patients. Along with the desire to extend their benefits, there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses, prolonging survival from lung cancer.

Our studies show that extended dexamethasone (Dex) treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor (GR) overexpressing lung adenocarcinoma (AC) cell populations. Further, following withdrawal of Dexamethasone, proteins associated with the senescence associated secretory phenotype (SASP), particularly CCL2, CCL4, CXCL1 and CXCL2 strongly attracted and expanded T-cells, NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells.

Our overarching hypothesis is that in lung adenocarcinoma patients who are not on baseline steroids, pre-treatment with Dexamethasone will induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal. The investigators will test this hypothesis through the conduct of the following aims.

Specific Aim 1: Use FLT-PET imaging and blood analysis to test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal will induce persistent senescence related cell cycle arrest in 1 lesion in 60% of patients, (based on GR expression) accompanied by release of SASP proteins and activation of T and NK cells.

Specific Aim 2: Test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal and subsequent re-challenge with pembrolizumab will yield an overall response rate (ORR) of 33% to pembrolizumab in association with tumor GR status, SASP and immune cell activation.

These aims will be conducted through a Phase II clinical trial designed as a single-arm two-stage study in Veterans whose lung adenocarcinoma has progressed on immune checkpoint inhibitors. Based on the investigators' preliminary data, the investigators expect that Dexamethasone will induce tumor senescence in at least one lesion in 60% of patients and secondarily improve overall response to pembrolizumab by 33%. Success with these aims would inform a larger study that could potentially change the way the investigators approach patients with primary or acquired resistance to immune checkpoint inhibitors with an off the shelf medication that could re-sensitize lung adenocarcinoma to immune checkpoint inhibitors. The proposed research could substantially benefit Veterans with metastatic NSCLC, a group with the most genomically complex lung cancers and poor survival.

Arms: arm 1: escalating doses of pretreatment dexamethasone in patients who have failed initial immunotherapy to 1. assess changes in FLT PET uptake 2. assess overall response rates of pretreatment dexamethasone (dose from 1) on subsequent immunotherapy re-challenge
Interventions: intervention 1: Dexamthasone
Intervention descriptions: intervention 1: escalating doses of pretreatment dexamethasone in patients who have failed initial immunotherapy to 1. assess changes in FLT PET uptake 2. assess overall response rates of pretreatment dexamethasone (dose from 1) on subsequent immunotherapy re-challenge

Protocol documents:
Prot_SAP_001.pdf: 
1 
 
 
 
TITLE: Induction of Senescence using Dexamethasone to Re-sensitize NSCLC to Anti- 
PD1 Therapy. 
 
PRINCIPAL INVESTIGATOR: 
Nithya Ramnath, MBBS 
Hematology/Oncology VA Ann Arbor Healthcare System 
2215 Fuller Rd. (111E) 
Ann Arbor, MI 48105 
Phone: 734-232-6789 
Fax: 734-647-1417 
Email: nithyar@med.umich.edu 
Coordinating Center: 
VA Ann Arbor Healthcare System 
 
Sub-Investigators at VAAAHS 
Irina Dobrosotskaya, 
MD 
Yaseen Mohiuddin, MD  
Garth Strohbehn, MD 
Megan Caram, MD 
Sarah Yentz, MD 
 
 
 
Study Coordinator 
Brittany Pannecouk, BS, CCRP 
Rachel Dedinsky, BS 
Shelby Raupp, BS, MBA 
 
Biostatistician: 
Seong-ho Kim, PhD 
 
Initial version: 
 
Nov 26, 2018 
 
FINAL 
 
Nov 26, 2021 
Amendment 1:  
Dec 12, 2019 
Amendment 2:  
Sep 23, 2020 
Amendment 3:  
March 16, 2021 
Amendment 4:  
July 21, 2021 
 


2 
 
 
SUMMARY Of CHANGES 
Section 
Description of Change 
Title Page 
• Version was updated 
• Date of version was updated 
• List of amendments was updated and 
reformatted with dates  
Section 5.1 Inclusion Criteria 
• 
Changed hemoglobin eligibility criteria 
from 9 to 8.0 g/dL  
• 
Changed coagulation screening 
requirements to only required if clinically 
indicated or on anticoagulants 
Section 5.2 Exclusion Criteria 
• 
Changed exclusion criteria #5 for history 
of non-infectious pneumonitis to 
history of non-infectious pneumonitis 
within the past 12 months 
Section 7.2 Treatment Calendars 
• 
Added coagulation screening 
requirements to Cohort 1, 2, and 3 
Schedules of Events to accurately reflect 
screening activities 
• 
Added footnote to Cohort 1, 2, and 3 
Schedules of Events to reflect changed 
coagulation screening requirements to 
only required if clinically indicated or on 
anticoagulants  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
 
 
TABLE OF CONTENTS 
 
 
 
ABBREVIATIONS ..................................................................................................... 7 
1.0 
TRIAL SUMMARY .......................................................................................... 9 
2.0 
TRIAL DESIGN ............................................................................................. 10 
2.1 
Trial Design ........................................................................................................ 10 
2.2 
Trial Diagram .................................................................................................... 12 
3.0 
OBJECTIVES ............................................................................................... 13 
3.1 
Primary Objective & Hypothesis ...................................................................... 13 
3.2 
Secondary Objectives ......................................................................................... 13 
3.3 
Exploratory Objectives ...................................................................................... 13 
4.0 
BACKGROUND & RATIONALE................................................................... 13 
4.1 
Background ........................................................................................................ 13 
4.1.1 Limitations of ICI and efforts to improve outcome ........................................ 14 
4.1.2 Preclinical and Clinical Trial Data ................................................................ 15 
4.2 
Rationale ............................................................................................................ 16 
4.2.1 Rationale for the Trial and Selected Subject Population .............................. 16 
4.2.2 Rationale for Dose Selection/Regimen ........................................................... 16 
4.2.3 Rationale for Endpoints ................................................................................. 18 
4.2.3.1 Efficacy Endpoints ...................................................................................... 18 
5.0 
PATIENT ELIGIBILITY ................................................................................. 19 
5.1 
Inclusion Criteria ............................................................................................... 19 
5.2 
Exclusion Criteria .............................................................................................. 21 


4 
 
6.0 
TREATMENT PLAN ..................................................................................... 23 
6.1 
Drug Administration.......................................................................................... 23 
6.1.1 Treatment ....................................................................................................... 23 
6.2 Pembrolizumab Dose Modification ....................................................................... 23 
6.3 
Dexamethasone dose modification..................................................................... 26 
6.4 
Diet/Activity/Other Considerations ................................................................... 26 
6.4.1 Contraception and Pregnancy ....................................................................... 26 
6.4.2 Use in Nursing Women .................................................................................. 28 
6.5 
Subject Withdrawal/Discontinuation Criteria .................................................. 28 
6.5.1 Discontinuation of Study Therapy after Complete Response (CR) .............. 29 
6.6 
Clinical Criteria for Early Trial Termination .................................................. 29 
7.0 
TRIAL PROCEDURES ................................................................................. 29 
7.1 
Trial Procedures ................................................................................................ 29 
7.1.1 Informed Consent........................................................................................... 30 
7.2 
Treatment Calendar .......................................................................................... 31 
7.3 
Management of Adverse Events ........................................................................ 34 
7.4 
Prohibited Concomitant Medications ............................................................... 36 
7.5 
Withdrawal/Discontinuation ............................................................................. 37 
7.5.1 End of Treatment Follow-up Visits ............................................................... 37 
7.5.2 Survival Follow-up ......................................................................................... 37 
8.0 
IMAGING AND MEASUREMENT OF DISEASE .......................................... 37 
8.1 
Disease Parameters ............................................................................................ 38 
8.2 
Guidelines for Evaluation of Measurable Disease ............................................ 39 
8.3 
Response Criteria ............................................................................................... 40 
9.0 
ADVERSE EVENTS ..................................................................................... 43 


5 
 
9.1 
Definitions .......................................................................................................... 44 
9.1.1 Adverse Event................................................................................................. 44 
9.1.2 Serious Adverse Event ................................................................................... 44 
9.1.3 Expected Adverse Events ............................................................................... 45 
9.1.4 Events Not Qualifying as SAEs ...................................................................... 45 
9.2 
Evaluating Adverse Events ................................................................................ 45 
9.3 
Reporting of Adverse Events ............................................................................. 46 
9.3.1 Reporting procedures for multi-site trials ..................................................... 46 
10.0 CORRELATIVE STUDIES ............................................................................ 46 
10.1 FDG-PET .............................................................................................................. 46 
10.2 FLT-PET ................................................................................................................ 46 
10.3 GR expression ........................................................................................................ 47 
10.4 SASP .......................................................................................................................47 
10.5 T and NK cells in PBMC ....................................................................................... 47 
11.0 STATISTICAL ANALYSIS PLAN ................................................................. 47 
11.1 
Statistical Design (see page 10 for Schema)....................................................... 47 
11.2 
Sample Size Justification ................................................................................... 48 
11.3 
Population for Analysis ...................................................................................... 49 
11.4 
Analysis of Primary Objective: ......................................................................... 49 
11.5 
Analysis of Secondary Objectives ...................................................................... 49 
12.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................... 50 
12.1 
Investigational Drugs ......................................................................................... 50 
12.2 
Clinical Supplies Disclosure ............................................................................... 51 
12.3 
Storage and Handling Requirements ................................................................ 51 


6 
 
13.0 ADMINISTRATIVE AND REGULATORY DETAILS ..................................... 51 
13.1 
Compliance with Trial Registration and Results Posting Requirements ......... 51 
13.2 
Quality Management System ............................................................................. 51 
13.3 
Data Management .............................................................................................. 51 
13.4 
Data and Safety Monitoring Procedures ........................................................... 52 
14.0 APPENDICES ............................................................................................... 53 
I. ECOG Performance Status....................................................................................... 53 
II. Common Terminology Criteria for Adverse Events V4.03 (CTCAE) .................... 53 
III. Procedures for Patients on Study ........................................................................... 54 
IV. MEDICATION DIARIES…………………………………………………………...55 
A. PATIENT’S MEDICATION DIARY COHORT 1……………………………..55 
B. PATIENT’S MEDICATION DIARY COHORT 2……………………………..57 
C. PATIENT’S MEDICATION DIARY COHORT 3……………………………..59 
V. References……………………………………………………………………………..62 
 
 
 
 
LIST OF FIGURES 
 
Figure 1:   Trial Design 
11 
 
 
 
LIST OF TABLES 
 
Table 1: 
Adequate organ function laboratory values 
20 
Table 2: 
Treatment drugs 
23 
Table 3: 
Pembrolizumab infusion reaction dose modification and treatment 
guidelines 
25 
Table 4: 
Dose modification and toxicity management guidelines for immune- 
related AEs associated with pembrolizumab 
34 


7 
 
ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ALK 
Anaplastic Lymphoma Kinase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEX 
Dexamethasone 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECI 
Events of Clinical Interest 
EGFR 
Epidermal Growth Factor Receptor 
ERC 
Ethics Review Committee 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
irRECIST 
Immune Response RECIST 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
per os/by mouth/orally 
PR 
Partial Response 


8 
 
 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TEAE 
Treatment-emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
WBC 
White Blood Cells 


9 
 
 
1.0 
TRIAL SUMMARY 
 
Abbreviated Title 
Induction of Senescence using Dexamethasone to Re- 
sensitize NSCLC to Anti-PD1 Therapy 
Trial Phase 
II 
Trial Type 
Interventional 
Study Centers 
VA Ann Arbor Healthcare System 
Hypothesis 
Pre-treatment 
of 
NSCLC 
with 
dexamethasone 
followed 
by 
pembrolizumab will result in induction of senescence with production of 
SASP and immune activation markers. Senescence will result in improved 
response to pembrolizumab. 
Objectives 
Primary: 
- 
To determine whether dexamethasone induces senescence in 
>60% of patients with stage IV NSCLC who have progressed 
after initial immunotherapy 
Secondary: 
- 
In patients whose NSCLC has progressed on first line 
immunotherapy, determine the pre-treatment Dexamethasone 
duration needed to induce ORR to pembrolizumab of >33% 
- 
Determine ORR to pembrolizumab assessed by FDG PET 
- 
Determine the relationship between sensitivity to Dexamethasone 
and ORR using pre- and post-FLT PET and FDG PET scans 
respectively. 
- 
To evaluate response based on immune-related RECIST (ir- 
RECIST) criteria and compare to response rate as evaluated by 
RECIST v1.1. 
Exploratory: 
- 
Determine SASP and activation of T and NK cells, measured in 
peripheral blood. 
- 
Functional characterization, including activation markers and 
intracellular cytokine profile, of immune cell subsets will be 
evaluated by multi-parametric flow cytometry. 
Type of control 
Historical controls of patients treated with docetaxel treatment whose 
FLTPET response was 30% and overall response rate was ≤7%. 
Study drugs: dose and 
administration 
Dexamethasone cohorts, PO, 4mg BID given for 7 or 10 or 13 days 
(followed by taper over 2-4 days and 3 day wash out) prior to first dose of 
pembrolizumab, followed by DEX 4mg BID for 7 or 10 or 13 days 
(followed by taper over 2-4 days and 3 day wash out) days prior to 
subsequent pembrolizumab x 3 cycles. 
Cohort 1 & 2: Pembrolizumab, IV, 200mg on day 1 of a 21-day cycle 
Cohort 3: Pembrolizumab, IV, 200mg on day 1 of a 28-day 
Duration of administration 
12 weeks 
Inclusion Criteria 
• 
Stage IIIA/B following CRT and durvalumab or Stage IV 
NSCLC whose tumors do not have a mutation in epidermal 
sensitizing growth factor (EGFR) or BRAF or rearrangements in 
ALK (anaplastic lymphoma kinase) or ROS-1and have 
progressed on therapy with PD1 inhibitor 


10 
 
 
• 
Presence of measurable disease according to RECIST v1.1 
• 
ECOG performance status 0-2No significant weight loss; >30% 
in 90-days 
• 
Adequate organ function defined as AST and ALT ≤ 2.5 × ULN, 
bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥ 40 ml/min 
• 
Adequate hematologic parameters 
• 
Life expectancy of at least 6 months 
• 
Sufficient tissue sample of adequate quality for correlative 
studies 
Exclusion Criteria 
• 
Presence of significant comorbidities precluding participation in 
a clinical study as determined by investigator 
• 
Has active autoimmune disease that has required systemic 
treatment in the past 2 years 
• 
Baseline corticosteroid use at study entry 
• 
ECOG performance status 3-4 
• 
Pregnancy or lactation 
Number of trial subjects 
21 to 39 patients 
Statistical design 
Simon’s optimal design with lead in cohorts. 
Estimated duration of trial 
2 years from 1st patient in, to last patient out 
Estimated average length of 
treatment per patient 
3 months 
 
 
2.0 
TRIAL DESIGN 
 
2.1 
Trial Design 
 
This study is a small Phase II clinical trial designed as a single-arm two-stage study with 
Dexamethasone dose escalation cohorts (4mg BID on days 1-7, 1-10 or 1-13). The trial will 
include FLT-PET and FDG-PET imaging to measure tumor senescence to Dexamethasone and 
treatment response respectively, and also blood analysis for SASP and markers of immune 
activation. This study is to assess whether senescence induced by oral dexamethasone 
resensitizes NSCLC patients to intravenous pembrolizumab. 
 
We will use a single arm phase II two-stage design with 3 Dex cohorts (4 mg bid, on Days 1- 
7. 1-10 and 1-14) to achieve 80% power at a 1-sided alpha 10% level. Each cohort will consist 
of 5 patients. On the basis of Simon’s optimal design, the first cohort will be accrued in the 
first stage. If there are 3 or more “responses” occur among this cohort, 7 additional patients 
will be accrued and treated with the same Dex dose for a total of 12 patients; if 7 or more 
respond at this dose level, we will add 9 more patients for a total of 21 patients (with 20% drop 
out, n = 31). If no response is noted on FLTPET, 2nd cohort will open up with a 10 day fixed 
dose Dex and so on as depicted in Schema. 


11 
 
 
 
 
 
 
The secondary objective is to establish that the true ORR of Dex followed by 
pembrolizumab will be at least 33% (p1 = 0.33) vs. docetaxel treatment (as the historical 
control) whose ORR is < 7% (p0 = 0.07). The ORR will be assessed at a 12 week FDG PET 
scan. The required sample size for both lead-in FLTPET response and phase 2 studies will 
range 21 to 31 patients. As secondary objectives, we will explore associations of the change in 
FLT-PET with ORR assessed by FDG-PET, level of plasma SASP, and immune cell 
activation. The change in FLT-PET will be compared by ORR using an unpaired t-test and the 
associations with the level of plasma SASP and immune cell activation will be examined by a 
correlation analysis. The power is not formally justified because these are exploratory. 
The patients will be assessed starting with a standard of care FDG-PET within 28-days of 1st 
dose of dexamethasone along with FLT-PET at baseline (Day 0) and after the last dose of 
dexamethasone. Response will be assessed through FDG-PET at 12 weeks and with CT 
imaging every 3 months thereafter (standard of care) until progression. Blood samples for 
T/NK cell counts, SASP including cytokines and chemokines, and immune cell subsets will be 
collected. The study will use Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1) for disease evaluation. Adverse event (AE) monitoring will occur prior to each 
cycle (21 days) and events will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. Patients will continue on trial until confirmed 
progression as defined by RECIST v1.1, develops unacceptable toxicity or intercurrent illness 
that prevents further administration of treatment, withdrawal from study, removal by the 
investigator, becomes pregnant, demonstrates noncompliance with trial requirements, or has 
received 24 months of treatment with pembrolizumab. Patients may continue on treatment 
despite RECIST v1.1-defined progression if the subject is felt to be continuing to derive 
clinical benefit as determined by the investigator. Additional information including the irRC 


12 
 
 
(immune-related response criteria) may be used by the investigator in deciding continuing 
treatment beyond RECIST v1.1-defined progression. 
 
At the end of treatment, all patients will continue to be followed for a minimum of 30 days for 
AE monitoring. Subjects will have post-treatment follow-up for disease status, including 
initiation of non-study cancer therapy until death, withdrawal of consent, or becoming lost to 
follow-up. 
 
2.2 
Trial Diagram 
 
The trial design is depicted below in Figure 1. 
Figure 1: 
Trial Design 
 


13 
 
 
3.0 
OBJECTIVES 
 
3.1 
Primary Objective & Hypothesis 
 
(1) Objective: To determine the extent of senescence (as measured by change in FLT-Pet 
of single target lesion) induced by Dexamethasone administered for 7 or 10 or 13 days 
 
- Hypothesis: The use of Dexamethasone in NSCLC patients who have progressed after 
first line immune/chemoimmunotherapy will result in senescence induction in 60% of 
patients, along with production of senescence associated secretory proteins (SASP) and 
immune activation. 
 
3.2 
Secondary Objectives 
 
(1) Objective: Determine the pre-treatment dexamethasone dose and duration needed to 
induce ORR to pembrolizumab of ≥33% in patients whose NSCLC has progressed on 1st 
line immunotherapy. 
 
(2) Objective: Determine ORR to Pembrolizumab assessed by FDG-PET 
 
(3) Objective: Determine the relationship between sensitivity to dexamethasone using pre- 
and post- FLT PET scans and ORR (by FDG PET). 
 
(4)  Objective: Determine the relationship between sensitivity to dexamethasone using pre- 
and post- FLT PET scans and GR expression by IHC. 
 
(5) Objective: Evaluate response based on immune-related RECIST (ir-RECIST) criteria and 
compare to response rate as evaluated by RECIST v1. 
 
3.3 
Exploratory Objectives 
 
(1) 
Objective: To induce SASP and activation of T and NK cells, measured in peripheral 
blood. 
 
(2) 
Objective: Functional characterization, including activation markers and intracellular 
cytokine profile, of immune cell subsets will be evaluated by multi-parametric flow 
cytometry. 
 
 
4.0 
BACKGROUND & RATIONALE 
 
4.1 
Background 
 
Disease Under Treatment 


14 
 
 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality 
worldwide. The prognosis for stage IV NSCLC remains dismal, with a 5-year survival rate of 
1-2%. (1) In addition to standard first-line platinum-based chemotherapy, other therapeutic 
options include tyrosine kinase inhibitors for patients with eligible mutations in the EGFR, 
ALK, or ROS-1 genes, and immune checkpoint inhibitors (ICIs). Currently, both PD-1 
(programmed cell death protein 1) and PD-L1 inhibitors are approved for the treatment of 
advanced NSCLC, irrespective of histology. Multiple phase II/III trials have demonstrated 
their superiority in terms of response rate and overall survival compared to docetaxel 
chemotherapy(2-4)However, response to these ICIs are about 20% (5)with few patients 
achieving long term durable clinical benefit (16% at 5years) (6) . There is an urgent need to 
identify approaches to prolong durable clinical benefit and thereby further improve long term 
survival 
 
Study 
Drugs 
Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. It is approved in the United States for the treatment of stage IV NSCLC 
with PD-L1 ≥50% in the front-line setting or for metastatic disease with PD-L1 ≥1% after 
progression on platinum-based chemotherapy (7). It also recently received accelerated 
approval by the FDA to be used in conjunction with carboplatin and pemetrexed as upfront 
therapy followed pembrolizumab +/- pemetrexed maintenance irrespective of PD-L1 
expression in non-squamous etiologies (8) 
 
Dexamethasone: 
 
Dexamethasone (Dex) is a synthetic glucocorticoid that acts by binding to the glucocorticoid 
receptor. The effects of dexamethasone are pleiotropic and context dependent. In Lewis lung 
cancer models, Dex exhibited effective tumor growth inhibition, which was associated with 
down-regulation of JAK3/STAT, hypoxia inducible factor 1α, vascular endothelial growth 
factor and IL-6 (9)However, long term Dex can also lead to suppression of the immune system, 
hyperglycemia, psychosis, avascular necrosis, and osteoporosis. We have shown that in the 
context of lung cancer, a 7-14 day course of Dex treatment leads to senescence with 
upregulation of p27 (10). These effects were most pronounced in lung cancer cells with 
moderate to high expression of glucocorticoid receptor (GR). Dex induced senescence in turn 
led to immune cell infiltration including T and NK cells (unpublished data). In the current 
proposal, we plan to harness this context dependent property of Dex in lung cancer and 
determine whether senesce will lead to re-sensitization to checkpoint inhibitors. 
 
4.1.1 Limitations of ICI and efforts to improve outcome: As discussed previously, a large 
proportion of patients do not respond because of primary or acquired resistance (7, 11, 12). 
Accumulating evidence suggests that tumor resistance to ICIs has been attributed to a lack 
of antigenic stimulation of T cells as well as inadequate infiltration of effector lymphocytes 
in the tumor (13). Cancer cell intrinsic phenomena such as dynamic genomic alterations and 


15 
 
 
senescence shape the immune microenvironment (14). Hence treatments that induce global 
phenotypic changes in the tumor cells may enhance effector immune cell infiltration and 
sensitize the tumors to ICI. There are several clinical trials that are attempting to target the 
tumor to make them more immunogenic. As an example, we and others have proposed the use 
of hypofractionated radiation to sensitize tumors to ICI (ClinicalTrials.gov Identifier: 
NCT03035890, NCT03035890). Others are attempting to sensitize cancers to ICI using 
epigenetic modifiers, oncolytic viruses or by altering the microbiome (15) To date, these have 
led to modest or incremental advances in the field. Therefore, there remains a pressing need 
to establish new mechanism-based strategies to sensitize or re-sensitize lung adenocarcinoma 
(AC) to ICIs. This proposal applies a new mechanistic rationale, developed from pre-clinical 
and clinical data, to sensitize tumors to immunotherapy by first inducing tumor senescence. 
We will utilize a recently discovered stress response pathway mediated by the glucocorticoid 
receptor (GR) that is specific to lung AC and induces senescence through a non-canonical 
mechanism. 
 
4.1.2 Preclinical and Clinical Trial Data 
 
Tumor resistance to PD1/PDL1 inhibitors has been attributed to a lack of antigenic stimulation 
of T cells and inadequate infiltration of effector lymphocytes in the tumor (14). Cancer cell 
intrinsic phenomena such as genomic alterations and senescence shape the immune 
microenvironment (16). Hence treatments that induce global phenotypic changes in the tumor 
cells may enhance effector immune cell infiltration and sensitize the tumors to immune 
checkpoint inhibition. Depending on the tumor cell context, when malignant cells become 
senescent, the tumors can evoke an anti-tumor immune response primarily mediated by 
infiltration of monocytes, T-cells and NK cells in response to senescence associated secretory 
proteins (SASP) produced by the tumor (13, 17, 18). Indeed, attempts have been made to find 
small molecules that induce senescence in various cancer cells using short-term high 
throughput screening assays (19, 20). We have arrived at a rational approach to inducing 
senescence in lung AC cells based on previous published observations. We have reported that 
treatment with dexamethasone (Dex), which is used to alleviate side effects of pemetrexed 
chemotherapy, causes glucocorticoid receptor (GR) status-dependent reversible G1 arrest, 
attenuating the cytotoxicity of pemetrexed (21). The effect of Dex was also evident from FLT- 
PET imaging of 4 patients that demonstrated that within 24h of treatment with Dex (4 mg 
b.i.d.), 3/4 patients showed S-phase suppression in all or some of their tumor lesions (22). As 
steady state G1 arrest cannot be maintained indefinitely, we examined the effect of extended 
exposure to Dex (10). We discovered that in various lung AC cell lines and recombinant 
isogenic cell models with moderate to high GR that was within the clinical spectrum of tumor 
GR expression, treatment with Dex led to a senescence phenotype within 7 days as well as 
progressive irreversible cell cycle blockade. These effects of exposure to Dex were due to a 
gradual accumulation of P27 through transcriptional activation by Dex. This direct effect of 
Dex on the tumor cells could explain recent findings from a large retrospective study that 
perioperative treatment of patients with lung adenocarcinoma, but not ovarian or colon cancer, 
increased survival, leading to a current open trial to confirm this effect (NCT03172988). 


16 
 
 
4.2 
Rationale 
 
4.2.1 Rationale for the Trial and Selected Subject Population 
 
Further studies (unpublished) showed that following withdrawal of Dex, secretory 
factors from the senescent cells 1. very strongly attracted T-cells and NK cells, the two immune 
cell types that have been principally implicated in anti-tumor response during PD1-targeted 
immunotherapy, 2. induced expansion and activation of NK cells, 3. modestly reduced MHC 
class I in some tumor cells, but made the cells vulnerable to NK cell cytolysis via induction of 
NKG2D ligand MIC-A/B, 4. enhanced the expression of PD1 in both T cells and NK cells and 
5. did not increase PDL1 expression in tumor cells. These findings set the stage for “jump 
starting” a renewed response to PD1 inhibitors in patients whose lung ACs have progressed on 
initial PD1 inhibitor therapy by pre-treating tumors with Dex. Based on our FLT-PET studies 
and lung AC GR expression and distribution, we expect 33-50% of patients to respond to this 
approach using Dex. 
A natural concern related to the use of Dex to sensitize tumors to immunotherapy is the 
known effect of Dex in suppressing lymphocytes, although the current standard of care front 
line combination pembrolizumab + chemotherapy treatment for lung AC does include Dex 
administered at doses of 4 mg b.i.d. for 3 days spanning chemo-immunotherapy. This question 
is easily addressed, based on literature data and the treatment design. First, the moderate dose 
range of Dex used (4 mg b.i.d.) in this study may be expected to cause only a modest decrease 
in lymphocyte counts (23). Second, the effect of glucocorticoids on lymphocyte count is rapidly 
reversible (24) whereas Dex will be withdrawn for 3 days following induction of the 
senescence phenotype in the tumor cells, prior to immunotherapy. Finally, the preliminary data 
strongly support an immune sensitizing role for SASP from Dex treated lung AC cells. 
 
Veteran Population: Lung cancer is a devastating disease that affects American War 
Veterans disproportionately and is the most common cause of cancer related death (25). 
Specifically, Veterans diagnosed with lung adenocarcinoma (AC) are more likely to present 
with advanced, metastatic disease that is associated with a median survival of 8.2 months. 
Compared to the general population, fewer Veterans present a driver mutant lung AC genotype 
that can be treated with targeted therapies. In this group of patients, immunotherapy has 
emerged as a promising therapeutic strategy that aims to harness the immune system to fight 
cancer. One such approach involves immune checkpoint inhibitors (ICI), specifically targeting 
the programmed death receptor or ligand (PD1/PDL1). However, response rates to ICI are 
modest (15-20%) with a modest prolongation of median survival to 13-15 months (26). The 
vast majority of Veterans (80%) either fail to respond (primary resistance) to initial ICI based 
therapy or progress (acquired resistance) after initial response. Following initial chemo- 
immunotherapy or immunotherapy, the cancer progresses and second line salvage 
chemotherapy options such as docetaxel have very poor response rates of ~ 7%. As such, 
survival is often less than 6 months in these patients. There is an unmet, urgent need for 
effective therapies in this group. 
 
4.2.2 Rationale for Dose Selection/Regimen 
 
Pembrolizumab 


17 
 
 
An open-label Phase I trial (KEYNOTE-001) has been conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475). The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well 
tolerated and no dose-limiting toxicities were observed. This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been 
identified to date. Recent data from other clinical studies within the pembrolizumab program 
has shown that a lower dose of pembrolizumab and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (27). Pharmacodynamic data 
(IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This 
early PK and pharmacodynamic data provided the scientific rationale for testing a Q2W and 
Q3W dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all body weights. 
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W 
body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for pembrolizumab as shown in the melanoma indication. The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab (28)showing that 
the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe. 


18 
 
 
Dexamethasone 
Rationale for dose and duration: 
 
Based on our preclinical data, the concentration of DEX required to cause senescence in lung 
cancer cells was about 100nM (10). This concentration can be achieved using the dose of DEX 
at 4mg BID for 7-13 days. The effects on senescence by DEX was also directly proportional 
to the intensity of GR expression Given intratumor heterogeneity and the problems of using 
archival tissue to test this biomarker, we are not pre-selecting patients in this initial study. 
Instead, we will vary the duration of pre-treatment DEX to 7, 10 or 13 days for the run in part 
of the study, prior to initial dose of pembrolizumab. 
 
There has been no phase I data that has specifically evaluated pre-treatment with 
dexamethasone prior to pembrolizumab. There is however data that suggest that the 2 should 
not be administered concurrently (29). We are therefore proposing a wash out period of at least 
3 days (t ½ 36-54h) before administration of pembrolizumab. There are not any serious adverse 
events that appear to overlap between the two agents based on review of published phase I/II/III 
and data. 
 
4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints 
 
The primary endpoint of this study is a biomarker endpoint. There is a need to probe for 
mechanism given the degree of heterogeneity in humans at the molecular level and then see if 
there is any relationship between a clinical outcome and putative mechanism. We therefore 
chose induction of senescence as the primary endpoint. Based on our preliminary data, at least 
50% of pts had a >30% change in FLT-PET in their target lesion post DEX. We will therefore 
use this as our primary endpoint. 
 
Secondary endpoints will include ORR as we are studying the impact of senescence on jump 
starting response to failed immunotherapy. Response rate in this setting would therefore be an 
appropriate endpoint as these patients go onto salvage chemotherapy as standard of care with 
poor response rates of 7 %. 
 
Biomarker Research 
 
Blood samples will be collected and analyzed for T/NK cell counts as well as SASP, including 
various cytokines and chemokines using a multiplex cytokine array. Phenotypic and functional 
characterization, including activation markers and intracellular cytokine profile, of immune 
cell subsets will be evaluated by multi-parametric flow cytometry. The change in FLT-PET 
will be compared by ORR using an unpaired t-test and the associations with the level of plasma 
SASP and immune cell activation will be examined by a correlation analysis.  Any increase in 
the absolute number, proliferation or activation of T cells and NK cells in the peripheral blood 
would indicate a positive response to PD1 therapy (30, 31). The power is not formally justified 
because these are exploratory and the comparisons are between pre- and post- treatment 
samples from individual patients. 


19 
 
 
Multi-factorial immune profiling. Briefly, plasma and PBMC will be isolated from the 
peripheral blood following standard percoll-gradient centrifugation. A multiplex Luminex 
assay (R&D Systems) will simultaneously query 45 different cytokines, chemokines, soluble 
receptors and growth factors (including, IFN-ϒ, IL-2, IL-2R, IL-6, IL-7, IL-12, IL-15, TNF- 
α, CCL-2, CCL-4, GRO-α/β, IL-8, IL-10 and VEGF) in the plasma. PBMC will be analyzed 
via a 12-color flow cytometry to assess: 
1. alterations in the absolute number and relative frequency of CD4/CD8 T cells and 
cytotoxic (CD56lowCD16high) and regulatory (CD56highCD16low) NK cells; 
2. Proliferation (Ki67) and activation (NKG2D, Perforin, IFN-gamma) markers as 
well as 
3. PD1 status of T and NK cell subsets. 
 
Immunohistochemistry (IHC): Dr. Murphy, pathologist and co-I at the Ann Arbor VA, will 
identify and check for quality control for tumor cellularity from biopsy samples. Antibody to 
GR will be used to assess tumor GR expression. Vecta Elite ABC-HRP Rabbit IgG kit (Vector 
Labs, Catalog#: PK-4001) will be used to stain slides for GR (Cell signaling, catalog#: 
12041S). Antigen retrieval will be performed using Vector Antigen Unmasking solution (Citric 
Acid Based, Vector Labs, Catalog#: H-3300) using a previously optimized protocol. GR 
staining will be scored independently by two pathologists, one at the VA (Dr. Murphy) and 
one at the KCI pathology core (Dr. Fulvio Lonardo). Quantitative expression will also be 
determined by AQUA. 
 
RNA extraction and measurement of mRNA expression: Retrieval of RNA from formalin-
fixed, paraffin-embedded biopsied tissue sections will be performed using the RNeasy FFPE™ 
Kit from Qiagen. Global degradation/transcript size range will be assessed by analyzing cDNA 
on agarose gels. RNA quantity and quality will be estimated by spectrophotometry. mRNAs 
for GRα and GRβ will be measured using specially designed TaqMan RT-PCR probes 
previously designed and optimized by us. 
 
Measurement of plasma Dex levels: Serum Dex concentrations will be determined at the 
KCI/WSU Pharmacology Core Service using liquid chromatography coupled with tandem 
mass spectrometry (LC-MS/MS) with the linear calibration curve at 5 - 5000 nM Dex in human 
serum. 
 
5.0 
PATIENT ELIGIBILITY 
 
5.1 
Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1. Be willing and able to provide written informed consent/assent for the trial. 
 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have a life expectancy of at least 6 months. 


20 
 
 
4. Have a histologically confirmed diagnosis of stage IV NSCLC (includes patients who 
have progressed on durvalumab for Stage III NSCLC) and have at least one measurable 
lesion based on RECIST v1.1. 
 
5. Have disease progression on or after treatment with an anti-PD-L1/PD-L1 mAb 
administered either as monotherapy, or in combination with other checkpoint inhibitors 
or other therapies.  Anti-PD-1/PD-L1 treatment progression is defined by meeting all 
the following criteria: 
 
 Most recent treatment with an anti-PD-1/PD-L1 mAb 
 Has received at least 2 doses of an anti-PD-1/PD-L1 mAb 
 Has demonstrated disease progression on or after an anti-PD-1/PD-L1 mAb 
as defined by RECIST 1.1. OR clinical progression at the investigator’s 
discretion 
 
6. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale (Appendix 
15.1). 
 
7. Demonstrate adequate organ function as defined in Table 1; all screening labs should 
be performed within 28 days of enrollment. 
 
Table 1: 
Adequate organ function laboratory values 
 
System 
Laboratory Value 
Hematologic 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥8.0 g/dL without transfusion or EPO dependency (within 7 
days of assessment) 
Renal 
Serum creatinine OR 
Measured or calculated creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥40 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
≥2.5 g/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) (only required if 
on anticoagulants or clinically indicated) 
Activated Partial Thromboplastin Time 
(aPTT) (only required if on 
anticoagulants or clinically indicated) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a serum pregnancy within 14 days 
of enrollment and 72 hours prior to receiving the first dose of study medications. 
 


21 
 
9. Female subjects of childbearing potential must be willing to use a highly effective 
method of contraception as outlined in Section 6.3.3 for the course of the study through 
180 days after the last dose of study medications. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
 
10. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 6.3.3, starting with the first dose of study therapy 
through 180 days after the last dose of study therapy. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
 
11.  Adequate tissue sample for correlative studies. A new sample is not necessary if 
archival specimen is available and has adequate amount of tumor content (at least 
30%). This needs to be determined by a pathologist. 
 
5.2 
Exclusion Criteria 
 
The first dose of trial treatment is considered to be first dose of dexamethasone. The subject 
must be excluded from participating in the trial if the subject: 
 
1. Received palliative radiation within 7 days of enrollment. 
 
2. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to enrollment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 7 
days prior enrollment. This exception does not include carcinomatous meningitis which 
is excluded regardless of clinical stability. 
 
3. Has active autoimmune disease that has required systemic treatment within the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). 
 
Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
 
4. Subjects requiring daily corticosteroids >10mg of prednisone (or its equivalent) would 
be excluded from the study. 


22 
 
 
Note: Subjects with asthma that require intermittent use of bronchodilators, 
inhaled steroids, or local steroid injections would NOT be excluded from the study. 
 
5. Has evidence of interstitial lung disease or a history of non-infectious pneumonitis 
within the past 12 months that  required oral or intravenous glucocorticoids to assist with 
management. 
 
Note: Lymphangitic spread of the NSCLC is not exclusionary. 
 
6. Has an active infection requiring systemic therapy. 
 
7. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
8. Subjects with cognitive functioning/impairment based on medical record review ad 
physician decision. 
 
9. Is pregnant, breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with informed consent through 180 days after 
the last dose of trial treatment. 
 
10. Has a diagnosis of immunodeficiency (including Human Immunodeficiency Virus 
(HIV) or acquired immunodeficiency (AIDS)-related illness) or is receiving systemic 
steroid therapy or any other form of immunosuppressive therapy within 7 days prior to 
enrollment. 
 
11. Has a known history of active TB (Bacillus Tuberculosis). 
 
12. Has known active Hepatitis B or Hepatitis C. 
13. Has received a live vaccine within 30 days of enrollment. 
 
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are 
live attenuated vaccines, and are not allowed. 
 
14. BASELINE CORTICOSTEROID AT STUDY ENTRY - subjects may not be on any 
steroids (dexamethasone, prednisone, etc) at the time of consent/study start. 


23 
 
 
6.0 
TREATMENT PLAN 
 
6.1 
Drug Administration 
 
6.1.1 Treatment 
 
Both dexamethasone and pembrolizumab are standard medications and will be used from 
commercial standard supply. The first dose of trial treatment is considered to be first dose of 
dexamethasone. Trial treatment should begin within 14 days of enrollment. 
 
 
Table 2:         Treatment drugs 
 
Drug 
Dose/Potency 
Dose Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 21-day 
cycle 
 
Dexamethasone will be administered orally, prior to each dose of pembrolizumab for 3 cycles 
in the following cohorts: 
 
Cohort 1: 4 mg BID for 7 days, followed by taper 2 mg BID for 1 day and 1 mg BID and 3 day 
wash out. 
 
Cohort 2: 4mg BID for 10 days, followed by 2 mg BID for 2 days, 1 mg BID for 1 day and 3 
day wash out. 
 
Cohort 3: 4 mg BID for 13 days, 2mg BID for 3 days, 1 mg BID for 1day and 3 day wash out 
Pembrolizumab 200 mg (IV) will be administered per institutional standard of care guidelines. 
Subjects will be given a pill diary and instructed to complete for each day of administration of 
Dexamethasone. Missed and/or vomited doses should be recorded on the diary as such. 
Subjects will be asked to bring their pill diary to each study visit. 
 
6.2 Pembrolizumab Dose Modification 
 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 


24 
 
 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
 
For dose modification/management of immune-related adverse events, please see section 7.3 
Table 7. 
 
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Investigator. The reason for interruption should be documented in the 
patient's study record. 


25 
 
 
Table 3: 
Pembrolizumab infusion reaction dose modification and treatment 
guidelines 
 
 
NCI CTCAE Grade 
Treatment 
Premedication and Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
- IV fluids 
-Antihistamines 
-NSAIDs 
-Acetaminophen 
-Narcotics 
-Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of 
analgesic). 
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g. 
from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
-Epinephrine** 
-IV fluids 
-Antihistamines 
-NSAIDs 
-Acetaminophen 
-Narcotics 
-Oxygen 
-Pressers 
-Corticosteroids 
-Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
-Hospitalization may be indicated. 
No subsequent dosing 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Subject is permanently discontinued from further study drug 
treatment. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0.3 (CTCAE) at http://ctep.cancer.gov 


26 
 
 
6.3 Dexamethasone dose modification: CBC and Metabolic profile will be monitored 
once weekly while on DEX. Any Grade III or greater non-hematological side effect will 
result in holding the DEX with resumption only when AE is Grade 1 or lower, and patient 
is asymptomatic. If symptomatic, DEX will be permanently discontinued. 
 
6.4 Diet/Activity/Other Considerations: No special considerations. In diabetics, we will 
encourage stricter adherence to sugar free meals 
 
6.4.1 Contraception and Pregnancy 
 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab have transient adverse effects on the composition of sperm. 
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
 
Female subjects will be considered of non-reproductive potential if they are either: 
 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
 
OR 
 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
 
OR 
 
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 180 days after the last 
dose of study drug by complying with one of the following: 
 
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) highly effective contraception during heterosexual activity. 
Highly effective methods of contraception are‡: 
Single method (one of the following is acceptable): 


27 
 
 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin- 
only pill) associated with inhibition of ovulation, contraceptive skin patch, vaginal 
contraceptive ring, or subcutaneous contraceptive injection 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
 
Patients should be informed that taking the study medications may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 180 days after 
the last dose of trial therapy. If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
 
If a patient inadvertently becomes pregnant while on study, the subject will immediately be 
removed from the study and the investigator should notify the IRB within 24 hrs of knowledge. 
The site will contact the subject at least monthly and document the subject’s status until the 
pregnancy has been completed or terminated. 
 
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn. If a male subject impregnates 
his female partner the study personnel must be informed immediately and the pregnancy 
reported to the IRB within 24 hours of knowledge. 


28 
 
 
6.4.2 Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. In addition, 
subjects should not breastfeed for 180 days after the last dose of study medication. 
 
6.5 
Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn if enrollment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding discontinuation or 
withdrawal are provided in Section 7.5. 
 
A subject must be discontinued from study treatment for any of the following reasons: 
 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 
• Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue treatment with confirmed 
radiographic progression if clinically stable or clinically improved at the discretion 
of the investigators. 
 
• Unacceptable adverse experiences as described in Section 6.2 and 7.3 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 7.5.1. After the end 
of treatment, each subject will be followed for 30 days for adverse event monitoring. Serious 
adverse events will be collected for 30 days after the end of treatment as described in Section 
9.0). End of treatment and survival follow-up procedures are listed in section 7.2. Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up 


29 
 
 
for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up. After documented disease progression 
each subject will be followed every 6 months through the medical record for overall survival 
until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
6.5.1 Discontinuation of Study Therapy after Complete Response (CR) 
 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab. 
 
6.6 
Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete 
 
2. Poor adherence to protocol and regulatory requirements 
 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
 
4. Plans to modify or discontinue the development of the study drug 
 
7.0 
TRIAL PROCEDURES 
 
7.1 
Trial Procedures 
 
Patient registration for this trial will be managed by VA Ann Arbor Healthcare System as 
described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the site on the Screening and Enrollment 
Log. 
 
It is the responsibility of the investigator to determine patient eligibility. After patient eligibility 
has been determined, the completed Eligibility Worksheet will be filed in the patient binder with 
the signed informed consent form in a locked office and locked cabinets. Electronic copies will 
be located on the VA secured T Drive. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them and will not receive study treatment. 
 
The Schedule of Events Appendix A summarizes the trial procedures to be performed at each 
visit. It may be necessary to perform these procedures at unscheduled time points if deemed 
clinically necessary by the investigator. 


30 
 
 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
7.1.1 Informed Consent 
 
The Coordinator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. Specifics about a trial and the trial population will 
be added to the consent form template at the protocol level. The informed consent will adhere 
to IRB requirements, and applicable laws and regulations. 


31 
 
 
7.2 
Treatment Calendar 
 
SCHEDULE OF EVENTS COHORT 1 
 
Procedure 
Screening 
(within 
28 days 
prior to 
Day 0)1 
Baseline 
Day 0 
(C1D1) 
Lead 
In C2 
and 
C3 
(C2 
and 
3D1) 
(± 
3Days) 
(C4+) 
(± 3 
Days) 
EOT 
Follow 
Up1 
Informed Consent 
X 
Medical History 
X 
Physical exam 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
CBCPD 
X 
X 
X 
X 
X 
Comp 
X 
X 
X 
X 
X 
Coagulation (PT/aPTT)7 
X 
 
 
 
 
FDG PET/CT-Chest (VA 
Ann Arbor)2 
X 
 
X 
X 
CT Abdomen/Pelvis 3 
X 
Research Blood4 
X 
X 
X 
FLT PET (University of 
Michigan) 
X 
X 
Dexamethasone5 
X 
X 
X 
Pembrolizumab6 
X 
X 
X 
 
1 Follow Up: Phone call 6 weeks after EOT including any new treatments 
2 FDG PET/CT-Chest: C4D1 (±7days), then Every 12 weeks (±7days) 
3 CT-Abdomen/Pelvis: at screening, C4D1 (±7days), then Every 12 weeks (±7days) only if disease is present in 
that area 
4Research Blood: T/TK, SAP, cytokines, chemokines, immune cell subsets; Drawn with 1st FLT PET, 2nd 
FLT PET, C1D1, C2D1, C3D1 only 
5 Dexamethasone given orally. Start immediately after FLT PET Day 0 – Day 9. Lead in Day 9-17 
6Pembrolizumab given up to 1 year every 21 days 
7Only required if clinically indicated or on anticoagulants


32 
 
 
SCHEDULE OF EVENTS COHORT 2 
 
Procedure 
Screening 
(within 28 
days prior 
to Day 0)1 
Baseline 
Day 0 
(C1D1) 
Lead In 
C2 and 
C3 
(C2 and 
3D1) 
(± 
3Days) 
(C4+) 
(± 3 
Days) 
EOT Follow 
Up1 
Informed Consent 
X 
Medical History 
X 
Physical exam 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
CBCPD 
X 
X 
X 
X 
X 
Comp 
X 
X 
X 
X 
X 
Coagulation (PT/aPTT)7 
X 
 
 
 
 
FDG PET/CT-Chest (VA Ann 
Arbor)2 
X 
 
X 
X 
CT Abdomen/Pelvis 3 
X 
Research Blood4 
X 
X 
X 
FLT PET (University of 
Michigan) 
X 
X 
Dexamethasone5 
X 
X 
X 
Pembrolizumab6 
X 
X 
X 
 
 
1 Follow Up: Phone call 6 weeks after EOT including any new treatments 
2 FDG PET/CT-Chest: C4D1 (±7days), then Every 12 weeks (±7days) 
3 CT-Abdomen/Pelvis: at screening, C4D1 (±7days), then Every 12 weeks (±7days) only if disease is present in 
that area 
4Research Blood: T/TK, SAP, cytokines, chemokines, immune cell subsets; Drawn with 1st FLT PET, 2nd 
FLT PET, C1D1, C2D1, C3D1 only 
5 Dexamethasone given orally. Start immediately after FLT PET Day 0 – Day 9. Lead in Day 9-17 
6Pembrolizumab given up to 1 year every 21 days 
7Only required if clinically indicated or on anticoagulants 


33 
 
 
SCHEDULE OF EVENTS COHORT 3 
 
Procedure 
Screening 
(within 28 
days prior 
to Day 0)1 
Baseline 
Day 0 
(C1D1) 
Lead In 
C2 and 
C3 
(C2 and 
3D1) (± 
3Days) 
(C4+) 
(± 3 
Days) 
EOT 
Follow 
Up1 
Informed Consent 
X 
Medical History 
X 
Physical exam 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
CBCPD 
X 
X 
X 
X 
X 
Comp 
X 
X 
X 
X 
X 
Coagulation (PT/aPTT)7 
X 
 
 
 
 
 FDG PET/CT-Chest (VA Ann 
Arbor)2 
X 
 
X 
X 
CT Abdomen/Pelvis 3 
X 
Research Blood4 
X 
X 
X 
FLT PET (University of 
X 
X 
Dexamethasone5 
X 
X 
X 
Pembrolizumab6 
X 
X 
X 
 
 
 
1 Follow Up: Phone call 6 weeks after EOT including any new treatments 
2 FDG PET/CT-Chest: C4D1 (±7days), then Every 12 weeks (±7days) 
3 CT-Abdomen/Pelvis: at screening, C4D1 (±7days), then Every 12 weeks (±7days) only if disease is present in 
that area 
4Research Blood: T/TK, SAP, cytokines, chemokines, immune cell subsets; Drawn with 1st FLT PET, 2nd 
FLT PET, C1D1, C2D1, C3D1 only 
5 Dexamethasone given orally. Start immediately after FLT PET Day 0 – Day 9. Lead in Day 9-17 
6Pembrolizumab given up to 1 year every 21 days 
7Only required if clinically indicated or on anticoagulants 


34 
 
 
7.3 
Management of Adverse Events 
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 4. 
 
Table 4: 
Dose modification and toxicity management guidelines for immune-related 
AEs associated with pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
Immune-related 
AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4. 
0) 
Action 
taken to 
pembrolizu
mab 
irAE 
management with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor subjects for signs and 
symptoms of pneumonitis 
• 
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 
4, or 
recurrent 
grade 2 
Permanently 
discontinue 


35 
 
 
Diarrhea / colitis 
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor subjects for signs and 
symptoms of enterocolitis (i.e. 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(i.e. peritoneal signs and ileus). 
• 
Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider 
GI consultation and performing 
endoscopy to rule out colitis. 
• 
Subjects with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Please see section 6.2.3 regarding the management of overlapping hepatotoxicity with 
rucaparib and pembrolizumab. 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglyce 
mia 
associated 
with 
evidence of 
β-cell failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
subjects with 
T1DM 
• Administer 
anti- 
hyperglycemic 
in subjects with 
hyperglycemia 
• 
Monitor subjects for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and initiate 
hormonal 
replacements 
as clinically 
indicated. 
• 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non- 
selective beta- 
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and symptoms 
of thyroid disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine 
or 
• 
Monitor for signs and symptoms 
of thyroid disorders. 


36 
 
 
liothyroinine) 
per standard of 
care 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 1- 
2mg/kg or 
equivalent) 
followed by 
taper. 
• 
Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on 
severity of AE, 
administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Grade 3, or 
intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
NOTES: 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. 
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM) 
 
7.4 
Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
1. Antineoplastic systemic chemotherapy or biological therapy 
2. Immunotherapy not specified in this protocol 
3. Chemotherapy not specified in this protocol 
4. Investigational agents 
5. Radiation therapy 
- 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion. 
6. Live vaccines within 30 days prior to enrollment and while participating in the trial. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 


37 
 
 
7. Daily systemic glucocorticoids with dose >10mg of prednisone (or its equivalent) for 
any purpose other than to modulate symptoms from an event of clinical interest of 
suspected immunologic etiology. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
7.5 
Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 9.0. 
 
7.5.1 End of Treatment Follow-up Visits 
 
The mandatory Safety Follow-Up Visit should be conducted within 30 +/- 10 days after the 
last dose of pembrolizumab. Subjects with an AE of Grade >1 will be further followed until 
the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, 
whichever occurs first. Procedures should be conducted according to the Treatment Calendar 
in Section 7.2. SAEs that occur within 30 days of the end of treatment should be followed and 
recorded. 
 
7.5.2 Survival Follow-up 
 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject will be followed through his/her medical record and assessed for survival status 
until death or 2 years. Data will be collected every 6 months. 
 
8.0 
IMAGING AND MEASUREMENT OF DISEASE 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (32) 
 
Immunotherapy drugs can initially cause inflammation in the early stages of treatment. 
Immune-related RECIST (irRECIST) utilizes RECISTv1.1 but considers an inflammatory 
response (or “pseudo-progression”) as normal. The main difference between RECISTv1.1 and 
irRECIST is that patients can stay on trial after the first progressive disease (PD) assessment 
(as per RECISTv1.1) if using immune-related RECIST criteria. This PD per RECISTv1.1 is 
then re-labeled as immune related stable disease (irSD) per irRECIST (33) and requires 
addition of unidimensional measurements of all new lesions (that meet the definition of target 
lesion) to be added to the sum of longest diameters (SLD) calculation for response assessment. 
Importantly, immune-related progression (irPD) must be confirmed by a follow-up scan at 


38 
 
 
least 4 weeks (within 4-8 weeks) following the initial PD/irSD assessment in order to take the 
patient off the trial. 
 
Subjects that are deemed to have clinical progression and unstable should not be continued on 
therapy after PD (per RECISTv1.1) and are therefore not required to have repeat tumor 
imaging for confirmation as per irPD definition. It is at the discretion of the site investigator 
whether to continue a subject on study treatment until repeat imaging is obtained. This clinical 
judgment decision by the site investigator should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. 
 
Definitions 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least 2 cycle(s) 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.) 
 
8.1 
Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter in the plane of measurement is to be recorded) with 
a minimum size of: 
 
• 10 mm by CT scan (or MRI) for studies with a slice thickness of ≤5mm, or twice 
the slice thickness 
• 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
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. 
 
Note: Tumor lesions that are situated in a previously irradiated area will only be considered 
measurable, if they have had subsequent progression by at least 5 mm. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using CT scan), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 


39 
 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total 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), 
representative of all involved organs, and those that lend themselves to reproducible repeated 
measurements. If a non-nodal lesion is either not present or is initially measured with longest 
diameter <10mm as a non-target then grows to >10mm after baseline, this lesion then becomes 
a new target lesion as per irRECIST criteria. The non-nodal longest diameter is then added to 
the sum of diameters, and patient response is calculated with the new lesion. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10 mm but <15 mm) should be considered non-target lesions. Nodes that have a short 
axis <10 mm are considered nonpathological and should not be recorded or followed. 
 
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 as noted above, 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. If a non-target lymph node grows to >15mm after 
baseline, this node then becomes a new target lesion as per irRECIST. The nodal short axis is 
then added to the sum of diameters, and patient response is calculated with the new lesion. 
 
Non-target lesions: All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, ‘absent’, or 
in rare cases ‘unequivocal progression’ (more details to follow). In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’) 
 
8.2 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before enrollment. 
 
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 


40 
 
 
should always be done rather than 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 
and > 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
CT and MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When 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). 
 
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. 
 
8.3 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two separate 
observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD. There can be no appearance of new 
lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started, or the appearance of one 
or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 


41 
 
 
Incomplete Response/Stable Disease (SD): 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. 
 
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. 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category 
Also 
Requires: 
CR 
CR 
No 
CR 
≥4 wks. confirmation 
CR 
Non-CR/SD 
No 
PR 
≥4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
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 
* 
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. 
 
Treatment Beyond Progression 
 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. 
 
Subjects will be permitted to continue study treatment beyond initial RECISTv1.1 defined PD, 
assessed by the investigator, as long as they meet the following criteria: 


42 
 
 
• Investigator determined clinical benefit 
• Tolerance of study drug 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases) 
• Tumor markers are stable/improving, if expressed 
 
A radiographic assessment/ scan should be performed within 4-8 weeks of initial investigator- 
assessed progression to determine whether there has been a decrease in the tumor size or 
continued PD (termed irPD). The assessment of clinical benefit should be balanced by clinical 
judgment as to whether the subject is clinically deteriorating and unlikely to receive any benefit 
from continued treatment. 
 
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according 
to the Study Calendar (see Table 7.2). 
 
For the subjects who continue study therapy beyond progression, further progression is defined 
as an additional 20% increase in tumor burden with a minimum 5 mm absolute increase from 
time of initial PD. This includes an increase in the sum of diameters of all target lesions and/ 
or the diameters of new measurable lesions compared to the time of initial PD. Study treatment 
should be discontinued permanently upon documentation of further progression (i.e. irPD). 
 
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 recurrent 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. 
 
Progression-Free Survival 
 
Progression-free survival is defined as the duration of time from start of treatment to time of 
progression. 


43 
 
 
9.0 
ADVERSE EVENTS 
 
Adverse event monitoring and reporting is a routine part of every clinical trial and is done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Data on adverse events will be collected from the time of the 
initial dose of dexamethasone through 30 days after the last dose of pembrolizumab (whichever 
is later). Serious adverse events will be collected from the time of the initial dose of 
dexamethasone through 30 days after the last dose pembrolizumab (whichever is later). Any 
serious adverse event that occurs more than 30 days after the last dose of pembrolizumab and 
is considered related to the study must also be reported. Serious Adverse Events (SAEs) will 
continue to be followed until: 
 
• Resolution or the symptoms or signs that constitute the serious adverse event return to 
baseline; 
 
• There is satisfactory explanation other than the study drugs for the changes observed; 
• The patient is lost to follow-up or withdraws consent; or 
• Death. 
The investigator is responsible for the detection, documentation, grading and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions of 
AEs and SAEs are given below. It is the responsibility of the principal investigator to ensure 
that all staff involved in the trial is familiar with the content of this section. 
 
Any medical condition or laboratory abnormality with an onset date before enrollment onto 
study is considered to be pre-existing in nature. Any known pre-existing conditions that are 
ongoing at time of study entry should be considered medical history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 9.1, 
occurring from the initial dose of dexamethasone through 30 days following the last dose of 
pembrolizumab must be recorded as an adverse event regardless of frequency, severity (grade) 
or assessed relationship to the study drugs. 
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a 
pre-existing condition that occurs after the patient begins study is also considered an adverse 
event. 
 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol- 
specified procedure or intervention. If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 


44 
 
 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the IRB. 
 
 
9.1 
Definitions 
 
9.1.1 Adverse Event 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding or vital sign which 
requires protocol treatment to be modified, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure. Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the study drugs, is also an adverse event. 
 
Progression of the cancer under study and/or symptoms related to progression of the 
underlying cancer are not considered an adverse event. 
 
9.1.2 Serious Adverse Event 
 
An adverse event is considered “serious” if, in the view of the investigator it results in any of 
the following outcomes: 
 
o Death 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
 
o A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of either the 
investigator or sponsors, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event that, had it occurred in a more severe 
form, might have caused death. 
 
o Inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. 
o A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o A congenital anomaly/birth defect 


45 
 
 
o Important medical event: Any event 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 and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition of 
“Serious Adverse Event”. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the development of 
drug dependency or drug abuse. 
 
9.1.3 Expected Adverse Events 
 
An adverse event (AE) is considered “expected” if: 
 
• For approved and marketed drugs, those adverse events are described in the 
approved Package Insert. 
 
9.1.4 Events Not Qualifying as SAEs 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course of 
the study. Preplanned hospitalizations or procedures for preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs. However, if the preexisting condition worsened 
during the course of the study, it should be reported as an SAE. Progression of the cancer 
under study and/or symptoms related to progression of the underlying cancer are not 
considered a serious adverse event unless it resulted in death. 
 
9.2 
Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0.3 All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the 
CTCAE 
version 
4.03 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site. 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf) Any adverse event which changes CTCAE grade over the 
course of a given episode will have each change of grade recorded. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 


46 
 
 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment/intervention 
 
9.3 
Reporting of Adverse Events 
 
9.3.1   Reporting procedures for multi-site trials 
 
All adverse events (AEs), serious adverse events (SAEs) and unanticipated problems (UPs), 
will be reported to the IRB per current institutional standards. 
10.0 
CORRELATIVE STUDIES 
 
10.1 FDG-PET: [18F]-fluorodeoxyglucose (FDG) has been used extensively as a glucose 
analogue to image glycolysis in the body. Its accumulates in many cancers, most notably lung 
cancer due to their elevated glycolytic rate compared to normal background tissue. This has 
allowed FDG to be the standard for oncologic staging prior to therapy, and one of the main 
modalities to monitor recurrent disease/treatment response to therapy. In FDG PET/CT, 
significant variation in tracer uptake has been suggested to be 30 % for the SUV max using 
PERCIST criteria (34) Although this metric has been suggested, we will also look at 
normalized SUV max using an internal reference tissue given that tumor burden and 
hyperglycemia has been shown to effect PERCIST criteria (35, 36) Additionally, total lesion 
glycolysis (the SUV mean of the segmented volume multiplied by the tumor volume) has been 
shown to be a better estimation of FDG uptake and account for variation of a very “hot tumor” 
that is small compared to a “warm tumor” that is large (35) 
 
10.2 FLT-PET: [18F]-3-fluro-deoxy-thymidine (FLT) is a thymidine analogue as FDG is an 
analogue to glucose. It is an NIH held IND drug with a current/active RDRC at the University 
of Michigan. FLT’s incorporation into the cell occurs through thymidine kinase within the 
DNA synthesis machinery. Once in the cell it is phosphorylated and trapped within the cytosol. 
The degree of uptake correlates to the degree of DNA synthesis/proliferation, analogous to Ki- 
67. FLT PET/CT imaging will be used both prior to and after DEX treatment (37). The initial 
scan will provide a baseline DNA synthesis rate based on the uptake within the tumor. 
Following DEX therapy, if there is senescence as predicted and resultant G1 arrest, there will 
be fewer cells in S phase (DNA synthesis) and a corresponding reduction in FLT uptake in the 
tumor. The reduction in FLPET is hypothesized to be directly proportional to reduced FDG 
uptake, denoting response to therapy. FLT PET can eventually be used a biomarker to identify 
who would benefit from the proposed approach in this study. 


47 
 
 
10.3 GR expression 
 
A specific cut-off for tumoral GR expression is not a pre-requisite for enrollment onto this 
protocol. Tumoral GR expression will be determined by immunohistochemistry (IHC) 
methods. GR expression will be divided as low (<1%), intermediate (1-49%), and high (≥50%). 
 
10.4 SASP 
 
The tumor cells will remain senescent and continue secreting SASP even after Dex washout. 
The SASP is expected to enhance the frequency and cytolytic functions of T and NK cells in 
the peripheral blood as well as in the tumor, especially in combination with the checkpoint 
inhibitor, Pembrolizumab. The SASP will be analyzed by a multiplex cytokine array 
 
10.5 T and NK cells in PBMC 
 
T cells and NK cells are major contributors to cytolytic function against the tumor, which is 
often blocked by PD1-PDL1 interaction. Although the number of T cells would deplete to some 
extent during Dex treatment, it is expected to recover quickly during/following the 3-day 
washout., while a multi-parametric flow cytometric analysis will detect any change in the 
number and functions of T and NK cells in the peripheral blood. 
 
11.0 
STATISTICAL ANALYSIS PLAN 
 
11.1 
Statistical Design (see page 10 for Schema) 
 
In the first stage, three DEX escalation cohorts will be evaluated sequentially from Cohort 
A to Cohort C until two or more patients have the FLT-PET response (i.e., ≥30% reduction in 
FLT-PET uptake in at least one target lesion) and, otherwise, the trial will be terminated due 
to futility. When a lead-in cohort has two or more FLT-PET responses, this lead-in cohort will 
be considered the optimal DEX duration and the primary endpoint will be evaluated in the 
following second and third stages using this optimal DEX duration. That is, after the optimal 
DEX duration is decided in the first stage, six additional patients will be enrolled in the second 
stage with the same DEX duration as the associated cohort. If four or less patients respond 
among 11 patients, the trial will be terminated. Otherwise, 10 additional patients will be 
enrolled in the third stage. The null hypothesis (p0 = 30%) will be rejected if 10 or more FLT- 
PET responses are observed in 21 patients. This design yields a 1-sided type I error rate of 5% 
and power of 80% when the true FLT-PET response rate is 60% (i.e., p1 = 60%). The minimum 
sample size will be 11 patients when Cohort A becomes the optimal duration and the trial is 
terminated at the end of the second stage. The maximum sample size will be 31 patients when 
Cohort C becomes the optimal duration and the patients are enrolled into the third stage. 
We will also explore the associations between the FLT-PET response and the changes in 
senescence associated secretory proteins (SASP) and lymphocyte, phenotypic and functional 
markers (LPFM), (ii) monitor the changes and trajectories in SASP and LPFM, and (iii) explore 
the association between the FLT-PET response and GR expression at cycle 0. The expression 
levels of SASP and LPFM/GR will be measured using plasma and tissue samples, 


48 
 
 
respectively. The secondary endpoints are the changes in SASP and LPFM expression levels 
between cycle 0 and cycle 1 as well as the expression level of GR at cycle 0. The association 
between the FLT-PET response and the changes in the expression levels of each of SASP and 
LPFM will be examined using logistic regression models. The expression levels of SASP and 
LPFM between cycle 0 and cycle 1 will be examined using a paired t-test, if needed, after data 
transformation (such as log or square root transformation). The association between the FLT- 
PET response and the GR expression level will be assessed using logistic regression models. 
The trajectories from cycle 0 to cycle 4 for the expression levels of each of SASP and LPFM 
will be examined to see if the expression levels increase monotonically across cycles. To do 
this, linear mixed-effects models will be used, if needed, after data transformation. In addition, 
in case that either Cohort B or C becomes the optimal duration, we will descriptively compare 
the changes in SASP and LPFM expression levels from cycle 0 to cycle 1 between lead-in 
cohorts. Because these are a discovery study to generate hypotheses, no multiple comparison 
correction will be made. However, if either the sample size is less than 12 patients or a level 
(i.e., response vs. non-response) has less than 5 events; all secondary objectives will be 
exploratory and will be summarized descriptively. All statistical analyses will be based on 
complete data and no missing data analysis will be performed. 
The secondary objective is to assess the effect of DEX on pembrolizumab in terms of 
overall response rate (ORR), which is the primary endpoint. Based on our previous pre-clinical 
and clinical studies, we hypothesize that the true ORR of DEX followed by pembrolizumab 
will be at least 33% (i.e., p1 = 0.33) vs. the historical control whose ORR is at most 7% (i.e., 
p0 = 0.07). The ORR will be statistically evaluated when the FLT-PET response trial enters 
the third stage, where the number of patients with the selected optimal DEX duration will be 
21. Otherwise, the ORR will be summarized descriptively. The null hypothesis (p0 = 7%) will 
be rejected if five or more responses are observed in 21 patients, which yields a 1-sided type I 
error rate of 5% and power of 87% when the true ORR is 33% (i.e.., p1 = 33%). 
We will also to explore the associations between ORR and the changes in expression 
levels of each of SASP and LPFM from cycle 0 to cycle 1, (ii) to explore the association 
between ORR and GR expression at cycle 0, and (iii) to explore the progression-free survival 
(PFS). The associations between ORR and the changes of SASP and LPFM and between ORR 
and the GR expression will be examined using logistic regression models and no multiple 
comparison correction will be made because these are a discovery study to generate 
hypotheses. The distribution of PFS will be summarized graphically using the Kaplan-Meier 
(KM) curve and the median PFS and associated 95% confidence interval will be estimated 
using KM estimate. If either the sample size is less than 12 patients or a level (i.e., response 
vs. non-response) has less than 5 events, the secondary objectives will be exploratory and will 
be summarized descriptively. All statistical analyses will be based on complete data and no 
missing data analysis will be performed. 
 
11.2 
Sample Size Justification 
 
The clinical trial is a single arm phase II intervention trial in Veterans as second line therapy, 
after progression on initial chemo-immunotherapy or immunotherapy for NSCLC. The 
enrolled patient will be in the study for 3 months and will then be followed for up to 2 years. 
We currently see at least 2-3 patients per month who will satisfy eligibility criteria and thus 


49 
 
 
the enrollment will be completed within 2 years (min 21 and max 39 patients). A sample size 
of 21 patients will not be powered for all the comparisons. But the data information obtained 
from this study will provide us preliminary information to design a more definitive study 
 
The sample size was justified based on the primary objective. The FLT-PET response will be 
evaluated using a Phase II single-arm three-stage design with three lead-in efficacy (futility) 
cohorts. The sample size was estimated to achieve 80% power with a 1-sided 5% type I error 
rate and the estimated sample size is varied according to the selected optimal duration, which 
ranges from 21 patients (when Cohort A is optimal) to 31 patients (when Cohort C is optimal). 
Considering up to 20% drop-out rate, the required sample size will be between 21 patients (i.e., 
no drop-out with Cohort A as the optimal duration) and 39 patients (i.e., 20% drop-out with 
Cohort C as the optimal duration). For the secondary objective, the use of 21 patients (when 
the FLT-PET response trial enters the third stage) will allow us to achieve 87% power when 
the true ORR is 33% with a 1-sided type I error rate of 5%. We expect that the accrual rate will 
be at least 35 eligible and evaluable patients per year. 
 
11.3 
Population for Analysis 
 
Intent-to-Treat Population: All patients consented and enrolled in the trial. 
 
Evaluable Population: Only those patients who have received at least one cycle of therapy with 
dexamethasone and pembrolizumab will be considered evaluable. 
 
Safety Evaluable Population: Patients who receive any treatment on protocol will be 
considered evaluable for safety. 
 
11.4 Analysis of Primary Objective: The primary objective is to identify the 
smallest duration of fixed dose Dex that results in a >30% reduction in 
FLTPET. We will utilize a 2 stage design with 3 cohorts (see Statistical 
schema). The hypothesis is that the true “response” in FLTPET (reduction 
in FLTPET by >30% following Dex in at least 1 target lesion) will be 60% 
(p1=60) vs. p0 30% (based on preliminary data that chemotherapy such as 
docetaxel results in irreversible cell cycle arrest as measured by S-phase 
surrogate on FLT-PET (39). 
 
Secondarily, we will compare FLTPET “response” to GR expression and 
generation of SASP and immune effector cells. We will also track the trend in 
immune effector cell response at later time points (cycle 2 and 3) to test 
contributory effects of pembrolizumab and Dex on the immune phenotype in the 
blood. 
 
11.5 Analysis of Secondary Objectives The secondary objective is to establish 
that the true ORR of Dex followed by pembrolizumab will be at least 33% 
(p1 = 0.33) vs. docetaxel treatment (as the historical control) whose ORR is 


50 
 
 
< 7% (p0 = 0.07). The ORR will be assessed at a 12 week FDG PET scan. 
The required sample size for both lead-in FLTPET response and phase 2 
studies will range 21 to 31 patients. As secondary objectives, we will explore 
associations of the change in FLT-PET with ORR assessed by FDG-PET, 
level of plasma SASP, and immune cell activation. The change in FLT-PET 
will be compared by ORR using an unpaired t-test and the associations with 
the level of plasma SASP and immune cell activation will be examined by a 
correlation analysis. The power is not formally justified because these are 
exploratory 
 
 
12.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
12.1 Investigational Drugs 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study drug 
in accordance with the protocol and any applicable laws and regulations. 
 
Dexamethasone is available through commercial supply. It will be administered orally 
according to study schema. 
 
Pembrolizumab is available through commercial supply. It will be administered intravenously 
every 21 days per institutional standard policy 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
Dexamethasone is available through commercial supply and will be administered 7 days prior 
with 3 days off before each pembrolizumab infusion. 
 
Drug Name: 
Dexamethasone 
INN: 
Dexamethasone 
Formulation: 
Tablet; 


51 
 
 
How Supplied: 
2mg white, scored tablet 
4mg green, scored tablet 
6 mg aqua, scored tablet 
Come in high-density polyethylene bottles or equivalent with 
child-resistant caps. Patients may receive 1 or more strengths. 
Each bottle contains 100 tablets 
Storage Conditions: 
20-25 °C (68 and 77° F) protect from moisture 
12.2 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the and trial site personnel are not blinded to 
treatment. Drug identity (name, strength) is included in the label text. 
 
12.3 Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
13.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
13.1 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the PI of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
 
13.2 Quality Management System 
 
The Ann Arbor VA Research Office audits clinical trials every quarter and random charts are 
examined for any discrepancies as relates to HIPPA adherence and IRB approved form usage 
 
13.3 Data Management 
 
All information will be recorded locally and entered into VA RedCap Case Report Forms 
(CRFs) on the web-based electronic data capture (EDC) system. Online access is password 
protected. 
 
CRFs will be reviewed and source verified by the PI and the study coordinator. Discrepant, 
unusual and incomplete data will be queried by the MSC. The investigator or study coordinator 


52 
 
 
will be responsible for providing resolutions to the data queries, as appropriate. The 
investigator must ensure that all data queries are dealt with promptly. 
 
The data submission schedule is as follows: 
• At the time of registration 
o Subject entry into VA RedCap 
 Subject Status 
 Demographics 
• During study participation 
o All data should be entered online within 10 business days of data acquisition. 
Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 9.3 of the protocol. 
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
 
13.4 Data and Safety Monitoring Procedures 
 
A Data and Safety Monitoring Committee (DSMC) will be set up as an arm’s length committee. 
The DSMC will be comprised of VA oncologists not involved with the study and VA 
Pharmacist. This committee is responsible for monitoring the safety and data integrity of the 
trial. 
 
The committee is required to meet monthly to discuss matters related to: 
 
• Enrollment rate relative to expectations, characteristics of participants 
• Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
Protocol deviations are to be documented and reported to the IRB at the continuing review, or 
sooner (per policy) 


53 
 
 
14.0 
APPENDICES 
 
I. ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
II. Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
( https://evs.nci.nih.gov/ftp1/CTCAE/About.html. ) 


54 
 
 
III Procedure for patients on study 
 
1. Patient will sign consent 
2. Patient will have regular standard of care procedures and they will be reviewed and 
used for eligibility. 
3. Patient will be scheduled for baseline FLT PET and FLT PET prior to 
Pembrolizumab and all future clinic appointments so they know when they will be 
ahead of time 
4. Patient will be called the day before for a reminder of their FLT PET and to start 
Dexamethasone after FLT PET 
5. Patient will go to the University of Michigan for FLT PET and take 1st dose of 
Dexamethasone immediately afterwards – Coordinator will meet patient for Research 
blood draw and reimburse patient for this visit ($25) 
6. Patient will be called and reminded to stop taking dexamethasone 
7. Patient will be called and reminded about their appointments the next day which are 
the last FLT PET, visit with Dr. Ramnath, cycle 1 of Pembrolizumab infusion 
8. Patient will go to the University of Michigan for FLT PET and then come to VA Ann 
Arbor to begin Pembrolizumab treatment – Patient will be reimbursed to this visit 
($25) 
9. The same thing will happen for the next 2 cycles regarding starting and stopping 
dexamethasone without the FLT PET 
10. Patients will have imaging (FDG-PET and CT-Chest, CT-Abdomen and Pelvis 
only required if disease is present in that area) at screening, C4D1 (±7days), 
then Every 12 weeks (±7days)


55 
 
IVA. PATIENT’S MEDICATION DIARY COHORT 1 
CYCLE    1 – 3    
 
 
     
Today’s date _____________________ Agent:  Dexamethasone   
Patient Initials_____________________ Patient Study ID___________________ 
 
INSTRUCTIONS TO THE PATIENT-: 
• 
You will take Dexamethasone orally twice a day, approximately 12 hours apart 
• 
 You should take your capsule(s) at approximately the same time each morning and evening. 
 
Dexamethasone Taper  
4mg Dex morning and evenings on Days 10-16; then again on Days 31-37 
2mg Dex morning and evenings on Day 17; then again on Day 38 
1mg Dex morning and evenings on Day 18; then again on Day 39 
 
Day 
 
Date 
 
 
Time of Dose 
Dexamethasone 
Comments 
AM 
PM 
_____ mg 
 
 
F 
FLT PET @ UM @ ________; Blood Draw; Start Dexamethasone 
 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
No Dexamethasone 
 
M 
 
No Dexamethasone 
 
Tu 
 
No Dexamethasone 
1  
W 
 
FLT PET @ UM @__________; Blood Draw; RV w/Ramnath @ __________;              
PEMBROLIZUMAB INFUSION (Cycle 1 Day 1 = 1st Dose) 
2 
Th 
 
 
 
 
3 
F 
 
 
 
 
4 
Sa 
 
 
 
 
5 
Su 
 
 
 
 
6 
M 
 
 
 
 
7 
Tu 
 
 
 
 
8 
W 
 
 
 
 
9 
Th 
 
 
  
10 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   


56 
 
11 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   
12 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
13 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
14 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
15 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
16 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
17 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
18 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
19 
Su 
 
No Dexamethasone 
20 
M 
 
No Dexamethasone 
21 
Tu 
 
No Dexamethasone 
22  
W 
 
Blood Draw; RV w/Ramnath @ __________;                                          
PEMBROLIZUMAB INFUSION (Cycle 2 Day 1 = 2nd Dose) 
23 
Th 
 
 
 
 
24 
F 
 
 
 
 
25 
Sa 
 
 
 
 
26 
Su 
 
 
 
 
27 
M 
 
 
 
 
28 
Tu 
 
 
 
 
29 
W 
 
 
 
 
30 
Th 
 
 
  
31 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
32 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   
33 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
34 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
35 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
36 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
37 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
38 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
39 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
40 
Su 
 
No Dexamethasone 
41 
M 
 
No Dexamethasone 
42 
Tu 
 
No Dexamethasone 
43  
W 
 
Blood Draw; RV w/Ramnath @ __________;                                          
PEMBROLIZUMAB INFUSION (Cycle 3 Day 1 =3rd Dose) 
 
 
 
 


57 
 
IVB. PATIENT’S MEDICATION DIARY COHORT 2  
CYCLE    1 – 3    
 
 
     
Today’s date _____________________ Agent:  Dexamethasone   
Patient Initials_____________________ Patient Study ID___________________ 
 
INSTRUCTIONS TO THE PATIENT-: 
• 
You will take Dexamethasone orally twice a day, approximately 12 hours apart 
• 
 You should take your capsule(s) at approximately the same time each morning and evening. 
 
Dexamethasone Taper  
4mg Dex morning and evenings on Days 6-15; then again on Days 27-36 
2mg Dex morning and evenings on Day 16-17; then again on Day 37-38 
1mg Dex morning and evenings on Day 18; then again on Day 39 
 
Day 
 
Date 
 
 
Time of Dose 
Dexamethasone 
Comments 
AM 
PM 
_____ mg 
 
 
M 
FLT PET @ UM @ ________; Blood Draw; Start Dexamethasone 
 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
No Dexamethasone 
 
M 
 
No Dexamethasone 
 
Tu 
 
No Dexamethasone 
1  
W 
 
FLT PET @ UM @__________; Blood Draw; RV w/Ramnath @ __________;              
PEMBROLIZUMAB INFUSION (Cycle 1 Day 1 = 1st Dose) 
2 
Th 
 
 
3 
F 
 
 
4 
Sa 
 
 
5 
Su 
 
 
6 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
7 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   


58 
 
8 
W 
 
AM 
PM 
_____mg AM 
_____mg PM   
9 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM   
10 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
11 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   
12 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
13 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
14 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   
15 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
16 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
17 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
18 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
19 
Su 
 
No Dexamethasone 
20 
M 
 
No Dexamethasone 
21 
Tu 
 
No Dexamethasone 
22  
W 
 
Blood Draw; RV w/Ramnath @ __________;                                          
PEMBROLIZUMAB INFUSION (Cycle 2 Day 1 = 2nd Dose) 
23 
Th 
 
 
24 
F 
 
 
25 
Sa 
 
 
26 
Su 
 
 
27 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
28 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   
29 
W 
 
AM 
PM 
_____mg AM 
_____mg PM   
30 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM   
31 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
32 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   
33 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
34 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
35 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   
36 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
37 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
38 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
39 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
40 
Su 
 
No Dexamethasone 
41 
M 
 
No Dexamethasone 
42 
Tu 
 
No Dexamethasone 
43  
W 
 
Blood Draw; RV w/Ramnath @ __________;                                          
PEMBROLIZUMAB INFUSION (Cycle 3 Day 1 =3rd Dose) 
 


59 
 
IVC. PATIENT’S MEDICATION DIARY COHORT 3  
CYCLE    1 – 3    
 
 
     
Today’s date _____________________ Agent:  Dexamethasone   
Patient Initials_____________________ Patient Study ID___________________ 
 
INSTRUCTIONS TO THE PATIENT-: 
• 
You will take Dexamethasone orally twice a day, approximately 12 hours apart 
• 
 You should take your capsule(s) at approximately the same time each morning and evening. 
 
Dexamethasone Taper  
4mg Dex morning and evenings on Days 9-21; then again on Days 37-49 
2mg Dex morning and evenings on Days 22-24; then again on Days 50-52 
1mg Dex morning and evenings on Day 25; then again on Day 53 
 
Day 
 
Date 
 
 
Time of Dose 
Dexamethasone 
Comments 
AM 
PM 
_____ mg 
 
 
TH 
FLT PET @ UM @ ________; Blood Draw; Start Dexamethasone 
 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
 
 
Su 
 
No Dexamethasone 
 
M 
 
No Dexamethasone 
 
Tu 
 
No Dexamethasone 
1  
W 
 
FLT PET @ UM @__________; Blood Draw; RV w/Ramnath @ __________;              
PEMBROLIZUMAB INFUSION (Cycle 1 Day 1 = 1st Dose) 
2 
Th 
 
 


60 
 
3 
F 
 
 
4 
Sa 
 
 
5 
Su 
 
 
6 
M 
 
 
7 
Tu 
 
 
8 
W 
 
 
9 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM   
10 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
11 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   
12 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
13 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
14 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   
15 
W 
 
AM 
PM 
_____mg AM 
_____mg PM   
16 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM   
17 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
18 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
19 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM  
20 
M 
 
AM 
PM 
_____mg AM 
_____mg PM  
21 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM  
22 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
23 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
24 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
25 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
26 
Su 
 
No Dexamethasone 
27 
M 
 
No Dexamethasone 
28 
Tu 
 
No Dexamethasone 
29 
W 
 
Blood Draw; RV w/Ramnath @ __________;                                          
PEMBROLIZUMAB INFUSION (Cycle 2 Day 1 = 2nd Dose) 
30 
Th 
 
 
31 
F 
 
 
32 
Sa 
 
 
33 
Su 
 
 
34 
M 
 
 
35 
Tu 
 
 
36 
W 
 
 
37 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM   
38 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
39 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   


61 
 
40 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
41 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
42 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   
43 
W 
 
AM 
PM 
_____mg AM 
_____mg PM   
44 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM   
45 
F 
 
AM 
PM 
_____mg AM 
_____mg PM   
46 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM   
47 
Su 
 
AM 
PM 
_____mg AM 
_____mg PM   
48 
M 
 
AM 
PM 
_____mg AM 
_____mg PM   
49 
Tu 
 
AM 
PM 
_____mg AM 
_____mg PM   
50 
W 
 
AM 
PM 
_____mg AM 
_____mg PM  
51 
Th 
 
AM 
PM 
_____mg AM 
_____mg PM  
52 
F 
 
AM 
PM 
_____mg AM 
_____mg PM  
53 
Sa 
 
AM 
PM 
_____mg AM 
_____mg PM  
54 
Su 
 
No Dexamethasone 
55 
M 
 
No Dexamethasone 
56 
Tu 
 
No Dexamethasone 
57  
W 
 
Blood Draw; RV w/Ramnath @ __________;                                          
PEMBROLIZUMAB INFUSION (Cycle 3 Day 1 =3rd Dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


62 
 
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1. 
W. Xia et al., Improvement of survival for non-small cell lung cancer over time. Onco 
Targets Ther 10, 4295-4303 (2017). 
2. 
H. Borghaei et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non- 
Small-Cell Lung Cancer. N Engl J Med 373, 1627-1639 (2015). 
3. 
J. Brahmer et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non- 
Small-Cell Lung Cancer. N Engl J Med 373, 123-135 (2015). 
4. 
R. S. Herbst et al., Pembrolizumab versus docetaxel for previously treated, PD-L1- 
positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet 387, 1540-1550 (2016). 
5. 
J. Malhotra, S. K. Jabbour, J. Aisner, Current state of immunotherapy for non-small 
cell lung cancer. Transl Lung Cancer Res 6, 196-211 (2017). 
6. 
S. Gettinger et al., Five-Year Follow-Up of Nivolumab in Previously Treated 
Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study. J Clin 
Oncol 36, 1675-1684 (2018). 
7. 
E. B. Garon et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med 372, 2018-2028 (2015). 
8. 
C. J. Langer et al., Carboplatin and pemetrexed with or without pembrolizumab for 
advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of 
the open-label KEYNOTE-021 study. Lancet Oncol 17, 1497-1508 (2016). 
9. 
Y. Geng, J. Wang, H. Jing, H. W. Wang, Y. X. Bao, Inhibitory effect of dexamethasone 
on Lewis mice lung cancer cells. Genet Mol Res 13, 6827-6836 (2014). 
10. 
M. Patki et al., Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence 
Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over- 
expressing Glucocorticoid Receptor. Sci Rep 8, 16006 (2018). 
11. 
V. K. Anagnostou, J. R. Brahmer, Cancer immunotherapy: a future paradigm shift in 
the treatment of non-small cell lung cancer. Clin Cancer Res 21, 976-984 (2015). 
12. 
P. Sharma, S. Hu-Lieskovan, J. A. Wargo, A. Ribas, Primary, Adaptive, and Acquired 
Resistance to Cancer Immunotherapy. Cell 168, 707-723 (2017). 
13. 
L. Wang et al., High-Throughput Functional Genetic and Compound Screens Identify 
Targets for Senescence Induction in Cancer. Cell Rep 21, 773-783 (2017). 
14. 
R. Seelige, S. Searles, J. D. Bui, Mechanisms regulating immune surveillance of 
cellular stress in cancer. Cell Mol Life Sci 75, 225-240 (2018). 
15. 
T. Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune 
Checkpoints. Int J Mol Sci 19,  (2018). 
16. 
S. G. Rao, J. G. Jackson, SASP: Tumor Suppressor or Promoter? Yes! Trends Cancer 
2, 676-687 (2016). 
17. 
M. D. Wellenstein, K. E. de Visser, Cancer-Cell-Intrinsic Mechanisms Shaping the 
Tumor Immune Landscape. Immunity 48, 399-416 (2018). 
18. 
A. Marcus et al., Recognition of tumors by the innate immune system and natural killer 
cells. Adv Immunol 122, 91-128 (2014). 
19. 
M. Sadaie et al., Cell-based screen for altered nuclear phenotypes reveals senescence 
progression in polyploid cells after Aurora kinase B inhibition. Mol Biol Cell 26, 2971- 
2985 (2015). 


63 
 
 
20. 
C. J. Cairney et al., A 'synthetic-sickness' screen for senescence re-engagement targets 
in mutant cancer backgrounds. PLoS Genet 13, e1006942 (2017). 
21. 
M. Patki et al., Glucocorticoid receptor status is a principal determinant of variability 
in the sensitivity of non-small-cell lung cancer cells to pemetrexed. J Thorac Oncol 9, 
519-526 (2014). 
22. 
C. I. McHugh et al., Using Radiolabeled 3'-Deoxy-3'-(18)F-Fluorothymidine with PET 
to Monitor the Effect of Dexamethasone on Non-Small Cell Lung Cancer. J Nucl Med 
59, 1544-1550 (2018). 
23. 
N. Serra-Bonett, S. Al Snih, M. A. Rodriguez, Effect of low-dose prednisone on 
leukocyte counts and subpopulations in patients with rheumatoid arthritis. J Clin 
Rheumatol 15, 148-149 (2009). 
24. 
G. D. Pountain, M. T. Keogan, B. L. Hazleman, D. L. Brown, Effects of single dose 
compared with three days' prednisolone treatment of healthy volunteers: contrasting 
effects on circulating lymphocyte subsets. J Clin Pathol 46, 1089-1092 (1993). 
25. 
L. L. Zullig et al., Cancer incidence among patients of the U.S. Veterans Affairs Health 
Care System. Mil Med 177, 693-701 (2012). 
26. 
A. Qin et al., Clinical Determinants of Durable Clinical Benefit of Pembrolizumab in 
Veterans With Advanced Non-Small-Cell Lung Cancer. Clin Lung Cancer 18, 559-564 
(2017). 
27. 
T. Shimizu et al., Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal 
antibody) in Japanese patients with advanced solid tumors. Invest New Drugs 34, 347- 
354 (2016). 
28. 
R. de Greef et al., Pembrolizumab: Role of Modeling and Simulation in Bringing a 
Novel Immunotherapy to Patients With Melanoma. CPT Pharmacometrics Syst 
Pharmacol 6, 5-7 (2017). 
29. 
K. C. Arbour et al., Impact of Baseline Steroids on Efficacy of Programmed Cell Death-
1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung 
Cancer. J Clin Oncol 36, 2872-2878 (2018). 
30. 
A. Osa et al., Clinical implications of monitoring nivolumab immunokinetics in non- 
small cell lung cancer patients. JCI Insight 3, (2018). 
31. 
S. L. Topalian, J. M. Taube, R. A. Anders, D. M. Pardoll, Mechanism-driven 
biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 
16, 275-287 (2016). 
32. 
E. A. Eisenhauer et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 45, 228-247 (2009). 
33. 
J. D. Wolchok et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res 15, 7412-7420 (2009). 
34. 
R. L. Wahl, H. Jacene, Y. Kasamon, M. A. Lodge, From RECIST to PERCIST: 
Evolving Considerations for PET response criteria in solid tumors. J Nucl Med 50 
Suppl 1, 122S-150S (2009). 
35. 
B. L. Viglianti et al., Effects of Tumor Burden on Reference Tissue Standardized 
Uptake for PET Imaging: Modification of PERCIST Criteria. Radiology 287, 993-1002 
(2018). 


64 
 
 
36. 
B. L. Viglianti et al., Effect of hyperglycemia on brain and liver (18)F-FDG 
standardized uptake value (FDG SUV) measured by quantitative positron emission 
tomography (PET) imaging. Biomed Pharmacother 88, 1038-1045 (2017). 
37. 
V. R. Bollineni, G. M. Kramer, E. P. Jansma, Y. Liu, W. J. Oyen, A systematic review 
on [(18)F]FLT-PET uptake as a measure of treatment response in cancer patients. Eur 
J Cancer 55, 81-97 (2016). 
38. 
R. Simon, Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10, 
1-10 (1989). 
39. 
J. P. Crandall et al., A comparison of FLT to FDG PET/CT in the early assessment of 
chemotherapy response in stages IB-IIIA resectable NSCLC. EJNMMI Res 7, 8 (2017). 

ICF_000.pdf: 
VA INFORMED CONSENT CHECKLIST
*Complete this checklist for each consent obtained and file with the original informed consent document*
RESEARCH STUDY IDENTIFICATION (Required information)
STUDY TITLE:  Induction of Senescence using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy
PI: Dr. Nithya Ramnath
NAME OF STUDY TEAM MEMBER OBTAINING CONSENT:______________________________________
ROLE OF STUDY TEAM MEMBER OBTAINING CONSENT: ______________________________________
A.
Date ALL required SIGNATURES (Subject, Witness (If required by IRB) and Person Obtaining 
Consent), their PRINTED NAMES and the DATES they signed the informed consent document (ICD) 
have been Checked and Verified Accurate and appear in the proper location
B.
DATE AND TIME (ICD) WAS REVIEWED AND DEEMED COMPLETE AND VALID
**Must be prior to date/time of Subject’s First Study Activity**
C.
DATE AND TIME OF THE SUBJECT’S FIRST STUDY ACTIVITY OR INVOLVEMENT 
Verify and Initial each requirement below.
1.  
Informed consent and HIPAA Authorization, if required by VA-IRB was obtained from this subject prior 
to study participation.  
2.
A VA Scope of Practice Form has been signed by the PI and approved by the VA IRB which 
designates me as an authorized agent of the PI and qualified to obtain consent for this study. 
3.
This prospective subject was given adequate time necessary to carefully and fully read the Informed 
consent document (ICD) and all questions were answered to his/her satisfaction.  
4.
All aspects of this subject’s study involvement, including the purpose of the study, known and potential 
risks, possible benefits and alternatives to study participation were explained and discussed prior to 
subject signing the ICD. 
5.
If required, a scanned image of the Research Enrollment Note, Consent Form and/or HIPAA 
Authorization will be entered into the subject’s electronic medical record (CPRS).
6.
Subject has been consented using the most recently approved, VA date-stamped version of the 
consent form (VA Form 10-1086) and HIPAA Authorization Form (VA Form 10-0493).  
7.
A copy of the completed and signed, original informed consent document has been issued to this 
subject and the subject was instructed to retain that copy for reference and to ask any and all 
questions that might arise throughout their study involvement.  
8.
The subject has been shown where in the ICD to locate study team phone number(s) and the phone 
number of the VAAAHS IRB Coordinator. The subject has been reminded to call with any questions or 
concerns.  Cathy Kaczmarek @ 734.845.3439
9.
The subject has been informed that participation is entirely voluntary and that they may withdraw their 
participation at any time and for any reason.  
10.
Original ICDs and all copies are printed and issued as single-sided documents and that the original 
signed ICD must be kept in the investigator’s project files on VA property.
11.
Upon completion of the Informed Consent Process, this subject’s name was added to the Master List 
of All Subjects.  [Per revised VHA Handbook 1200.05 (11/12/14) a MLS is no longer required, but a list 
of all enrolled participants is considered good research practice.]
12.
I know I can contact the VAAAHS IRB Coordinator at 734.845.3439 or the Research Compliance 
Officer at 734.845.4013 if I have questions or concerns regarding the consent of this or any individual 
considering study participation.
RESEARCH SUBJECT IDENTIFICATION: (Required information)
 
  
    |     |     |
         /          /        
Last Name
First Name
Mid. Init.
Last-4 SSN      Todays Date  (mm/dd/yy)
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath 
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 1 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
Key Information
WHAT IS THE STUDY ABOUT AND WHY ARE WE DOING IT?
The purpose is to determine whether  giving a 7 to13-day course of Dexamethasone (a steroid), should be usual care 
when we use immunotherapy to treat patients with non-small cell lung cancer (NSCLC). Right now, immunotherapy is 
given without any steroids – or given if patients’ immune systems are too weak. We are trying to see if the 
dexamethasone will improve the body’s immune system, , perhaps allowing future immunotherapy to work better. The 
study is being funded by the Department of Veterans Affairs. 
WHAT DOES THE STUDY INVOLVE AND HOW LONG WILL IT LAST?  
Your participation in this study may last up to 6 years.  
CT scans will be completed as your physician would regularly order them - approximately every 3 months.
Additional research procedures will include:

2 FLT-PET scans at the University of Michigan to determine steroid uptake prior to giving immunotherapy 

Extra tubes of blood at time of routine blood draw to look at correlation of your blood samples, Dexamethasone 
uptake on FLT PET scans, and response to treatment. 

Short course of Dexamethasone (steroid) before your first three immunotherapy infusions.
WHAT ARE KEY REASONS YOU MIGHT CHOOSE TO VOLUNTEER FOR THIS STUDY?
You may choose to volunteer to see if you will respond to immunotherapy again, or if your immunotherapy course will 
work better with the addition of Dexamethasone. It may help your body’s immune system tolerate immunotherapy again 
to treat your lung cancer. 
WHAT ARE KEY REASONS YOU MIGHT CHOOSE NOT TO VOLUNTEER FOR THIS STUDY?
This treatment may not help, and your disease could grow. There have been studies showing that the addition of 
dexamethasone with immunotherapy produced worse outcomes. Dexamethasone may weaken your immune system 
putting you at a higher risk for infections that could make you feel worse. An example is pneumonia.
You may want to try a different treatment to target your cancer, choose palliative, or comfort care.
DO YOU HAVE TO TAKE PART IN THE STUDY?
If you decide to take part in the study, it should be because you understand the risks and potential benefits and would 
like to volunteer. Your participation in this study is voluntary, and you will not lose any services, benefits or rights you 
would normally have if you choose not to volunteer. 
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS OR CONCERNS? The person in charge of the study is Dr. Nithya 
Ramnath of the VA Ann Arbor Healthcare System.  If you have questions, suggestions, or concerns regarding this study 
or you want to withdraw from the study please contact Brittany Pannecouk (study coordinator) at (734) 845-3966. 
RESEARCH SUBJECT IDENTIFICATION: (Required information)
  
    |     |     |
         /          /        
Last Name
First Name
Mid. Init.
Last-4 SSN       Todays Date (mm/dd/yy)
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath 
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 2 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
RESEARCH DETAILS
WHAT IS THE PURPOSE OF THIS STUDY?
You are being asked to join a research study. As you read this form about the study, ask any questions you 
have. Feel free to take this document with you and talk the study over with your family, friends, and doctor 
before you decide. Being in the study is voluntary. You may decide not to join, and you may stop at any time. 
No matter what you decide to do, none of your VA benefits will be affected in any way. When all your questions 
are answered and if you decide to join the study, you will then be asked to sign this form to begin the study. By 
signing this form, it means you understand the study, risks, and you want to join the study. You will be given a 
copy of this consent form. 
You are being asked to join this study because you have Non-Small Cell Lung Cancer (NSCLC). You are 
eligible because you have progressed on an FDA-approved therapy for lung cancer called immunotherapy. 
These therapies help your body’s own immune system fight cancer. Some examples are: pembrolizumab 
(Keytruda), or nivolumab (Opdivo), durvalumab (Imfinzi).  We are trying to find out if giving a strong steroid 
(dexamethasone) for 7-13 days and then stopping it (at least 72 hours before resuming immunotherapy) will 
jump start your immune system to respond to immunotherapy again, perhaps allowing the immunotherapy to 
work better. Our study is based on rigorous laboratory experiments where we have noted such an effect. 
HOW LONG WILL I BE IN THE STUDY?
We plan to enroll up to 39 patients at the VA Ann Arbor Healthcare System. The study will last a total of 6 
years: 1 year of treatment and 5 years of follow up, until withdrawal of consent or death. If you decide you no 
longer want to participate you may withdraw consent at any time.
WHAT WILL HAPPEN AND WHAT CAN I EXPECT IF I TAKE PART IN THIS STUDY?
During this study there will be a screening/baseline period to make sure you are able to  be involved in the 
study. Once we know you are eligible you will begin the treatment phase. If you progress, or no longer want to 
be in the study, we will complete end-of-treatment tests. Once you have finished the end-of-treatment tests, we 
will follow your medical record for survival status. If you decide to withdraw consent, we will not contact you or 
look at your medical record any further, but we will keep the information already collected.
SCREENING / BASELINE: The following will happen within 28 days of enrolling into the study:
1.
You will need to sign consent before any screening procedures.
2.
The following information will be reviewed from your medical record collected during your routine 
standard of care visits:
a.
Review of your medical history, past treatments, medications, vitals, physical exam.
b.
Review of lab results from your routine blood draw.
c.
Review of a routine standard CT scan of the chest, abdomen, and pelvis.
d.
Review of a routine FDG-PET scan.
3.
The following will be completed as research only:
a.
If you have tumor tissue left over from a previous biopsy (archival tissue), the study team will 
request a sample of the tissue to send for research testing. We will be looking at the genes in 
the tissue that control immune response.
b.
An FLT-PET scan will be completed at the University of Michigan with a research blood 
collection (approx. 6 teaspoons).
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath 
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 3 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
c.
Begin steroid, Dexamethasone. How long you will take the steroid will depend on which group 
you are assigned to. 
d.
Undergo a second FLT-PET scan at the University of Michigan with another research blood 
sample collection (approx. 6 teaspoons) the same day you restart your immunotherapy infusion.
Treatment: 
During the treatment phase you will be assigned to one of the below groups. Group assignment depends on 
how the subject before you tolerated the treatment. Each group will have different dexamethasone (steroid) 
tapers. This will happen before your 1st, 2nd, and 3rd infusions only. You will be given a drug diary, so you 
know when to start, stop, and how much steroid to take daily, depending on which group you are in. 
Group 1: Dexamethasone 4mg twice a day for 7 days, 
2mg twice a day for 2 days, 
1mg twice a day for 1 day, 
3 days off steroid,
Immunotherapy infusion
Group 2: Dexamethasone 4mg twice a day for 10 days,
2mg twice a day for 2 days,
1mg twice a day for 1 day,
3 days off steroid,
Immunotherapy infusion
Group 3: Dexamethasone 4mg twice a day for 13 days,
2mg twice a day for 2 days,
1mg twice a day for 1 day,
3 days off steroid,
Immunotherapy infusion
Research blood samples (approx. 6 teaspoons) will be taken at the same time as your routine labs before your 
1st, 2nd, and 3rd infusions. These samples will have all our personal identifiers removed and a special code 
will be given to them. The samples will then be delivered to Karmanos Cancer Institute (Dr. Ratnam’s 
laboratory) at Wayne State University to look and see if there are any markers that could cause activation of 
your cancer. We are sending your samples outside of the VA because they have a specific machine to be able 
to analyze your samples that we do not have here at the VA.  
Your immunotherapy infusion will be given every 3 weeks (21 days) or every 4 weeks (28 days). The infusion 
runs over 30 minutes, but you can expect your appointment to be at least 1 hour to account for time to put in 
the IV for the infusion and to disconnect you after the infusion is done. These infusions can be given for up to 1 
year. 
As part of routine care the study team will do the following:

Collect your clinical information from your medical record such as lab values, scan results, medications, 
adverse events, and any toxicities. 

You will have routine CT scans about every 12 weeks (3 months) to see how you are responding to 
treatment.
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath 
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 4 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
For the research portion study

Your information will be given a unique study code and entered in VA Redcap. This is a password 
protected database behind the VA firewall.
End of Treatment / Follow Up
If you stop getting immunotherapy for any reason, you will then enter follow up. The study team will review your 
medical record or call you every 6 months for 5 years to see if you started any new treatments and check your 
survival status. 
Risks of Immunotherapy (pembrolizumab, durvalumab, nivolumab): The pharmacist will discuss the risks 
with you and will give you an information sheet. Below are some side effects. This is routine clinical care and 
not research:
Most Common: at least 1 out of 10 people may experience the following

Inflammation of organs (Hepatitis, 
pancreatitis, esophagitis, etc.)

Rash

Shortness of breath

Chest Pain, pressure, or fast heartbeat

Unexplained bruising or bleeding

Change in eyesight

Very bad joint and/or muscle pain

Weakness

Dizziness

Fever or chills

Flushing

Excessive sweating

Burning, numbness or tingling 

White patches on skin

Loose Stools (diarrhea)

Change in taste

Not able to sleep
Least Common: at least 1 out of 100 people may experience the following

Pyrexia

Cough

Increased liver enzymes

Low red blood cell count (anemia)

Increased creatinine

Hypoglycemia

Headache

Neuropathy

Weight loss

Nausea

Vomiting
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 5 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
Risks of Dexamethasone (Steroid) – This drug is given as research
Most Common: at least 1 out 10 people may experience the following

Increased appetite

Swelling of face, fingers, hands, feet, or lower legs

Weight gain

Agitation

Anxiety

Headache

Nervousness

Nausea

Vomiting

Abdominal Pain

Diarrhea

Acne

Mood changes

Increased thirst
Least Common: at least 1 out of 100 people may experience the following

Signs of infection

Bone/joint pain

Irregular heartbeat

Eye pain/pressure

Heartburn

Black stools

Puffy face

Swelling of ankles/feet

Pain/redness/swelling of arms and legs

Tiredness
Blood drawing
There may be some discomfort, bruising, or bleeding at the site where the blood is drawn. Rarely, fainting 
occurs because of drawing blood.
FLT-PET Scan
The research FLT PET exposes you to small amounts of radiation because of the radiotracer and scanner that 
is used. We do everything we can to make sure it is the least amount of radiation possible. You could also 
experience some claustrophobia because the scanner is small. The total radiation that is involved for both 
scans is 21.7 mSv which is equivalent to 7 years of natural background radiation that you are exposed to in 
your everyday life.
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 6 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
Confidentiality Risk
There is also a risk of a breach of confidentiality. VA Approved research staff assigned to this study will be 
looking at your medical record for data collection. The University of Michigan will be doing the PET scan and 
drawing extra blood, which could cause a breach. To protect your confidentiality, you will be given a unique 
code to link you to the research data collected from your medical record. Your personal information will be 
removed from the blood samples that are sent to Wayne State and will only be labeled with your unique code, 
date of draw and time of draw.
Women of Childbearing Potential
The safe use of immunotherapy in pregnant women and nursing mothers has not been established. 
Consequently, there may be risks to you (or to your embryo or fetus) if you are or may become pregnant that 
are unknown. Women of childbearing potential enrolling in this study must (i) have been using a birth control 
measure (an intrauterine device (IUD), birth control pills, a condom, diaphragm, or abstinence) for the previous 
three months, (ii) must have a negative pregnancy test, and (iii) must agree to continue to use a birth control 
measure for the duration of the study. If, while participating in the study, you suspect you have become 
pregnant, please contact the study physician immediately. Women are of childbearing potential unless they 
have been surgically sterilized (for example tubal ligation or hysterectomy) or are post-menopausal, that is, no 
menstrual period for more than 6 months. Nursing mothers may not participate in this study.
WHAT ARE THE POSSIBLE BENEFITS OF THIS STUDY?
We do not know if you will get any benefits from taking part in this research study.  However, there is a 
possible benefit of you re-responding to immunotherapy to treat your cancer.  
The information we get from this study might help others with your same condition if we see subjects re-
respond to immunotherapy treatments with the addition of the steroids.  
WHAT OTHER CHOICES DO I HAVE IF I DO NOT WANT TO JOIN THIS STUDY?
You may choose not to participate in this study.  If this is your decision, depending on the extent of your 
disease there may be other cancer treatments available that you haven’t tried yet. You may also choose to be 
seen by palliative care, or choose hospice help as well.
 
You may discuss these options with your doctor. 
HOW WILL MY PRIVATE INFORMATION BE PROTECTED?
Your personal information will be removed from the data we collect from your medical record and blood 
samples. You will be assigned a unique code to link you to your samples and research record. Only the 
research staff will know this link. This information will be kept on a secure drive located on the VA server. We 
will enter your coded data into a database that is password protected, behind the VA firewall. Your information 
and samples collected as part of the research, will not be used or distributed for future research studies.
We will include information about your study participation in your medical record.
While this study is being conducted, you will not have access to your research related health records.
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 7 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
This will not affect your VA healthcare including your doctor's ability to see your records as part of your normal 
care and will not affect your right to have access to the research records after the study is completed.
If results of this study are reported in medical journals or at meetings, you will not be identified by name, by 
recognizable photograph, or by any other means without your specific consent. 
No information by which you can be identified will be released or published unless required by law.
We will let you and your physician know of any important discoveries made during this study which may affect 
you, your condition, or your willingness to participate in this study.
Federal Oversight agencies and offices may have access to your records.
Health Information Portability and Accountability Act (HIPAA)
There are rules to protect your private health information. Federal and state laws and the federal medical law, 
known as the HIPAA Privacy Rule, also protect your privacy. By signing this form, you provide your permission 
called your ‘authorization,’ for the use and disclosure of information protected by the HIPAA Privacy Rule.
Dr. Ramnath (Principal Investigator) and her Study Team study will collect information about you. This includes 
things learned from the procedures described in this consent form. They may also collect other information 
including your name, address, date of birth, and information from your medical records such as medical 
history, past treatments, lab results, scan results. Your unique study code and medical information will be 
shared with Wayne State, but no personal identifiers will be shared with them. The university of Michigan will 
be given personal information, so they can arrange for the PET scan to be done.
The research team may also need to disclose your health information and the information it collects to others 
as part of the study progress. Others may include the VA Clinical Science Research & Development (CSR&D); 
the VA Clinical Science Research & Development Data Monitoring Committee (DMC); Institutional Review 
Board and local Research & Development Committee, Office of Human Research Protections (OHRP), the VA 
Office of Research Oversight (ORO). This study is being funded by a VA merit grant.
Your health information disclosed pursuant to this authorization may no longer be protected by Federal 
laws or regulations and may be subject to re-disclosure by the recipient. 
You can revoke this authorization, in writing, at any time.  To revoke your authorization, you must write to the 
Principal Investigator of this study or you can ask a member of the research team to give you a form to revoke 
the authorization.  Your request will be valid when the Principal Investigator receives it.  If you revoke this 
authorization, you will not be able to continue to participate in the study.  This will not affect your rights as a 
VHA patient to treatment or benefit outside of the study.  If you revoke this authorization, Dr. Nithya Ramnath 
and her research team can continue to use information about you that was collected before receipt of the 
revocation. The research team will not collect information about you after you revoke the authorization.
Treatment, payment or enrollment/eligibility for benefits cannot be conditioned on you signing this 
authorization.  This authorization will expire at the end of the research study unless revoked prior to that 
time.
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 8 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
WHAT ARE THE COSTS TO ME IF I TAKE PART IN THIS STUDY?
You will not be charged for any treatments or procedures that are part of this study.  If you usually pay co-
payments for VA care and medications, you will still pay these co-payments for VA care and medications that 
are not part of this study.  
WILL I BE REIMBURSED FOR MY PARTICIPATION? 
You will be given $25 each time you go to the University of Michigan for the FLT-PET Scan, or $50 total for the 
two scans needed for the study.  This is to help offset the cost of parking and to help with meals or gas. This 
payment will be given in the form of a check or electronic transfer of funds (EFT) directly into your account that 
is set up with the VA if you have one – you can tell us which payment method you prefer.
WHAT WILL HAPPEN IF I AM INJURED BECAUSE OF MY BEING IN THE STUDY?
If you become injured because of the study, the VA will provide treatment for research related injury in 
accordance with applicable federal regulations (38 CFR 17.85). However, there will be no compensation 
should you be injured while on study.   
If you should have a medical concern or get hurt or sick because of taking part in this study, call: 
DURING THE DAY:
Ms. Brittany Pannecouk at (734) 845-3966 and 
AFTER HOURS:
Call the VA Operator at (734) 769-7100 or (800) 361-7387 and ask then to page the on-call 
Hematology/Oncology doctor.                                  
Emergency and ongoing medical treatment will be provided as needed.  
DO I HAVE TO TAKE PART IN THE STUDY?
Study participation is voluntary. If you do not want to take part in the study, there will be no penalty or loss of 
benefits that you are entitled to. You may withdraw at any time and still receive the same routine care that you 
would otherwise have received. 
Data already collected prior to the withdrawal, will be reviewed for the study but we will not collect further 
information, except from public records, such as survival data.  Specimens already collected cannot be 
withdrawn.
RIGHT OF INVESTIGATOR TO TERMINATE MY PARTICIPATION 
The investigator may take you off study if you are not tolerating the treatment, have progressed, or feel it is no 
longer in your best interest. If you do come off study for any of those reasons, we would like to follow your 
medical record for new treatments and survival status.
WHO DO I CONTACT ABOUT THIS STUDY IF I HAVE QUESTIONS?
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020


Department of Veterans Affairs
Research Consent Form
Title of Study: 
Induction of Senescence using Dexamethasone to Re-sensitize Non-Small Cell Lung 
Cancer (NSCLC) to Anti-PD1 Therapy
Principal Investigator:
Dr. Nithya Ramnath
VAMC:  VA Ann Arbor 
   Healthcare System
VA Form 10-1086
Page 9 of 9
[VALID ONLY WITH CURRENT VA IRB DATE STICKER]    
If you have any questions, complaints, or concerns about the research or related matters you may contact any 
of the below individuals
Dr. Ramnath, Principal Investigator, (734) 845-5800
Brittany Pannecouk, Study Coordinator, (734) 845-3966
Dr. Kemp Cease Co-Investigator (734) 845-5800
Dr. Paul Swiecicki Co-Investigator (734) 845-5800  
If you have questions about your rights as a study participant, or you want to make sure this is a valid VA 
study, you may contact the Institutional Review Board (IRB). This is the Board that is responsible for 
overseeing the safety of human participants in this study.  You may call the IRB Coordinators at (734) 845-
3440 if you have questions, complaints or concerns about the study or if you would like to obtain information or 
offer input.  
WILL I BE TOLD NEW INFORMATION ABOUT THIS STUDY?
You will be notified of any new findings developed during the research study that may affect your willingness to 
continue participation. 
Any clinically relevant research results will be disclosed to you by study staff either over the phone or at your 
next clinic visit. 
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY
Dr./Mr./Ms.___________________________ has explained the research study to me.  I have been told of the 
risks or discomforts and possible benefits of the study. I have been told of other choices of treatment available 
to me.  I have been given the chance to ask questions and obtain answers.  
By signing this document below, I voluntarily consent to participate in this and authorize the use and disclosure 
of my health information for this study.  I also confirm that I have read this consent, or it has been read to me.  I 
will receive a copy of this consent after I sign it.
I agree to participate in this research study as has been explained in this document.
_________________________
Participant’s Name (Print)
____________________________
Participant’s Signature
___________
Today’s Date
Person Obtaining Informed Consent
_________________________
Name (Print)
____________________________
Signature
___________
Today’s Date
VAAAHS Research IRB
IRB NUMBER: IRB-2019-1156
IRB APPROVAL DATE: 11/12/2020