Older Non-Small Cell Lung Cancer Patients (>/= 70 Years of Age) Treated With First-Line MK-3475 (Pembrolizumab)+/- Chemotherapy (Oncologist's/Patient's Choice)
Phase: PHASE2
Conditions: Metastatic Lung Adenocarcinoma, Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Adenocarcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: Alliance for Clinical Trials in Oncology

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ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A171901 
OLDER NON-SMALL CELL LUNG CANCER PATIENTS (>/= 70 YEARS OF AGE) TREATED WITH FIRST-
LINE MK-3475 (PEMBROLIZUMAB) +/- CHEMOTHERAPY (ONCOLOGIST’S/PATIENT’S CHOICE) 
Commercial agent: Pembrolizumab; IND: Exempt 
ClinicalTrials.gov Identifier: NCT04533451 
 
Study Chair 
Cancer in the Older Adult Committee 
Chair 
Study Co-chair 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
Community Oncology Co-chair 
Correlative Study Co-chair 
 
 
 
  
 
 
 
 
 
Pharmacogenomics and Population 
Pharmacology Co-chair 
Respiratory Committee Chair 
 
 
 
 
  
 
 
Cancer in the Older Adult Co-chair  
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
 
 
 
 
 
 
 
Data Manager 
Protocol Coordinator  
 
  
  
  
 
 
 
Participating Organizations:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN/ECOG-ACRIN Cancer Research 
Group, NRG/NRG Oncology, SWOG/SWOG  

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Study Resources: 
Expedited Adverse Event Reporting 
 
Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
Biospecimen Management System 
 
 
Protocol Contacts: 
 
A171901 Nursing Contact 
  
 
  
 
 
A171901 Pharmacy Contact 
 
  
   
 
Biospecimens Accessioning and Processing 
(BAP) 
 
 
       
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
appropriate Alliance Biorepository  
Questions regarding drug administration 
Pharmacy Contact 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
 
to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
 for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website 
Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
 
Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on 
the protocol-specific page on the CTSU website) and submitting it as instructed on the form. 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 

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Older Non-Small Cell Lung Cancer Patients (>/= 70 Years of Age) Treated with First-Line MK-
3475 (pembrolizumab) +/- Chemotherapy (Oncologist’s/Patient’s Choice) 
Eligibility Criteria (see Section 3.2) 
Required Initial Laboratory Values (See § 3.2.8) 
• Histologic or cytologic diagnosis of non-small cell lung 
cancer (adenocarcinoma). Stage IV or recurrent 
metastatic non-small cell lung cancer. (See §3.2.1.) 
ANC ≥ 1500/mm3 (1.5 x 109/L 
• Planning to begin MK-3475 (pembrolizumab) treatment 
within 14 days of registration, with or without 
combination chemotherapy. (See §3.2.2) Patients with 
autoimmune disorder, post-organ transplantation, or are 
receiving ongoing immunosuppression treatment are 
ineligible (See §3.2.3) . 
Platelet count: 
Calculated creatinine 
clearance: 
≥ 100,000/mm3 (100x 109/L) 
≥ 30 ml/min* for patients 
enrolled to pembrolizumab 
alone and > 45 ml/min for 
patients enrolled to 
chemotherapy + pembrolizumab 
• Prior adjuvant therapy is allowed and must have been 
completed at least 6 months prior to registration. (See 
§3.2.4) 
• No planned radiation or other cancer treatment in the 3 
months following registration (See §3.2.5) 
Total bilirubin 
 
AST and/or ALT 
≤ 1.5 ULN (< 3 ULN if 
Gilbert’s disease) 
≤ 3 x ULN (≤ 5.0 x ULN if liver 
metastases present) 
• No untreated brain metastases. Patients must be off oral 
and IV corticosteroids and asymptomatic at registration. 
(See §3.2.6) 
Alkaline phosphatase ≤ 2.5 x ULN (≤5 x ULN if bone 
or liver metastases present) 
• 
Age ≥70 years of age. (See §3.2.7) 
*Calculated using the Cockcroft-Gault formula 
• Language: Patients must be able to read and comprehend 
English (See §3.2.9) 
  
 
Schema 
1 cycle = 21 days or 42 days (for patients who are on every 6 week cycle)  
R  
 
Treating physician/patient’s choice of: 
single agent MK-3475 (pembrolizumab) 
 
OR 
 
MK-3475 (pembrolizumab) + 
carboplatin + pemetrexed 
E  
G  
I 
 
S  
T  
E  
R  
 
Pembrolizumab treatment is to continue until disease progression (treating physician’s discretion) or 
unacceptable adverse event.  Patients will be followed for survival for 5 years after registration or until 
death, whichever comes first. 
 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 
Site staff who intend to administer the comprehensive geriatric assessment must complete the geriatric 
assessment training. (See Section 15.0) 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the credited 
Group may apply. 
 

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Table of Contents 
 
1.0 
BACKGROUND .................................................................................................................................... 7 
1.1 
Rationale and need for current trial ............................................................................................. 7 
1.2 
Lack of Adverse event data in checkpoint inhibitors .................................................................. 7 
1.3 
MK-3475 (pembrolizumab) adverse events ................................................................................ 9 
1.4 
Notable Aspects of the Proposed Trial Design ......................................................................... 11 
1.5 
Impact on standard of care and future clinical trials ................................................................. 11 
2.0 
OBJECTIVES ..................................................................................................................................... 12 
2.1 
Primary objective ...................................................................................................................... 12 
2.2 
Secondary objectives ................................................................................................................. 12 
2.3 
Exploratory objectives............................................................................................................... 12 
2.4 
Correlative science objectives ................................................................................................... 12 
3.0 
PATIENT SELECTION ....................................................................................................................... 13 
3.1 
On-Study Guidelines ................................................................................................................. 13 
3.2 
Eligibility Criteria ..................................................................................................................... 14 
4.0 
PATIENT REGISTRATION ................................................................................................................. 16 
4.1 
Investigator and Research Associate Registration with CTEP.................................................. 16 
4.2 
Cancer Trials Support Unit Registration Procedures ................................................................ 17 
4.3 
Patient Registration Requirements ............................................................................................ 19 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) ....................................... 20 
4.5 
Registration to Correlative and Companion Studies ................................................................. 22 
4.6 
Stratification Factors and Treatment Assignments ................................................................... 22 
5.0 
STUDY CALENDAR ........................................................................................................................... 23 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................................. 24 
6.1 
Data Collection and Submission ............................................................................................... 24 
6.2 
Specimen collection and submission ......................................................................................... 26 
6.3 
Submission of Patient Completed Measures ............................................................................. 27 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................................ 28 
7.1 
MK-3475 (pembrolizumab) ...................................................................................................... 29 
7.2 
Pemetrexed ................................................................................................................................ 29 
7.3 
Carboplatin ................................................................................................................................ 29 
8.0 
DOSE AND TREATMENT MODIFICATIONS ...................................................................................... 29 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ....................................... 29 
8.2 
Dose Modifications ................................................................................................................... 30 
9.0 
ADVERSE EVENTS ............................................................................................................................ 31 
9.1 
Routine Adverse Event Reporting ............................................................................................. 31 
9.2 
CTCAE Routine Reporting Requirements ................................................................................ 32 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) ................................................................ 32 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for MK-3475 
(pembrolizumab, NSC 776864) ................................................................................................ 36 
10.0 DRUG INFORMATION ....................................................................................................................... 42 
10.1 
MK-3475 (pembrolizumab) (Keytruda®) ................................................................................. 42 
10.2 
Pemetrexed (Alimta) ................................................................................................................. 44 
10.3 
Carboplatin (Paraplatin®, CBDCA) ......................................................................................... 46 

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11.0 MEASUREMENT OF EFFECT ............................................................................................................ 49 
11.1 
Patient reported outcome measures ........................................................................................... 49 
12.0 END OF TREATMENT/INTERVENTION ............................................................................................. 50 
12.1 
Duration of Protocol Treatment ................................................................................................ 50 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention .............................................. 50 
12.3 
Follow-up .................................................................................................................................. 50 
12.4 
Extraordinary Medical Circumstances ...................................................................................... 50 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention 51 
13.0 STATISTICAL CONSIDERATIONS ..................................................................................................... 52 
13.1 
Study design .............................................................................................................................. 52 
13.2 
Sample Size, Accrual Time and Study Duration ....................................................................... 52 
13.3 
Primary Study Observation ....................................................................................................... 52 
13.4 
Power Justification and Primary Analysis................................................................................. 52 
13.5 
Analysis Plans for Secondary, Exploratory Objectives ............................................................. 53 
13.6 
Study Monitoring (reports, summaries) .................................................................................... 55 
13.7 
Adverse Event Stopping Rule ................................................................................................... 55 
13.8 
Feasibility .................................................................................................................................. 55 
13.9 
Descriptive Factors .................................................................................................................... 55 
13.10 Inclusion of Women and Minorities .......................................................................................... 56 
14.0 CORRELATIVE AND COMPANION STUDIES .................................................................................... 57 
14.1 
Correlative Science: Using Immune Markers to Track Fatigue in Older Patients who Receive 
Pembrolizumab on Alliance A171901 (Alliance A171901-ST1) ............................................. 57 
14.2 
Pharmacokinetics and Population Pharmacokinetics of Pembrolizumab (Alliance A171901-
PP1) ........................................................................................................................................... 58 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ............................................. 61 
15.1 
Geriatric Assessment Training .................................................................................................. 61 
16.0 REFERENCES .................................................................................................................................... 62 
APPENDIX I: COMPREHENSIVE GERIATRIC ASSESSMENT ...................................................................... 65 
APPENDIX II: MFSI-SF ............................................................................................................................. 85 
APPENDIX III: GODIN LEISURE-TIME EXERCISE QUESTIONNAIRE ....................................................... 86 
APPENDIX IV: LINEAR ANALOGUE SELF-ASSESSMENT (LASA) ........................................................... 87 
APPENDIX V ELECTRONIC PATIENT-REPORTED OUTCOMES (EPRO) INSTRUCTIONS ........................ 89 
APPENDIX VI EPRO INSTRUCTION FLOW CHART FOR PATIENTS .......................................................... 94 
APPENDIX VII PATIENT INFORMATION SHEETS ..................................................................................... 95 
APPENDIX VIII PATIENT CLINICAL TRIAL WALLET CARD .................................................................. 97 
APPENDIX IX PATIENT THANK YOU LETTERS ......................................................................................... 98 
 
 
 
 
 

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1.0 
BACKGROUND 
There is a dearth of data on immunotherapy in older cancer patients. The number of older patients 
with cancer is increasing1. Yet, the optimal treatment for these patients remains understudied. With 
respect to immunotherapy, Marrone and Ford have commented, “Specific efficacy and safety data 
by age in the phase III trials leading to FDA approval of immune checkpoint inhibitors are limited” 
2. In 15 phase 3 studies that led to the approval of anti-PD-1 monotherapy, anti-CLA-4 
monotherapy, or anti-PD-1/CTLA-4 monotherapy, the following observations underscore a lack of 
well-defined, age-based data: 1)  the median age of patients enrolled was uniformly under 65 years; 
2) nearly half of these trials failed to denote the percentage of patients 65 years or older; and 3) of 
those studies where an elderly sub-cohort was identified, that sub-cohort, as alluded to above, 
comprised only a small subset of the total cohort and hence was unrepresentative of older cancer 
patients at large. These observations point to the need to ascertain whether previous findings with 
immunotherapy are relevant to older cancer patients. 
Further emphasizing this dearth of data and hence the need for prospectively-conducted clinical 
trials in older patients, Elias and others conducted a meta-analysis of PD-1 and PD-L1 inhibitors in 
older adults and reported comparable efficacy between patients who were 65 years of age and older 
and those younger 3.  However, among 53 trials, they noted that only 9 reported hazard ratios based 
on age, and, within this exceedingly small subgroup of trials, the percentage of patients who were 
65 years of age or older was less than 50%.  In contrast to what we propose here, this meta-analysis 
did not examine adverse events.  Importantly, our group has shown that trials specifically designed 
for older patients are far more likely to enroll much older patients – the “oldest of the old,” or 
patients in their 80’s or 90’s  -- than those designed for a more general population of cancer patients 
4, 5.  Thus, there is a clear need to conduct a trial such as the one described here. 
1.1 
Rationale and need for current trial 
The trial proposed here is timely and important because checkpoint inhibitors now define the 
standard of care in non-small cell lung cancer therapeutics. Reck and others randomly assigned 
305 previously-untreated non-small cell lung cancer patients to single agent pembrolizumab 
versus conventional chemotherapy in patients with PD-L1 expression ≥ 50% 6. Pembrolizumab 
patients manifested a median progression-free survival of 10.3 months (95% confidence interval 
(CI): 6.7 to not reached) versus 6.0 months (95% CI, 4.2 to 6.2) (hazard ratio: 0.50; 95% CI, 
0.37 to 0.68; P<0.001). Similarly, in a 123-patient randomized phase 2 trial, Langer and others 
showed that the objective tumor response rate was greater with pembrolizumab in combination 
with carboplatin and pemetrexed versus chemotherapy alone: 55% (95% CI: 42-68) versus 29% 
(CI: 18-41) 7. More recently, in a 616-patient study, Gandhi and others randomly assigned 
patients in a 2:1 ratio to either pembrolizumab plus chemotherapy versus placebo plus 
chemotherapy8.  The former was more beneficial; a median progression-free survival of 8.8 
months (95% CI, 7.6 to 9.2) was observed in the pembrolizumab-combination group and 4.9 
months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease 
progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Pembrolizumab is now often used 
in the first-line setting in patients with metastatic non-squamous non-small cell lung cancer, yet 
the safety profile of this agent in older patients has not been objectively evaluated. 
1.2 
Lack of Adverse event data in checkpoint inhibitors  
Adverse event information on checkpoint inhibitors in older patients is growing but only 
incrementally.  First, with pembrolizumab, data from 3991 patients with melanoma, non-small 
cell lung cancer, head and neck cancer, lymphoma, or urothelial cancer, show that only 16% of 
the cohort was 75 years of age or older 9.  Although subgroup analyses did not show major, age-
based differences in adverse events, this conclusion might not be relevant to most older cancer 
patients, as clinical trials with new agents appear to select for more fit older patients. Thus, one 

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could convincingly argue that further data are necessary to gain greater reassurance of the safety 
of pembrolizumab in older cancer patients.  Second, Betof and others recently reviewed 
retrospective data on 254 melanoma patients who were treated with anti-PD-1/PD-L1 10.  Within 
this group, 57 (22%) were <50 years of age, 85 (34%) between 50-64 years of age, 65 (26%) 
between 65-74 years of age, and 47 (19%) ≥75 years old.  One hundred and ten patients (43%) 
experienced adverse events from immunotherapy with colitis occurring in 25 (10%) and 
endocrine adverse events occurring in 26 (10%). Although this important study concluded that 
overall survival and rates of adverse events did not appear to differ based on age, its retrospective 
study design and relatively small number of older patients invite further investigation of age-
based adverse events with immunotherapy within the context of a prospective study.  Third, 
Grossi and others preliminarily evaluated 70 patients who were 75 years of age or older and all 
of whom participated in an Italian expanded access program for nivolumab, another checkpoint 
inhibitor 11.  These investigators observed that 8 (11%) patients discontinued therapy because of 
adverse events.  However, this older cohort of patients with squamous cell carcinoma was 
relatively small and not representative of a US population 7.  Fourth, Freeman and Weber 
examined data from 148 patients, 52 of whom were older than 65 years of age 12. 
These investigators observed no statistically significant, age-based differences in commonly 
observed adverse event rates such as diarrhea, rash, and vitiligo.  Again, however, numbers were 
small.  Finally, unpublished, pharmaceutical company data from Merck seem to show 
comparable adverse event profiles based on age (Table 1) 13.  However, these clinical trial data 
likely reflect bias, as only the most fit older patients were likely included; and these data are 
generated from a pharmaceutical company.   
Table 1: 
 
1.2.1 
Limitations of previous studies 
In summary, the above 5 studies provide some degree of reassurance of the safety of 
checkpoint inhibitors in older cancer patients. However, these conclusions appear to be 
tentative at best because they 1) are based on either relatively small cohorts or retrospective 
analyses, 2) rely on studies that have included older patients enrolled in age-unspecified 
trials which tend to capture a more fit group of older patients who are likely to generate a 
more acceptable adverse event profile, and 3) were often generated and reported under 
pharmaceutical company sponsorship. Such limitations underscore the importance of 
seeking robust, prospectively-collected data with no potential for bias in older cancer 
patients with the goal of better characterizing the adverse event profile of pembrolizumab 
in older patients. 

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1.3 
MK-3475 (pembrolizumab) adverse events  
With single agent pembrolizumab, < 20% of patients (age not specified) developed severe 
toxicity 14.  As per this drug’s package insert, the following adverse events of all grades occurred 
in > 10% of patients, with numbers in parentheses indicative of the percentage from the entire 
cohort: fatigue (25), rash (24), vitiligo (13), diarrhea (26), nausea (21), pruritus (17), arthralgia 
(18), back pain (12), cough (17), dyspnea (11), decreased appetite (16), headache (14), 
hyperglycemia (45), hypertriglyceridemia (43), hyponatremia (28), increased AST (27), 
hypercholesterolemia (20), anemia (35), and lymphopenia (33). Grade 3+ adverse events 
occurred at the following rates: fatigue (0.9), rash (0.2), arthralgia (0.4), back pain (0.9), dyspnea 
(0.9), decreased appetite (0.5), headache (0.2), hyperglycemia (4.2), hypertriglyceridemia (2.6), 
hyponatremia (4.6), increased AST (2.6), hypercholesterolemia (1.2), anemia (3.8), and 
lymphopenia (7). In view of this diffuse but unusual adverse event profile, here we propose to 
report on these adverse events both in aggregate – in effect, grade 3 or worse -- as well as 
descriptively. 
1.3.1 
Might Older Patients Have Different Adverse Event Outcomes Than Younger 
Patients? 
Although older cancer patients can benefit from cancer treatment, previous work from the 
Alliance for Cancer Clinical Trials in Oncology suggests that older patients manifest more 
frequent and severe adverse events.  These studies that show different, age-based adverse 
event profiles often relied on re-analyses of prospectively-conducted, age-unspecified 
trials; therefore, to reiterate, because presumably more fit older patients were included, 
these analyses likely under-represent the adverse events that are seen in older patients 
treated in a non-study setting.  First, Tallarico and others show that when examining non-
conventional chemotherapy, or biologic therapies, such as rituximab, alemtuzumab, 
lenalidomide, and other similar agents, older patients with chronic lymphocytic leukemia 
suffered more treatment toxicity than younger patients with an odds ratio for grade 3 and 
4 hematologic adverse events of 1.70 (95% CI= (1.57, 1.84); p=0.0089); and for non-
hematologic adverse events 1.47 (95% CI (1.39,1.55); p=0.022) 15.  
Second, similar conclusions were reached with conventional chemotherapy when studying 
older versus younger patients with gastroesophageal cancer or gastric cancer 16. Studying 
367 patients from 8 consecutive, first-line trials that included: i) etoposide + cisplatin; ii) 
5-fluorourucil + leucovorin; iii) 5-fluorouracil + levamisole; iv) irinotecan; v) docetaxel + 
irinotecan; vi) oxaliplatin + capecitabine; vii) docetaxel + capecitabine; and viii) 
bortezomib + paclitaxel + carboplatin, our group reported that 154 patients(42%) were 65 
years of age or older (range: 65-86 years of age),and 213 were younger (range: 20-64 years 
of age). Rates of grade 3 or worse adverse events across all chemotherapy cycles in 
univariate and multivariate analyses (adjusted for gender, performance score, and stratified 
by individual study) were significantly higher among older patients. Rates of neutropenia, 
fatigue, infection, and stomatitis in elderly versus younger patients were 31% versus 29% 
(p=0.02 by multivariate analyses), 15% versus 5% (p=0.01), 9% versus 4% (p=0.03), and 
6% versus 1% (p=0.04), respectively, although duration of chemotherapy, overall survival, 
and progression-free survival were comparable.  
Finally, disparities in adverse event rates in older patients are also relevant to those who 
receive radiation 17.  Our group analyzed data from a 263-patient phase III trial that 
examined etoposide and cisplatin plus either twice-daily radiotherapy or once-daily 
radiotherapy in patients with limited-stage small cell lung carcinoma. No difference in 
survival was observed between the 54 patients (21%) who were older than 70 years of age 
and the 209 (79%) younger patients.  However, notably, grade 4 or worse pneumonitis 

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occurred in 6% of older patients but in none of the younger patients (P = 0.008).  Similarly, 
death occurred in 3 of 54 (5.6%) older patients and in 1 of 209 (0.5%) younger patients (P 
= 0.03).  All these findings underscore the point that older patients manifest worse toxicity 
profiles with cancer treatment and that focusing on adverse events in older cancer patients 
is important. 
1.3.2 
Comprehensive Geriatric Assessment  
The comprehensive geriatric assessment (CGA) embraces the domains of functional status, 
comorbid medical conditions, cognition, nutritional assessment, psychosocial status, and 
social support; these domains are logically important in the care of older patients with 
cancer.  Of note, the incorporation of the CGA into a multi-site cancer clinical trial is 
feasible, as Hurria and others have demonstrated 18,19,20,21:  the mean time to completion is 
27 minutes (standard deviation = 10 minutes; range = 8 to 45 minutes) with most patients’ 
(87%) completing the self-administered section independently.  In a 15-site, 95-patient (85 
were assessable), study, CALGB 360401 showed 100% of patients completed their portion 
of the GA, 87% completed it without assistance, the time to complete the testing was 15 
minutes for patients, and 5 minutes for healthcare providers with 92% of patients being 
satisfied with the length of the questionnaire.  Moreover, among older chemotherapy-
treated cancer patients, the CGA was able to predict risk of toxicity.  Such risk increased 
with an increasing risk score, as derived from the CGA:  36.7% low, 62.4% medium, 70.2% 
high risk; P < .001.  These data point out the importance of incorporating the CGA as 
therapeutic decisions are made among older cancer patients who are potential candidates 
for chemotherapy.  However and importantly, these data also underscore the fact that 
similar validated data are not available for older patients who are considered candidates for 
checkpoint inhibitors, such as pembrolizumab.  Here we propose for the first time to begin 
to evaluate whether or not the CGA-based risk score developed for chemotherapy is also 
predictive of toxicities for older immunotherapy candidates.  If the previously developed 
CGA-based risk score does not appear to predict toxicities in older patients treated with 
immunotherapy, we will use the CGA data collected here to develop a risk score for older 
immunotherapy candidates and will plan a future study to validate the newly developed 
risk score. 
1.3.3 
Identifying a Subset of Tumor-Reactive CD8+T Cells in Peripheral Blood, Their 
Relationship to Fatigue, and CX3CR1 Subsets as a Mechanism-Based Explanation 
of MK-3475 (pembrolizumab)-Induced Fatigue 
Because fatigue is one of the most common adverse events with pembrolizumab (see 
above) and occurs in at least 25% of patients who receive this drug, we have chosen to 
further explore rates and mechanisms of this prevalent symptom in this proposal 22,23.  In 
an earlier publication within Nature, Dong and others from the Mayo Clinic described their 
discovery of PD-L1, the target for agents such as pembrolizumab.  These investigators 
continue to characterize mechanisms of tumor resistance to checkpoint inhibitors as well 
as biomarkers that might serve as predictors of tumor response 24,25.  These investigators 
recently observed that a subset of tumor-reactive CD8+ effector T cells, which express 
CX3CR1, proliferate in patients who respond to pembrolizumab 24,25.  Surprisingly, these 
CX3CR1 effector CD8+ T cells are maintained – and at times even increased -- with the 
addition of chemotherapy. Interestingly, although Dong and others did not specifically 
focus on fatigue, their observations on this subset of CD8+ T cells correlate with the 
patterns of fatigue observed with pembrolizumab therapy, and, from a plausibility 
standpoint, the proliferation of CX3CR1 effector CD8+ T cells is an energy-consuming 
process.   

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Moreover, Pereira and others have shown that exercise appears to result in a decline in 
CX3CR1-expressing CD8+Tcells, a finding that adds credence to our hypothesis that 
fatigue might be immunologically-mediated in this group of patients 26.  Based on these 
observations and the clinical, correlative patterns of fatigue over time and with the addition 
of chemotherapy, we hypothesize -- in this highly exploratory aim -- that this proliferation 
of CX3CR1-expressing CD8+ effector T cell subset results in severe, clinical fatigue.  To 
test this hypothesis, we will obtain peripheral blood and examine whether increasing 
numbers and percentages of CD8+ T cells that express CX3CR1are associated with worse 
fatigue scores at baseline and at 3 weeks for a total of 3 chemotherapy cycles 
(approximately 9 weeks).  This approach could provide insight into mechanisms 
underlying pembrolizumab-induced fatigue and could hence potentially give rise to the 
testing of other interventions at a later date, perhaps exercise-based, to palliate this 
prevalent symptom.  
1.4 
Notable Aspects of the Proposed Trial Design 
First, although this proposal focuses on first-line patients with metastatic non-small cell lung 
cancer, this work has broad implications for patients with various other cancer types and for 
those on other checkpoint inhibitors.  Checkpoint inhibitors are currently being used widely, 
and their use is expected to expand further 27,28,29,30,31,32.  The current study will likely provide 
important information and precedent that goes well beyond one drug for one cancer indication. 
Second, as shown by Langer and others, in patients with non-small cell lung cancer, 
administering a combination of pembrolizumab and chemotherapy is a reasonable approach 7. 
Therefore, in the current trial, we will allow patients to receive either single agent 
pembrolizumab or combination therapy with an anticipated 1:1 ratio, and we will report adverse 
events rates based on whether patients had received chemotherapy or not.  We acknowledge that 
in older cancer patients, pembrolizumab as a single agent might be perceived as a better 
option because of its favorable adverse event profile and recognize the importance of enabling 
patients and oncologists to have the latitude of monotherapy versus combination pembrolizumab 
with chemotherapy  7,8.  
This unrestricted study design element is considered a major advantage, as it enables us to 
acquire information on a particularly vulnerable group of older patients who are deemed poor 
candidates for chemotherapy by their oncologist.  Third, using a pragmatic approach, we will 
allow oncologists latitude with respect to chemotherapy dose reductions at trial initiation and 
over time.  This approach has clear precedent in other studies that have examined chemotherapy 
in older cancer patients 33.  Finally, we have incorporated into our trial design several measures 
to liberalize recruitment of older patients and thereby enroll a more population-based, 
representative group of older patients; these measures include 1) liberalization of dosing; 2) 
elimination of performance score in the eligibility.  These measures are designed to allow for a 
truly representative group of older non-small cell lung cancer patients.  
In summary, this trial addresses the adverse event profile of MK-3475 (pembrolizumab) in older 
lung cancer patients within the context of a non-pharmaceutical-sponsored study design.  It also 
includes other study design elements – a trial design for older patients and the option of up front 
chemotherapy dose reductions, all of which are conducive to the enrollment of a group of 
patients who are more representative of those in the general non-small cell, older lung cancer 
population.    
1.5 
Impact on standard of care and future clinical trials  
The information gleaned from the conduct of this trial will be essential as oncologists across the 
United States engage in informative discussions with older patients – in effect, the majority of 
those patients with lung cancer – as they together make decisions on whether or not to start 

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systemic cancer therapy.  In essence, the information derived from this trial would have a direct 
clinical impact.  Adverse event data obtained from this study would enable healthcare providers 
to counsel older patients appropriately and relevantly on what to expect when receiving these 
treatment regimens.  In addition, were we to observe high rates of a specific and severe adverse 
event within an older group of patients, we would be well-positioned to consider the 
development of symptom intervention trials aimed at mitigating such drug-induced toxicity in 
older cancer patients.   
2.0 
OBJECTIVES 
2.1 
Primary objective  
To estimate the adverse event profile of MK-3475 (pembrolizumab) over the first six months of 
treatment, in non-small cell lung cancer patients who are 70 years of age or older and who are 
treated with MK-3475 (pembrolizumab) +/- chemotherapy in a first-line setting.  
2.2 
Secondary objectives 
2.2.1 
To estimate overall survival. 
2.2.2 
To describe patient quality of life during the treatment using the Linear Analogue Self-
Assessment (LASA) questionnaire. 
2.2.3 
To explore whether Comprehensive Geriatric Assessment (CGA) -derived risk score is 
able to predict rates of severe adverse events in older cancer patients who receive MK-
3475 (pembrolizumab) or MK-3475 (pembrolizumab) + chemotherapy.   
2.3 
Exploratory objectives 
2.3.1 
To disaggregate the adverse events and identify potential causes of individual adverse 
events.  
2.3.2     To describe patient fatigue level as measured with the Multidimensional Fatigue 
Symptom Inventory – Short Form (MFSI-SF); exercise level using the Godin Leisure 
Time Exercise Questionnaire (GLTE); and other symptoms and concerns using the 
LASA questionnaires. 
2.3.3 
To estimate time-to-treatment failure for single-agent MK-3475 (pembrolizumab) and 
MK-3475 (pembrolizumab) + chemotherapy in older patients. 
2.4 
Correlative science objectives 
2.4.1 
To evaluate whether older patients who experience fatigue or other adverse effects would 
be correlated with a change of PD-L1  therapy-responsive T cell subset (i.e. CX3CR1+  
CD11ahighCD8+ T-cells) in their peripheral blood from baseline (prior to therapy) to 
post therapy.  (See Sections 6.2 and 14.1) 
2.4.2 
To determine the extent to which MK-3475 (pembrolizumab) demonstrates time 
dependent decrease in clearance in older adult patients (aged ≥ 70 years) with non-small 
cell lung cancer being treated with pembrolizumab monotherapy or in combination with 
cytotoxic chemotherapy. (See Sections 6.2 and 14.2) 
2.4.3 
To determine the intrapatient and interpatient variability in clearance in older adult (≥ 70 
years) patients with non-small cell lung cancer receiving pembrolizumab monotherapy 
and when combined with cytotoxic chemotherapy. (See Sections 6.2 and 14.2) 
2.4.4 
To preliminarily explore the correlation between pembrolizumab exposure (AUC) with 
observed immune related toxicities in this older adult (aged ≥70 years) patient population 

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receiving pembrolizumab monotherapy and when combined with cytotoxic 
chemotherapy. (See Sections 6.2 and 14.2) 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled 
diabetes mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥ 3 years. 
• 
No other concomitant medical or psychiatric condition that the treating oncologist 
believes would interfere with monitoring the patient while on study. 
 
 

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3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following pages. 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 3.2.1 
Documentation of Disease: Histologic or cytologic diagnosis of non-small cell 
lung cancer (adenocarcinoma).  Stage IV or recurrent metastatic non-small cell lung 
cancer. No planned initiation of definitive (potentially curative) concurrent chemo-radiation. 
___ 3.2.2 
Planning to begin MK-3475 (pembrolizumab) treatment within 14 days of 
registration, with or without combination chemotherapy.  
Treating physician considers pembrolizumab as appropriate and plans to proceed with one 
of the following treatment schedules: 
(a) MK-3475 (pembrolizumab) 200 mg IV flat dose every 21 days or 400 mg IV flat dose 
every 42 days.  
(b) MK-3475 (pembrolizumab) 200 mg IV/ 400 mg IV + carboplatin AUC=5 + pemetrexed 
500 mg/m2 (20% chemotherapy dose reduction is permitted per the discretion of the 
treating physician).  
___ 3.2.3 
Patients will be ineligible if they are post-organ transplantation or are 
receiving ongoing immunosuppression treatment. Patients will be ineligible if they have 
an active autoimmune disease that has required systemic treatment in past 2 years (i.e., 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Note: Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment. Patients who require inhaled corticosteroids would not be excluded from 
the study. Patients with vitiligo or resolved childhood asthma/atopy would not be excluded 
from the study. Patients who require local steroid injections (for example, a steroid injection 
to a joint) would not be excluded from the study. 
___ 3.2.4 
Prior adjuvant therapy is allowed and must have been completed at least 6 
months prior to registration.  
___ 3.2.5 
No planned radiation or other cancer treatment in the 3 months following 
registration. 
___ 3.2.6 
No untreated brain metastases. Patients must be off oral and IV 
corticosteroids for this condition and asymptomatic at registration. 
___ 3.2.7 
Age ≥ 70 years of age. (See next page, for additional eligibility criteria.) 
 
 

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___ 3.2.8 
Required Initial Laboratory Values:  
Absolute neutrophil count 
(ANC) 
≥ 1500/mm3  (1.5 x 109/L) 
Platelet count: ≥ 100,000/mm3 (100x 109/L) 
Calculated creatinine 
clearance:  
 
 
 
Total bilirubin 
AST and/or ALT 
≥ 30 ml/min* for patients enrolled to 
pembrolizumab alone and > 45 ml/min for 
patients enrolled to chemotherapy + 
pembrolizumab 
≤ 1.5 ULN (< 3 ULN if Gilbert’s disease) 
≤ 3 x ULN (≤ 5.0 x ULN if liver metastases 
present) 
Alkaline phosphatase ≤ 2.5 x ULN (≤5 x ULN if bone or liver 
metastases present) 
* Calculated using the Cockcroft-Gault formula 
___ 3.2.9 
Language: Patients must be able to speak and comprehend English in order to 
complete the mandatory patient-completed measures. 
 

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4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
 In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-
sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 

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• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).  
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
RCR Help Desk by email 
 
4.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
 to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites only) 
on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR 
profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 

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4.2.1 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Protocol specific requirements for A171901 site registration  
Evidence of Geriatric Assessment Training, as described in Section 15.0. At least one site 
staff member must have completed the Geriatric Assessment Training for the site to be 
approved for the study. 
4.2.3 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster. To view/download site registration forms:   
• 
Log in to the CTSU members’ website 
 using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select Alliance, and 
protocol number A171901. 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided. (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU.) 
4.2.4 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 
in order to receive further instruction and 
support. 
4.2.5 
Checking site’s registration status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 

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o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.3 
Patient Registration Requirements 
4.3.1 
Informed consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
4.3.2 
Patient-reported outcomes 
This study includes the use of the mandatory patient completed measures. The measures 
are available in English.  Participation in Alliance A171901 is restricted to patients who 
are able to speak, understand and read English. 
Electronic patient reported outcomes (ePRO): This study includes the use of ePRO, 
(electronic patient-reported outcomes). After the patient is registered to the trial, the CRP 
will complete a second registration to the Patient Cloud. The CRP will create a unique 
patient registration code by accessing the Patient Cloud through iMedidata Rave. Patients 
(with assistance from CRPs) will need to download the Patient Cloud app on their own 
device and use the unique registration code given by the CRP to create an account. Once 
completed, the patient will be able to complete the submission of patient reported outcomes 
electronically. 
Prior to registration, the patient should be asked about the availability of an electronic 
device and willingness to complete the patient-reported questionnaires on the device. See 
Appendix V for further instructions on setting up patient cloud. 
If sites intend to use a shared institutional device, the CRP can assist the patient with access 
and registration to the Patient Cloud app, with the patient completing the electronic data 
submission independently. Detailed instructions are included in Appendix V. If patients 
will be using devices supplied by the institution, CRPs will need to help the patient log into 
the device. 
Patient questionnaire booklets: 
Patient questionnaire booklets are to be ordered prior to the registration of any patients. 
Patient completed booklets can be ordered by downloading and completing the CTSU 
supply request form (located under the site registration documents section of the A171901 
CTSU web site) and submitting the form through the CTSU regulatory portal. Samples of 
the booklets are found in Appendices I-IV, which are to be used for reference and IRB 
submission only. They are not to be used for patient completion.  
Booklets should be offered only to those patients who are not willing and/or are unable to 
use an electronic device for completion of questionnaires. The patient should be informed 
that the same method of completion, that is paper or electronic, should be used by the 
patient throughout the duration of the study for all time points, as much as possible.  

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Geriatric Assessment: Healthcare professional questionnaire: 
This portion of the questionnaire is not included in the patient questionnaire booklets, and 
sites are required to print it from Appendix I and enter the responses in Medidata Rave 
after completion.  
4.3.4 
Protected Health Information 
Samples collected for the pharmacokinetics sub-study A171901-PP1 will be sent directly 
to 
Staff Scientist, Clinical Pharmacology Program at the National Cancer 
Institute at the following address: 
 
 
 
 
 
These samples will be labeled with patient initials, patient study ID and collection 
date/time.  
Protection of data shared with 
  
Once samples are received at the lab, any patient data received will be entered into a secure 
e-database that is encrypted and only accessible by 
authorized 
designees trained in human subjects’ research.  Additionally, the sample tubes themselves 
will be barcoded to be read by a secure e-database, and this also serves to de-identify the 
sample tube itself. 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold the 
OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 

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• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
• 
Site staff have completed the Geriatric Assessment training described in Section 15.0 
Assurance of drug provision:  
As MK-3475 (pembrolizumab) will be used on-label, patients and their treating physicians 
will secure their own supply of the drug. Arrangements with third party insurers, private 
or public, should be made prior to registration. The patient must be willing to pay for the 
balance of the drug’s cost that is not covered by third party insurance. 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
 or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
 For any additional questions, contact the CTSU 
Help Desk at 
 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
 
 

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4.5 
Registration to Correlative and Companion Studies 
4.5.1 
Registration to Substudies described in Section 14.0  
There are 2 required sub studies within Alliance A171901. These substudies do not require 
separate IRB approval. The substudies included within Alliance A171901 are: 
• 
Using Immune Markers to Track Fatigue in Older Patients who Receive 
Pembrolizumab on Alliance A171901, Alliance A171901-ST1 (Section 14.1) 
• 
Pharmacokinetics and Population Pharmacokinetics of Pembrolizumab, Alliance 
A171901-PP1 (Section 14.2) 
All patients should be registered to Alliance A171901-ST1 and A171901-PP1 at the same 
time they are registered to the treatment trial (A171901). Samples should be submitted per 
Section 6.2.   
4.6 
Stratification Factors and Treatment Assignments 
None.  Descriptive factors are listed in Section 13.9.  
 
 
 

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5.0 
STUDY CALENDAR 
Pre-Study Testing Intervals:  The pre-study testing intervals are guidelines only. Laboratory 
and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients 
on this study will be cared for by physicians experienced in the treatment and supportive care of 
patients on this trial.  
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
To be completed ≤ 14 DAYS before registration: All laboratory studies, history and physical and 
baseline adverse event assessment. 
To be completed ≤ 42 DAYS before registration: Any X-ray, scan of any type or ultrasound 
which is utilized for tumor measurement per protocol. 
 
Prior to 
Registration 
Day 1 of each cycle of 
treatment (with or without 
chemotherapy) 
End of Treatment€ 
Tests & Observations 
 
 
 
H&P, height, weight, PS* 
X 
X(1) 
X 
Adverse Event Assessment 
X 
X(1) (2) 
X 
Patient reported measures** 
 
 
 
CGA (Appendix I) 
 
A 
 
MFSI-SF (Appendix II) 
 
B  
X 
GLTE (Appendix III) 
 
B  
X 
LASA (Appendix IV) 
 
B  
X 
Laboratory Studies 
 
 
 
CBC w/ Differential, Platelets 
X 
X(1) 
X 
Serum Creatinine 
X 
X(1) 
X 
Albumin, glucose, AST, ALT, Alk. 
Phos., Bili 
X 
X(1) 
X 
TSH with reflex 
 
X(1) 
X  
Staging 
 
 
 
CT/any other imaging modality 
X 
C 
C 
Mandatory Correlative studies for all patients (A171901-ST1 and A171901-PP1): 
Whole Blood and Serum  
See Section 6.2 for specimen submission instructions 
* 
Height required at baseline only, not at every visit. Survival information is required annually until 5 years following registration. 
See also Section 12.0.  
** 
To be completed using ePRO. See Section 4.3.2 and Appendix V for further instructions. 
1 
Need not be repeated if done ≤ 14 days prior to treatment, for Day 1 of Cycle 1 only. For subsequent cycles, may be done within 
3 days prior to treatment.  
2 
Virtual visits will be allowed for all patients irrespective of treatment schedule. For patients who are on 6 week treatment cycles, 
AE assessments are to occur every 3 weeks by telephone or virtual visits. 
€ 
Within 21 days of last day of treatment.  
A 
Prior to treatment on Day 1 of Cycle 1 only, may be completed any time following consent and registration, prior to treatment  
B 
Every 3 weeks for the first 9 weeks only, for all patients.  To be completed prior to treatment on treatment visits.   
C 
Scanning and its frequency is left to the discretion of the treating physician. 
 

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6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 
Data submission schedule: 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The Data Submission Schedule is also available on the CTSU 
site within the study-specific Case Report Forms folder.  
6.1.2 
Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to 
 for registration types 
and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation email from iMedidata. To accept the invitation, site staff must either click on 
the link in the email or log in to iMedidata via the CTSU members’ website  under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 

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on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at 
or by contacting the CTSU Help Desk at 
   
6.1.3 
Supporting documentation to be submitted to the Alliance 
This study requires supporting documentation for diagnosis. Supporting documentation 
will include pathology and radiology reports and must be submitted at the following time 
points: 
Baseline: Pathology and radiology reports and clinic notes 
All supporting documentation should be de-identified according to institutional standards 
prior to upload into RAVE.  
6.1.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to 
manage unanswered queries and form delinquencies, monitor data quality and 
timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
 

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6.2 
Specimen collection and submission  
For all patients registered to Alliance A171901: The submission of these blood samples for 
review is required for all patients registered to this study. Biomarker and pharmacokinetic 
studies will be performed. All patients who provide their consent to participate in the main study 
will have provided their consent to participate in A171901-ST1 and A171901-PP1.  
Correlative Science Manual (CSM): The Alliance A171901 Correlative Science Manual 
(CSM) contains instructions for specimen collection, processing, and shipping. The manual can 
be found on the study-specific webpage on the Alliance, BioMS, and CTSU websites. Questions 
regarding the CSM should be directed to the contact(s) specified in the manual. 
Rationale and methods for the scientific components of these studies are described in Section 
14.0. For all patients who consent to participate in the main study, blood samples will be 
collected at the following time points for these mandatory sub-studies: 
 
 
Day 1 of Cycles 1, 2 
and 3€  
Day 1 of Cycle 6 
and Cycle 9€  
End of treatment¥ 
Mandatory for all patients registered to A171901; submit the following for 
A171901-ST1 and A171901-PP1 (All samples (except end of treatment) to be 
collected prior to infusion) 
 
Number and volume of tubes to draw 
Whole Blood1 
(EDTA tube) 
3x10 mL * 
 
3x10 mL 
Serum2 
(Red top 
Vacutainer) 
1x5 mL 
1x5 mL 
1x5 mL 
€ 
Day 1 samples for these cycles may be collected within 3 days prior to treatment, as long 
as the exact time and date of collection is recorded on the forms. The exact time and date of 
infusion start and stop (to assess duration of infusion) will be collected in Rave as well. 
¥ 
Within 21 days of last day of treatment (the date of the last infusion). Not required for 
patients who are not scheduled for a visit during this window.  
* 
Day 1 of Cycle 3 sample not required for patients receiving 400 mg pembrolizumab 
every 42 days. 
1 
Whole blood to be used for biomarker analyses described in Section 14.1.(A171901-ST1)  
2 
Serum from whole blood to be used for pharmacokinetic analyses described in Section 
14.2.  (A171901-PP1). Cycle 6 and Cycle 9 samples are required only for patients still 
receiving treatment. If collection of Cycle 9 sample is missed, samples may be collected on 
Day 1 of Cycle 12 instead. Effective with Update 1, serum samples are being sent to 
 
at the National Cancer Institute (NCI). Serum samples for A171901-PP1 at end of 
treatment are only required for patients consented following Update 1 to the study.  
 
 

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6.3 
Submission of Patient Completed Measures 
It is strongly recommended that patients are offered the option of completing the measures using 
ePRO. Paper booklets should be offered only to those patients who are not willing and/or are 
unable to use an electronic device for completion of questionnaires. 
Patient-completed questionnaire booklets for this study are to be ordered prior to the registration 
of any patients (see Section 4.3.2). Samples of questionnaire booklets are available in 
Appendices I-IV for reference and IRB submission only. They are not to be used for patient 
completion. Booklets must be given to patients to complete and patients should be instructed to 
return the booklets to site staff in person and site staff will enter patient responses into Rave. At 
visits in which booklets are to be completed, the booklet should be given to the patient before 
any discussion of the patient’s health status or test results.  
Verbal administration of the measures for visually impaired patients is permitted if the measure 
and verbal administration of the measure is conducted in a language understandable to the 
patients.  
Submission of Completed Booklets: The data from the booklets are to be entered into Medidata 
Rave by site staff. Patients should be instructed to return the booklets by mail or to return the 
booklets at their regularly scheduled clinic visit. Institutions should provide patients with 
sufficient self-addressed stamped envelopes for this purpose. 
Submission of measures completed in the patient cloud app:  The data from the patients’ 
responses are submitted directly from the device into the Rave database. There are no documents 
to audit. The electronic responses are the source documentation. See Appendix V.  
 
 

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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 14 days of registration.  
For questions regarding treatment, please see the study contacts page.  
It is acceptable for protocol treatment doses to be delivered within a +/- 3 day (business days) 
window before and after the protocol-defined date for Day 1 of a new cycle. For example, if the 
treatment due date is a Friday, the window for treatment includes the preceding Tuesday through 
the following Wednesday. In addition, patients are permitted to have a new cycle of 
chemotherapy/protocol treatment delayed up to 7 days for major life events (e.g., serious illness in 
a family member, major holiday, vacation that cannot be rescheduled) without this being considered 
a protocol violation.  Documentation to justify this delay should be provided. 
This study will be an open label Phase II study and will allow for either single agent MK-
3475(pembrolizumab) or the combination of MK-3475 (pembrolizumab) with carboplatin and 
pemetrexed (based on oncologists'/patient’s choice) as first-line therapy for patients with advanced 
non-small cell lung cancer.   
Treatment of single agent pembrolizumab versus combination therapy is based on treating 
physician’s or patient’s choice.  
Agent 
Starting Dose 
Route of 
Administration 
Frequency of 
Administration 
MK-3475 (pembrolizumab) 
200 mg 
Or  
400 mg 
IV 
Once every 21 days 
Or 
Once every 42 days 
OR 
Agent* 
Starting Dose 
Route of 
Administration 
Frequency of 
Administration 
MK-3475 (pembrolizumab) 
200 mg  
Or  
400 mg 
IV 
Once every 21 days 
Or 
Once every 42 days 
Pemetrexed** 
500 mg/m2 
IV 
Once every 21 days 
Carboplatin** 
AUC=5 
IV 
Once every 21 days 
* 
For pemetrexed and carboplatin, oncologists are allowed to start and continue therapy 
with up to a 20% dose reduction based on their discretion (not more than a 20% 
reduction; for example, a 30% dose reduction is not permitted).  Note that after the first 
cycle of chemotherapy, dose reductions are left to the discretion of the treating 
oncologist. 
** 
Patients treated with pemetrexed require folic acid and vitamin B12 supplementation to 
reduce treatment related side effects. The timing of the initiation of folic acid and B12 
administration is left to the discretion of the treating physician but should start no later 
than on the date of chemotherapy administration and is encouraged to start sooner.  
Pembrolizumab treatment (with or without combination chemotherapy) will continue until disease 
progression (disease progression is defined as symptomatic, rapidly progressive disease that 

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requires urgent intervention or occurs with a decline in performance status or is confirmed at 4 to 
6 weeks with repeat imaging) or unacceptable adverse event.  
7.1 
MK-3475 (pembrolizumab) 
MK-3475 (pembrolizumab) will be given as 200 mg administered as an intravenous infusion 
over 30 minutes or according to institutional standards, on Day 1 of every 21 day cycle until 
disease progression or unacceptable toxicity or; 400 mg administered as an intravenous infusion 
over 30 minutes or according to institutional standards, on Day 1 of every 42 day cycle until 
disease progression or unacceptable toxicity.  
It will be administered either as a single agent or with pemetrexed and carboplatin according to 
the treating physician’s discretion.  When administering pembrolizumab in combination with 
chemotherapy, it will be administered prior to chemotherapy. 
7.2 
Pemetrexed 
Pemetrexed will be given as 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of 
every 21-day cycle.  
7.3 
Carboplatin  
Carboplatin will be administered intravenously as per institutional guidelines on Day 1 of every 
21-day cycle. The number of carboplatin cycles is left to the discretion of the treating oncologist. 
Based on KEYNOTE-18934 , we recommend up to four cycles of carboplatin if tolerated. 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other treatment which would be considered treatment 
for the primary neoplasm or impact the primary objective.  As a general rule, 
simultaneous enrollment on any other treatment study, with or without investigational 
agents, is discouraged, although exceptions may be allowed in unusual circumstances by 
the study chair in collaboration with the executive officer and primary statistician. 
This includes any surgical intervention, radiotherapy, cryotherapy, ablation, etc., 
performed on the primary neoplasm. 
8.1.2 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical records. 
8.1.3 
Treatment with hormones or other chemotherapeutic agents may not be 
administered; except for hormones administered for non-disease-related conditions 
(e.g., insulin for diabetes). 
8.1.4 
Antiemetics may be used at the discretion of the attending physician. 
8.1.5 
Diarrhea management is per the discretion of the treating physician. Diarrhea could 
be managed conservatively with medications such as loperamide. 
Patients with severe diarrhea should be assessed for intravenous hydration and correction 
of electrolyte imbalances. 

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8.1.6 
Palliative radiation therapy may not be administered.  Patients who require radiation 
therapy during protocol treatment will be removed from protocol therapy due to disease 
progression. 
8.1.7 
Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology Clinical Practice 
Guideline Update.  J Clin Oncol 33: 3199-3212, 2015 and American Society of Clinical 
Oncology – American Society of Hematology Clinical Practice Guideline Update on the 
Use of Epoetin and Darbepoetin in Adult Patients with Cancer.  J Clin Oncol 28:4996-
5010, 2010. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. 
Filgrastim (G-CSF) tbo-filgrastim, and sargramostim (GM-CSF): Use of Filgrastim (G-
CSF)/pegfilgrastim, tbo-filgrastim and sargramostim (GM-CSF) is permitted at the 
discretion of the treating physician.  
8.1.8 
Hypersensitivity/infusion reactions 
Treat hypersensitivity and infusion reactions to drugs as per institutional standards. 
8.2 
Dose Modifications 
Dose modifications for MK-3475 (pembrolizumab), pemetrexed and carboplatin will be 
according to the current package insert and treating physician’s discretion.   
 
 

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9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using 
the terminology and grading categories defined in the NCI’s Common Terminology Criteria for 
Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
 Attribution to protocol 
treatment for each adverse event must be determined by the investigator and reported on the 
required forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further 
details on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Event Solicited 
Form is used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and every 3 weeks until 
end of treatment.  
CTCAE v5.0 Term 
CTCAE v5.0 System Organ Class 
(SOC) 
Hypothyroidism 
Endocrine Disorders  
Abdominal Pain  
Gastrointestinal disorders 
Diarrhea* 
Gastrointestinal disorders  
Constipation 
Gastrointestinal disorders 
Nausea  
Gastrointestinal disorders 
Vomiting 
Gastrointestinal disorders 
Fatigue 
General disorders and administration 
site conditions  
Neutrophil count decreased Blood and lymphatic system disorders 
Anemia 
Blood and lymphatic system disorders 
Platelet count decreased   
Investigations 
Blood bilirubin increased  
Investigations  
Alanine 
aminotransferase 
increased 
Investigations 
Anorexia  
Metabolism and nutrition disorders  
Arthralgia  
Musculoskeletal and connective tissue 
disorders  

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Cough  
Respiratory, thoracic, and mediastinal 
disorders 
Dyspnea  
Respiratory, thoracic, and mediastinal 
disorders 
Peripheral sensory 
neuropathy 
Nervous system disorders 
Confusion 
Nervous system disorders 
Acute kidney injury  
Renal and urinary disorders 
* 
Diarrhea will not be solicited at baseline, but number of stools per day will be 
collected, in order to assess diarrhea as a solicited adverse event during treatment.  
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) 
Adverse Events: Baseline CRF and Adverse Events CRF - Applies to AEs occurring 
between registration and within 30 days of the patient’s last treatment date.  
b) 
Late Adverse Events CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. The descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5 will be utilized for AE reporting.   
The 
CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  

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Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
9.3.1 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE ≤ 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
• 
Grade 1 
Timeframes 
• 
Grade 2 
Timeframes 
• 
Grade 3 
Timeframes 
• 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 

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• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
9.3.2 
Expedited AE reporting timelines defined 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 
calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
≤ Grade 4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other adverse events that result 
in ≥24-hour hospitalization or prolongation of an existing hospitalization must be reported 
via CTEP-AERS. 
New primary malignancies should be reported in Rave. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 
In CTCAE version 5.0, the new malignancies (both second and secondary) may be reported 

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as one of the following: (1) Leukemia secondary to oncology chemotherapy, (2) 
Myelodysplastic syndrome, (3) Treatment-related secondary malignancy, or (4) 
Neoplasms benign, malignant and unspecified-other. Whenever possible, the CTEP-AERS 
reports for new malignancies should include tumor pathology, history or prior tumors, prior 
treatment/current treatment including duration, any associated risk factors or evidence 
regarding how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor, and new malignancy treatment and outcome, if 
available. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
CTEP-AERS reports should be submitted electronically. 
 
 

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9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for MK-3475 
(pembrolizumab, NSC 776864) 
Revised MK-3475 CAEPR – Version 2.6, July 15, 2021   
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
for 
further clarification. Frequency is provided based on 3793 patients. Below is the CAEPR for 
MK-3475 (pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
       Version 2.6, July 15, 20211 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
 
 
 
 Lymph node pain2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis) 2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypohysitis2 
 
  
 
Hypopituitarism2 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)36 
Hepatobiliary disorders - Other 
(sclerosing cholangitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - Other 
(acute graft-versus-host-disease) 2,3 
  
 
 
Immune system disorders - Other 
(hemophagocytic 
lymphohistiocytosis) 2 
  
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation) 2 
 
  
 
Immune system disorders - Other 
(sarcoidosis) 2 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased2 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase increased2  
  
 
Blood bilirubin increased 
 
  
 
CPK increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  
 
 
Metabolism and nutrition 
disorders - Other (type 1 diabetes 
mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Avascular necrosis2 
 
  
 
Back pain 
 
  
 
Joint effusion2 
 
  
 
Joint range of motion decreased 
 
  
 
Musculoskeletal and connective tissue 
disorder - Other (tenosynovitis) 2 
 
  
 
Myalgia2 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome) 2 
  
 
 
Nervous system disorders - Other 
(neuromyopathy) 2 
  
 
 
Nervous system disorders - Other 
(non-infectious encephalitis) 2 
  
 
 
Nervous system disorders - Other 
(non-infectious meningitis) 2 
  
 
 
Nervous system disorders - Other 
(non-infectious myelitis) 
  
 
 
Nervous system disorders - Other 
(polyneuropathy) 2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis) 2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pleuritic pain2 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Skin and subcutaneous tissue disorders 
- Other (dermatitis) 2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving MK-3475 
(pembrolizumab).  Adverse events potentially related to MK-3475 (pembrolizumab) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse 
reactions were reversible and managed with interruptions of MK-3475 (pembrolizumab), administration 
of corticosteroids and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with MK-3475 (pembrolizumab) 
who received hematopoeitic stem cell transplants. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Myocardial infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 

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EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal 
hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; 
Rectal hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema 
limbs; Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general 
physical health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal 
and urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous 
tissue disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: MK-3475 (pembrolizumab) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 

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10.0 DRUG INFORMATION 
General considerations: All study agents are to be administered at the registering institution. 
10.1 
MK-3475 (pembrolizumab) (Keytruda®) 
Background: Highly selective anti-PD-1 humanized monoclonal antibody which inhibits 
programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block 
PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway inhibits the 
negative immune regulation caused by PD-1 receptor signaling. Anti-PD-1 antibodies reverse 
T-cell suppression and induce antitumor responses. 
IND Exempt: Pembrolizumab is IND exempt as used in this trial. This exemption has been 
determined by attestation that neither the investigator nor sponsor intends to seek a new 
indication for use or to support any other significant change in the labeling or product advertising 
for Pembrolizumab; this investigation will use an approved route of administration and dosage 
of Pembrolizumab and has no factors that increase the risk of the product; this investigation will 
be in compliance with 21CFR parts 56, 50, and 312.7; and neither the investigator nor sponsor 
will promote or represent that Pembrolizumab is safe or effective for the context that is under 
investigation in this study. 
Formulation 
Commercially available for injection 25mg/ml (4ml) [contains polysorbate 80] in a one-vial 
formulation. 
Preparation, storage and administration  
Follow institutional standards.  
Pharmacokinetic information 
Note:  Clearance is ~20% lower at steady state than with the first dose.  With weight-based 
dosing (2 mg/kg), pembrolizumab concentrations in pediatric patients are comparable to those 
of adults (at the same dose). 
Distribution: Vdss: 6.1 L 
Half-life elimination:  23 days 
Potential Drug Interactions 
There are no known significant drug interactions. 
Known potential toxicities 
Consult the package insert for the most current and complete information. 
Common known potential toxicities, > 10%:   
Cardiovascular: Facial edema 
Central nervous system:  Fatigue 
Dermatologic: Pruritus, skin rash 
Endocrine 
& 
metabolic: 
Hyperglycemia, 
hyponatremia, 
hypoalbuminemia, 
hypertriglyceridemia, hypocalcemia, decreased serum bicarbonate 
Gastrointestinal: Nausea, decreased appetite, constipation, diarrhea, vomiting, abdominal pain 
Hematologic & oncologic: Anemia, lymphocytopenia 

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Hepatic: Increased serum AST, increased serum ALT, increased serum alkaline phosphatase 
Neuromuscular & skeletal: Arthralgia 
Respiratory:  Cough, dyspnea 
Miscellaneous:  Fever 
Less common known potential toxicities, 1% - 10%: 
Central nervous system:  Confusion, peripheral neuropathy 
Endocrine & metabolic: Hypothyroidism, hyperthyroidism 
Gastrointestinal: Colitis 
Immunologic:  Antibody development 
Neuromuscular & skeletal:  Weakness, arthritis 
Respiratory:  Pneumonitis, pleural effusion, pneumonia, respiratory failure 
Rare known potential toxicities, <1% (Limited to important or life-threatening) 
Adrenocortical insufficiency (immune-mediated), bullous pemphigoid (immune-mediated), 
chronic inflammatory demyelinating polyradiculoneuropathy, diabetic ketoacidosis, exfoliative 
dermatitis (immune-mediated), Guillain-Barre syndrome (immune-mediated), hemolytic 
anemia (immune-mediated), hepatitis (including autoimmune hepatitis), hypophysitis, infusion-
related reaction, interstitial nephritis (with renal failure), myasthenia gravis (immune 
mediated),myositis (immune-mediated), nephritis (autoimmune), pancreatitis (immune-
mediated), partial epilepsy (immune-mediated; in a patient with inflammatory foci in brain 
parenchyma), thyroiditis, type I diabetes mellitus, uveitis (immune-mediated), vasculitis 
(immune-mediated) 
Procurement  
Commercial supplies.  Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Nursing Guidelines 
1. Pembrolizumab side effects vary greatly from those of traditional chemotherapy and 
can vary in severity from mild to life threatening. Instruct patients to report any side 
effects to the study team immediately. Side effects may be immediate or delayed up to 
months after discontinuation of therapy. Most side effects are reversible with prompt 
intervention of corticosteroids. 
2. Diarrhea can be seen however is less common than that seen with anti-CTLA-4 agents. 
However it can be severe, leading to colonic perforation. Instruct patients to report ANY 
increase in the number of stools and/or change in baseline, blood in the stool, abdominal 
pain to the study team immediately.  
3. Rash/pruritus/dermatitis is seen. Patients should report any rash to the study team. Treat 
per section 9.0 and monitor for effectiveness.  
4. Monitor LFT’s closely as elevations in these levels could indicate early onset 
autoimmune hepatitis. Patients should also be instructed to report any jaundice, or right 
upper quadrant pain to the study team immediately. 
5. Pneumonitis can be seen and may be mild (only seen on imaging) to severe. Patients 
should be instructed to report any SOB, dyspnea, cough, chest pain, etc. to the study 
team immediately. Patients reporting these symptoms should have a pulse ox checked 
and consider immediate imaging per the treating MD. 

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6. Endocrinopathies (including hypopituitarism, hypothyroidism, hypophysistis, and 
adrenal insufficiency) are seen with this agent. Patients may present only with the vague 
sense of fatigue and “not feeling well”. Additional symptoms may be that of nausea, 
sweating and decreased activity tolerance. Instruct patients to report these signs or 
symptoms immediately and obtain appropriate labs as ordered by MD.  
7. Patients who are started on steroid therapy for any side effects of pembrolizumab 
toxicity should be instructed to take the steroids as ordered, and not to discontinue 
abruptly as symptoms may return and be severe. Patients may be on steroid therapy for 
weeks. Instruct patients to report any increase or change in side effects with any dosage 
decrease as patients may need a slower taper.  
8. Fatigue is common and may or may not be associated with immune related side effects. 
Assess patient’s fatigue level prior to each cycle of therapy and report any changes to 
the study team. 
9. Patients should avoid receiving live vaccines within 30 days of study drug 
administration or per other study guidelines.  
10. Patients who have undergone an allogenic bone marrow transplant, have an increased 
risk of severe complications including early GVHD, and venoocclusive disease, if they 
have previously been treated with pembrolizumab. 
11. Myocarditis has been reported and associated with pembrolizumab. Instruct patients to 
report chest pain, SOB, or dyspnea to study team immediately and/or seek emergency 
medical attention. 
12. Autoimmune hematologic disorders including ITP and hemolytic anemia have been 
reported. Monitor blood counts closely and report any abnormalities to the study team. 
13. Rare neurologic disorders including Guillian-Barre syndrome and myasthenia gravis 
have been reported. Instruct patients to report any neurologic symptoms including 
weakness, parasthesias or numbness, tingling to the study team immediately. 
10.2 
Pemetrexed (Alimta) 
Background: Pemetrexed is a multitargeted antifolate (MTA). Pemetrexed inhibits thymidylate 
synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and 
aminoimidazole carboxamide ribonucleotide formyltransferase, the enzymes involved in folate 
metabolism and DNA synthesis, resulting in inhibition of purine and thymidine nucleotide and 
protein synthesis. 
Formulation 
Commercially available as a sterile lyophilized powder for intravenous infusion available in 
single-dose 100 and 500 mg vials. 
Preparation, storage and administration  
Follow your institutional standards.   
Pharmacokinetic information 
Distribution: Vdss: 16.1 L 
Protein Binding: ~73% to 81% 
Metabolism: Pemetrexed undergoes limited hepatic metabolism. Unchange pemetrexed 
accounts for the majority of the drug-related material in urine. 
Half-life elimination: Normal renal function: 3.5 hours; Clcr 40-59 mL/minute: 5.3-5.8 hours 

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Excretion: Urine (70% to 90% as unchanged drug) 
Potential Drug Interactions 
Increased Effect/Toxicity: The administration of ibuprofen 400 mg every 6 hours to patients 
resulted in a 22% increase in AUC and a 16% increase in CMAX. These alterations are no greater 
than those observed in patients with moderate renal impairment (CrCl 45 mL/min) and do not 
fall outside of what is considered an acceptable increase in exposure. Therefore, ibuprofen (400 
mg every 6 hours) can be given concurrently with pemetrexed in patients with normal renal 
function (CrCl greater than or equal to 80 mL/min). 
Ethanol/Nutrition/Herb Interactions: Lower ANC nadirs occur in patients with elevated baseline 
cystathionine or homocysteine concentrations. Levels of these substances can be reduced by 
folic acid and vitamin B12 supplementation. 
Known potential adverse events 
Consult the package insert for the most current and complete information. Percentages reported 
with single-agent therapy (in patients who received folate and B12 supplementation); dose 
limiting toxicities include myelosuppression (neutropenia, thrombocytopenia); fatigue and 
dermatitis. 
Common known potential toxicities, > 10%:   
Cardiovascular: Chest pain, edema, hypertension 
Central nervous system: Fatigue, fever, depression 
Dermatologic: Rash/desquamation, alopecia 
Gastrointestinal: Anorexia, nausea, constipation, vomiting, diarrhea, stomatitis 
Hematologic: Anemia, leukopenia, neutropenia 
Neuromuscular & skeletal: Neuropathy 
Respiratory: Dyspnea, pharyngitis 
Miscellaneous: Infection 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Thrombosis/embolism, cardiac ischemia 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Dysphagia/esophagitis/odynophagia 
Hematologic: Thrombocytopenia, febrile neutropenia 
Hepatic: ALT increased, AST increased 
Neuromuscular & skeletal: Arthralgia 
Renal: Creatinine clearance decreased, serum creatinine increased 
Miscellaneous: Allergic reaction/hypersensitivity 
Rare known potential toxicities, <1% (Limited to important or life-threatening) 
Colitis, renal failure 
Drug procurement 

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Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Nursing Guidelines  
1. Monitor blood counts.  Instruct patient to report fevers >101, excessive fatigue, 
bruising, or unusual bleeding. 
2. Advise patient about possible rash, pruritus and the need to report these problems, which 
can be treated by steroids. 
3. Supply warm packs to injection site if arm becomes inflamed. 
4. Administer antiemetics and antidiarrheals as ordered. 
5. Instruct patient that adequate hydration is important. Patient should report inability to 
maintain hydration. 
6. Instruct patient in energy-conserving techniques. 
7. Advise patient about possible hair loss. 
8. Monitor liver and renal function tests. 
9. Advise patient that urinary tract infections (UTIs) are possible, instruct in the signs and 
symptoms of a UTI and tell patients to report any of these to the health care team 
immediately. 
10. Advise patient about possibility of mouth sores.  Emphasize good oral care. 
11. Advise patient that he/she should contact his/her physician in the event of trouble 
swallowing folic acid pills.  
10.3 
Carboplatin (Paraplatin®, CBDCA) 
Background: Carboplatin is an alkylating agent which covalently binds to DNA; interferes with 
the function of DNA by producing intrerstrand DNA cross-links. 
Formulation 
Commercially available for injection as:  
Solution Reconstituted: 150 mg. 
Solution: 10 mg/mL (5 mL, 15 mL, 45 mL, 60 mL) 
Preparation, storage and administration 
Follow institutional standards. 
Pharmacokinetic information 
Distribution: Vd: 16 L/kg; into liver, kidney, skin, and tumor tissue. 
Protein binding: 0%; however the platinum from carboplatin becomes irreversibly bound to 
plasma proteins. 
Metabolism: Minimally hepatic to aquated and hydroxylated compounds. 
Half-life elimination: CrCl > 60 mL/min:  Carboplatin:  2.6-5.9 hours (based on dose of 300-
500 mg/m2); Platinum (from carboplatin): > 5 days. 
Excretion: Urine (~70% as carboplatin within 24 hours; 3% to 5% as platinum within 1-4 days). 
Potential Drug Interactions 
Increased Effect/Toxicity: Aminoglycosides increase risk of ototoxicity and/or nephrotoxicity.  

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Known potential adverse events 
Consult the package insert for the most current and complete information. Percentages reported 
with single-agent therapy. Note: Myelosuppression is dose related, schedule related, and 
infusion-rate dependent (increased incidences with higher doses, more frequent doses, and 
longer infusion times) and, in general, rapidly reversible upon discontinuation. 
Common known potential toxicities, > 10%:   
Central nervous system: Pain 
Endocrine & metabolic: Hyponatremia, hypomagnesemia, hypocalcemia, hypokalemia 
Gastrointestinal: Vomiting, abdominal pain, nausea 
Hematologic: Myelosuppression (dose related and dose limiting; nadir at ~21 days; recovery by 
~28 days), leukopenia, anemia, neutropenia, thrombocytopenia 
Hepatic: Alkaline phosphatase increased, AST increased 
Hypersensitivity:  Hypersensitivity 
Neuromuscular & skeletal: Weakness 
Renal: Creatinine clearance decreased, BUN increased 
Less common known potential toxicities, 1% - 10%:  
Central nervous system: Peripheral neuropathy, neurotoxicity 
Dermatologic: Alopecia 
Gastrointestinal: Constipation, diarrhea, stomatitis/mucositis, taste dysgeusia 
Hematologic: Hemorrhagic/bleeding complications 
Hepatic: Bilirubin increased 
Infection:  Infection 
Local: Pain at the injection site 
Neuromuscular & skeletal: Peripheral neuropathy 
Ocular: Visual disturbance 
Otic: Ototoxicity 
Renal: Creatinine increased 
Rare known potential toxicities, <1% (Limited to important or life-threatening) 
Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular accident, dehydration, 
embolism, erythema, febrile neutropenia, hemolytic anemia (acute), hemolytic uremic 
syndrome, hyper-/hypotension, injection site reaction (pain, redness, swelling), limb ischemia 
(acute), malaise, metastases, pruritus, skin rash, tissue necrosis (associated with extravasation), 
urticaria, vision loss 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 

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Nursing Guidelines 
1. Monitor CBC and PLTs.  Watch for profound neutropenia and give low count 
precautions and instructions as necessary.  Nadir occurs at approximately day 21 with 
recovery at day 28-30.  Thrombo-neutro-leukopenia may be cumulative.  
Thrombocytopenia can be dose-limiting and is more pronounced than with cisplatin.  It 
can be more severe in patients with previous chemotherapy, concurrent radiation 
therapy, or patients with impaired renal function.  Instruct patient to immediately report 
any unusual bruising or bleeding.  Anemia (70-90% of patients) may be symptomatic 
with asthenia being the most common complaint.  Instruct patient in energy saving 
lifestyle. 
2. Assess baseline renal function (creatinine clearance).  Reduced renal function can 
contribute to an increased risk of thrombocytopenia.  
3. Monitor fluid status - encourage hydration. 
4. Advise patient of probable taste alterations.  Frequent oral hygiene is helpful.  Instruct 
patient in appropriate interventions to achieve and maintain optimal nutritional status. 
5. Older patients (>65) may experience some peripheral neuropathy with paresthesias.  
Instruct patients to report any tingling, burning, loss of sensation. 
6. Mild nausea and vomiting occur in up to 94% of patients, 6-12 hours after treatment and 
may persist for 24 hours or longer.  Diarrhea/cramping/constipation has been 
experienced by approximately 17%.  Premedicate with antiemetics/antidiarrheals—
evaluate effectiveness. 
7. Administer following Taxol (in regimens that contain both drugs) to maximize cell kill. 
8. Patients have experienced allergic reactions while receiving carboplatin. Watch for 
signs and symptoms of hypersensitivity reactions. If these occur, stop drug immediately, 
notify MD, and treat appropriately. 
 
 

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11.0 MEASUREMENT OF EFFECT  
11.1 
Patient reported outcome measures 
11.1.1 Comprehensive Geriatric Assessment (CGA-Appendix I)  
For the secondary clinical study observation with the Comprehensive Geriatric Assessment 
(CGA), patients will complete the CGA prior to treatment at baseline (Day1 of Cycle 1).  
Using previously described methodology from Hurria and others and following patients 
prospectively over time, we will determine whether the baseline CGA assessment is able 
to predict grade 3 or worse adverse events in a similar manner as it does in older, 
chemotherapy-treated patients 21.  It will take approximately twenty five minutes to 
complete this questionnaire.  
11.1.2 Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF-Appendix II) 
For the secondary translational study observation that focuses on fatigue, patients will 
complete the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF; 
Appendix II) prior to treatment on Day 1 of the first three cycles (every 3 weeks for the 
first 9 weeks only) and end of treatment. This 30-item instrument asks questions directly 
relevant to fatigue, has been psychometrically validated, and serves as a well-accepted 
instrument for clinical trials that focus on fatigue. This instrument has been reviewed and 
compared to other instruments by Stein and Jacobson 37. Incorporating a questionnaire that 
is specific to fatigue seems appropriate and necessary for the translational work that also 
focuses on fatigue. As pointed out in a recent concept review from the NCI, we recognize 
that a “unique feature of the MFSI-SF is that it captures the full spectrum of the fatigue 
symptom profile using 5 empirically derived subscales: 1) general fatigue, 2) emotional 
fatigue, 3) physical fatigue, 4) mental fatigue and 5) vigor.”  As per NCI guidance, we 
intend to report total score as well as scores from 5 subscales based on study arm and 
patient demographics. Moreover, precedent exists within the Alliance for Clinical Trials 
for using this questionnaire 38.  It will take about 5 minutes to complete this measure.  
11.1.3 Godin Leisure Time Exercise Questionnaire (GLTE-Appendix III) 
Similarly, we will ask patients to complete the Godin Leisure-Time Exercise Questionnaire 
(GLTE), a previously validated and frequently used questionnaire that has demonstrated 
strong correlation between patient responses and activity, as assessed by means of an 
accelerometer among ill patients 39.  The brevity of this questionnaire also makes it a good 
choice because of minimization of patient burden.  The GLTE will be graded based on 
prior instructions on the Oncology Nursing Society website, which divides patients into 3 
groups where score of 24 or more is considered “active”, 14-23 is considered “moderately 
active”, and less than 14 is “insufficiently active/sedentary”.  This questionnaire will be 
completed prior to treatment on Day 1 of the first three cycles (every 3 weeks for the first 
9 weeks only) and end of treatment.  It will take about 5 minutes to complete this measure. 
11.1.4 Linear Analogue Self-Assessment (LASA-Appendix IV)  
In addition, cognizant of patient-burden from questionnaire completion, we will have 
patients complete a Linear Analogue Self-Assessment (LASA), a short series of 13 items 
that has been previously validated 40,41,42,43.  The LASA is used to assess patient quality of 
life, sleep disturbance and other patient-reported symptoms and concerns that may arise 
during cancer therapy. The LASA is particularly appealing because of its brevity and 
diminishment of patient burden. This questionnaire will be completed prior to treatment on 
Day 1 of the first three cycles (every 3 weeks for the first 9 weeks only) and end of 
treatment.  It will take about 5 minutes to complete this measure. 

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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Protocol treatment is to continue until disease progression or unacceptable toxicity. Please see 
the study calendar (Section 5.0) and the treatment section (Section 7.0) for treatment and 
following up time periods.  
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression in the judgement of the treating oncologist.  
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Termination of the study by sponsor 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 
Follow-up  
12.3.1 Duration of Follow-up  
Patients will undergo scheduled follow up assessments on Day 1 of every cycle, (every 3 
weeks for all patients) until end of treatment.  See study calendar (Section 5.0).  All patients 
will be followed annually for survival until 5 years following registration or death 
whichever occurs first. 
12.3.2 Follow-up for Patients who Stop Study Treatment Early  
Follow up for patients who stop due to toxicity, or receive non protocol therapy:  
Patients who discontinue study treatment due to toxicity or receive non-protocol therapy 
will be followed annually for survival only until 5 years following registration. They should 
be encouraged to complete end of treatment patient-reported questionnaire. The reason for 
discontinuation will be recorded on an Off-treatment form.  
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol study observations as required by the Study Calendar. 

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12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below.  
Baseline, off treatment, and post-treatment follow up (i.e., survival only) data submission 
required. See the Data Submission Schedule accompanying the All Forms Packet. 
 
 

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13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study design  
This is a phase II, open-label, multicenter clinical trial of non-small cell lung cancer patients of 
70 years of age or older receiving MK-3475 (pembrolizumab) with or without chemotherapy as 
their first line of treatment. 
13.2 
Sample Size, Accrual Time and Study Duration 
A minimum sample size of 90 evaluable patients will be enrolled to address the primary study 
observation.  We anticipate accruing an additional 10 patients to account for cancellations, major 
trial violations, or other reasons; and therefore the maximum projected accrual for this trial is 
100 patients.   
Accrual rate estimate is 6 patients per month, including a 6 month ramp up period, the whole 
accrual period is estimated to be 23 months.  Based on clinical experience in this older age 
group, we expect most patients to complete treatment within 2 years from starting therapy. 
Including an accrual period of 23 months, we anticipate that the primary study observation will 
be achieved approximately 47 months after trial activation. 
13.3 
Primary Study Observation   
The primary objective of this study is to estimate the adverse event profile of MK-3475 
(pembrolizumab) in non-small cell lung cancer patients who are 70 years of age or older and 
who are treated with MK-3475 (pembrolizumab) +/- chemotherapy in a first-line setting.  The 
primary outcome of interest is grade 3 or worse solicited adverse events listed in Section 9.1 as 
defined per NCI CTCAE v 5.0. Any eligible patient to have received at least one cycle of 
treatment will be considered evaluable. 
13.4 
Power Justification and Primary Analysis  
The sample size for this trial was determined considering both accrual feasibility for this patient 
population as well as a reasonable precision in estimating the proportion of patients who 
experience grade 3 or worse adverse events while receiving MK-3475 (pembrolizumab). 
The proportion of patients who experience grade 3 or worse adverse events in the first six 
months of treatment will be summarized by frequency and percentage along with a 95% CI 
separately by type of therapy (monotherapy or combination therapy) as well as combining the 
two cohorts.  
We assume that at least 50% of patients will receive monotherapy with pembrolizumab.  If the 
adverse event rates for the monotherapy and the combination therapy groups appear to be 
similar, we will consider combining the two cohorts when estimating the adverse event rates.  
Otherwise, they will be estimated separately.  Table 1 shows the precision in terms of the width 
of the 95% confidence interval for rates of adverse events (proportion of patients experiencing 
AEs) ranging from 10% to 90%, using the Clopper-Pearson exact confidence interval method. 
The widths of the 95% CI range from 19% to 31% when the therapy cohorts are analyzed 
separately and they range from 13% to 22% when the cohorts are analyzed together.  
Below is the estimation precision for various scenarios of observed proportions of patients 
receiving monotherapy or combination of chemotherapy and immunotherapy (n = 45) or the 
combined cohort (n = 90) with AEs. 
 
 

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Confidence interval estimates for adverse event rates: 
Observed proportion of 
patients with AEs 
Separate cohorts (N = 45) 
Combined cohort (N = 90) 
95% CI limits 
95% CI width 
95% CI limits 
95% CI width 
.1 
(0.031, 0.227) 
0.196 
(0.047, 0.181) 
0.135 
.3 
(0.173, 0.455) 
0.282 
(0.208, 0.406) 
0.198 
.5 
(0.347, 0.653) 
0.305 
(0.393, 0.607) 
0.215 
.7 
(0.545, 0.827) 
0.282 
(0.594, 0.792) 
0.198 
.9 
(0.773, 0.969) 
0.196 
(0.819, 0.953) 
0.135 
13.5 
Analysis Plans for Secondary, Exploratory Objectives 
13.5.1 Overall Survival 
Overall survival will be summarized using the Kaplan-Meier estimator, separately by 
monotherapy or combination therapy as well as by the combined cohort.  The event is death 
from any cause.  Patients who are alive at the last follow-up will be censored at the last 
follow-up time.  The time to event is the time interval from study registration to death or 
the last follow-up whichever occurs first.   
13.5.2 Quality of Life 
The overall quality of life score (the first question of the LASA questionnaire) at each time 
point as well as change from baseline will be summarized by mean (standard deviation), 
median (range) along with a longitudinal plot. The median QOL change from baseline to 
week 9 along with a 95% CI will be estimated using the Hodges-Lehmann method. 
13.5.3 Comprehensive Geriatric Assessment 
Items of the geriatric assessment questionnaire will be summarized by mean (standard 
deviation) and median (range) for continuous variables and frequency (percentage) for 
categorical data.  The CGA-based risk score will be computed for each patient. 21 The 
CGA-based risk scores range between 0 and 19. The risk score is a summation of the 
following clinical and CGA factors (number in parentheses is the score for the factor): age 
≥72 (2), GI or GU cancer (2), standard chemotherapy dose (2), polychemotherapy (2), 
hemoglobin <11g/dL for male or <10 g/dL for female (3), creatinine clearance <34 ml/min 
(3), fair or worse hearing (2), 1 or more falls in last 6 months (3), taking medications with 
some help or unable to (1), ability to walk 1 block is somewhat limited or limited a lot (2), 
decreased social activity because of physical/emotional health limited at least sometimes. 
Patients will be classified into one of the 3 risk groups (low: 0 – 5, medium: 6 – 9, and 
high: 10 – 19). The rate of grade 3 and worse AEs will be summarized for each risk group.  
The ability of the CGA-based risk score to predict toxicity will be evaluated by comparing 
the rates of grade 3 or worse AEs among the three risk groups using a chi-square test. For 
reporting purposes, we will provide the frequency of grade 3 or worse AEs by CGA-based 
risk group. 
If the CGA-based risk score developed by Hurria et al,21 does not predict grade 3 or worse 
AEs, we will use the data from this trial to explore development of a new CGA-based risk 
score for this patient population following the methods of Hurria et al.  We will first 
consider evaluate the association between grade 3 or worse AEs with each of the 
demographics, clinical factors, and items of the geriatric assessment using the chi-square 
test. All variables that reached a p-value of less than .1 will be considered in the model 
building procedure using multivariate logistic regression with best subset selection 
method44.  The risk score for each risk factor will be calculated by dividing the coefficient 
of the variable by the smallest coefficient in the final model.  The risk score will be 

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computed for each patient by summing over the scores for individual factors in the final 
model.  The sample will be divided into 3 risk categories approximately by low (first 
quartile of scores), medium (2nd and 3rd quartiles), and high (last quartile).  The risk score 
will be internally validated using 10-fold cross-validation. 
13.5.4. To disaggregate the solicited adverse events and identify potential causes of 
individual adverse events.  
 
Individual solicited adverse events listed in Section 9.1 will be tabulated and potential 
association between baseline demographics and clinical factors and individual adverse 
events will be evaluated in an exploratory and hypothesis generating manner; including but 
not limited to multi-variate logistic regression models considering the baseline 
demographics and the presence/absence of the AE. 
 
13.5.5 Fatigue, Exercise and other Symptoms and Concerns Questionnaires (exploratory 
objectives) 
Response from the MFSI-SF and the GLTE questionnaires will be scored using established 
algorithm as described in Sections 11.1.2 and 11.1.3.  The subscores and the total scores 
will be summarized by mean (standard deviation), median (range) along with a longitudinal 
plot. The mean score change from baseline along with a 95% CI will be estimated. 
Other LASA symptoms and concerns will be analyzed in the same manner as described in 
Section 13.5.2.  The subscale will be summarized. 
13.5.6 Time to treatment failure (exploratory objective) 
Treatment failure is defined as premature discontinuation (discontinuation of treatment 
before 34 cycles for patients on 3-week cycle and before 17 cycles for patients on 6-week 
cycle) of treatment due to disease progression, adverse events, death, or patient’s choice. 
Time to treatment failure is defined as the time interval from study registration to premature 
discontinuation or the last follow-up whichever occurs first.  Patients who are lost follow-
up without the defined event prior to 35 cycles will be censored at the time of their last 
follow-up. Time to treatment failure will be estimated using the Kaplan-Meier estimator. 

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13.6 
Study Monitoring (reports, summaries) 
This study will be monitored by the study team, including the study chair, the study statisticians, 
and other appropriate members of the study team on an anticipated quarterly basis upon 
enrollment of the first patient, although the team reserves the possibility of modifying this 
frequency as appropriate. Reports containing a summary of adverse events by treatment cohort 
will be reviewed. We will review Grade 4 and 5 adverse events deemed “unrelated” or “unlikely 
to be related,” to verify their attribution and to monitor the emergence of a previously 
unrecognized treatment-related adverse event. The study team will also monitor the accrual rate. 
Required submission of patient demographic data for this study will be submitted automatically 
via OPEN.   
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
13.7 
Adverse Event Stopping Rule 
The study team will be monitoring if: 
• 
4 out of the first 10 patients to become evaluable for adverse events experience a grade 4 
or grade 5 adverse event deemed to be at least possibly related to study treatment. 
• 
At any time after the first 10 patients become evaluable for adverse events, 40% or more 
patients experience a grade 4 or grade 5 adverse event deemed to be at least possibly related 
to study treatment. 
If the previous boundaries are crossed, the study will be assessed for suspension (but not 
suspended until the team has been able to discuss).  In addition, each grade 5 event will be 
reviewed on a case by case basis in a real time fashion to determine whether study accrual should 
be suspended. 
13.8 
Feasibility  
An interest and feasibility survey was sent to Alliance Community Oncology Committee 
members and demonstrated that 86% (28 respondents) stated that they see patients eligible for 
this study; 96% of 25 respondents indicated an interest in enrolling patients to such a trial. From 
the survey responses alone, interested sites would readily enroll to this trial. Conservatively, we 
estimate that we would enroll 6 patients per month with a 6 month ramp up with completion of 
accrual in 23 months.   
13.9 
Descriptive Factors  
a) concomitant chemotherapy (yes versus no) 
b) gender (male versus female) 
c) baseline performance score 
d) patient age at enrollment (>/= 80 years of age versus younger) 
e) whether cancer treatment was started prior to trial enrollment (yes versus no) 
f) Smoking history (defined as a patient who self-reports having smoked 100 or more 
cigarettes in his/her lifetime):  yes versus no 
g) PD-L1 expression (tumor proportion score (TPS)) 
 
 
 

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13.10 Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist. Therefore, although the planned analysis will, as always, look for differences in 
treatment effect based on racial and gender groupings, the sample size is not increased in order 
to provide additional power for subset analyses. The geographical region served by the Alliance, 
has a population which includes approximately 13.5% minorities. Based on prior Alliance 
studies involving similar disease sites, we expect about 12% of patients will be classified as 
minorities by race and about 56% of patients will be women. Expected sizes of race by gender 
subsets for patients registered to this study are shown in the following table. 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
0 
1 
1 
2 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or 
Other Pacific Islander 
1 
1 
0 
0 
2 
Black or African 
American 
2 
2 
0 
0 
4 
White 
40 
40 
4 
4 
88 
More Than One Race 
0 
0 
0 
0 
0 
Total 
45 
45 
5 
5 
100 
 
 

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14.0 CORRELATIVE AND COMPANION STUDIES  
There will be 2 required sub-studies within A171901. All patients who consent to participate in the 
main study (A171901) are required to provide blood samples for the biomarker analyses (A171901-
ST1) and pharmacokinetic analyses (A171901-PP1).  
14.1 
Correlative Science: Using Immune Markers to Track Fatigue in Older Patients who 
Receive Pembrolizumab on Alliance A171901 (Alliance A171901-ST1) 
14.1.1 Background 
It is becoming increasingly recognized that cancers can thrive upon evading the immune 
system.  Malignancies such as melanoma and renal cell carcinoma are known to exploit 
the programmed death 1 (PD-1) pathway in order to evade the immune system through 
adaptive immune resistance. 45, 46 Monoclonal antibodies targeting PD-1 have recently been 
introduced, and have been shown to improve survival when used in patients with advanced 
clear cell renal cell carcinoma (ccRCC) who have previously failed 1-2 prior anti-
angiogenic therapies.47  
The success of PD-1 blockade therapy in treatment of solid cancers is dependent on the 
presence of pre-existing tumor-reactive CD8+ T lymphocytes46. We and others have 
established that PD-1 and CD11a can be used to identify tumor-reactive CD8+ cytotoxic 
T lymphocytes in the peripheral blood or in tumor tissues 48-50.We observed that patients 
with advanced cancers have high levels of CD11ahighPD-1+ CD8+ T cells in peripheral 
blood 48.  
On the other hand, we recently identified that CX3CR1 defined a PD-1 therapy-responsive 
CD8+ T cells with effector memory phenotype and function25. In responders to PD-1 
therapy or combined (chemotherapy), CX3CR1 identified an increased CD8 T cell 
population with effector function and endure cytotoxic chemotherapy drugs25. Thus, 
measurement of CX3CR1+ among CD11a high CD8 T cells will give us a full coverage of 
therapy-responsive T cell population for understanding the potential cellular mechanism 
underlying clinical outcomes in patients following immunotherapy or combined therapy.  
14.1.2 Objectives 
To evaluate whether older patients who experience fatigue or other adverse effects would 
be correlated with a change of PD-1 therapy-responsive T cell subset (i.e. CX3CR1+  
CD11ahighCD8+ T-cells) in their peripheral blood from baseline (prior to therapy) to post 
therapy.   
14.1.3 Methods 
Our study will aim to collect 30 mL of whole blood at four time-points in the patient’s care: 
prior to treatment on Day 1 of the first 3 cycles, and at end of treatment. (Please see Section 
6.2 and CSM for more details). Patients are always assessed at these time points as per 
routine clinical care pathways relating to their treatment, therefore, the research blood 
draws should be coordinated with the blood they would have drawn as part of standard 
clinical care, to minimize the number of venipunctures.   
Specimen processing: 
Overview: After receipt by the Alliance biobank at Mayo Clinic, specimens will be 
processed by the lab of 
at Mayo Clinic. From whole blood, peripheral 
blood mononuclear cells (PBMCs) will be isolated. Flow cytometry will be used to identify 
the phenotype and frequency of T-cells. Output data will be stored in confidential 

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electronic data files and appropriate measured will be used to protect patient 
confidentiality.  
Flow cytometry analysis:  PBMC samples will be thawed on the day of analysis, and be 
incubated with appropriate antibodies to identify cell surface markers (CD3, CD8, CD11a, 
and CX3CR1) and functional markers (Ki67 for proliferation, Bim for pro-apoptosis and 
Granzyme B for effector function). All these markers will be presented as percentage of 
change from baseline to post -treatment for the same patient.      
The data collected from the samples, as described above, will be sent using encrypted 
secure spreadsheets to the Alliance SDC A171901 Statistician to prepare analysis datasets 
in conjunction with the clinical/outcome data. The A171901 Statistician will then 
coordinate the analyses with the A171901-ST1 Correlative Science Co-Chair, 
 
 Analyses will be conducted using the analysis dataset used for the analysis of the 
clinical endpoints to ensure consistent data is reported for the primary and secondary 
endpoints (e.g. data associated with censoring, proper inclusion of crossover data, and data 
to be excluded in cases of consent withdrawals for follow-up and correlative studies). 
Statistical Analysis: The levels of CX3CR1+ CD8+ T-cells will be summarized at Day 1 
at each cycle.  The level of CX3CR1+ CD8+ T-cells at each time point will be plotted 
against MSFI-SF scores and the GLTE scores to explore the correlation between 
CX3CR1+ CD8+ T-cells and fatigue and activity levels. 
14.2 
Pharmacokinetics and Population Pharmacokinetics of Pembrolizumab (Alliance 
A171901-PP1) 
14.2.1 Background 
MK-3475 (Pembrolizumab) is an anti-PD-1 targeted monoclonal (IGg4 kappa) antibody 
with a molecular weight of 149 Kda. It is FDA approved for the treatment of a number of 
solid tumors including melanoma, non-small cell lung cancer, head and neck cancer, renal 
cell cancer (refer FDA approved product label51). 
14.2.2 Objectives 
1. To determine the extent to which pembrolizumab demonstrates time dependent 
decrease in clearance in older adult patients (aged ≥70 years) with non-small cell 
lung cancer being treated with pembrolizumab monotherapy or in combination 
with cytotoxic chemotherapy. 
2. To determine the intrapatient and interpatient variability in clearance in older 
adult (≥70 years) patients with non-small cell lung cancer receiving 
pembrolizumab monotherapy and when combined with cytotoxic chemotherapy.  
3. To preliminarily explore the correlation between pembrolizumab exposure 
(AUC) with observed immune related toxicities in this older adult (aged ≥70 
years) patient population receiving pembrolizumab monotherapy and when 
combined with cytotoxic chemotherapy.  
14.2.3 Pharmacodynamics  
Based on dose/exposure efficacy and safety relationships, there were no clinically 
significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 
2 mg/kg every 3 weeks in patients with melanoma or NSCLC. 

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14.2.4 Pharmacokinetics and Population Pharmacokinetics  
Pembrolizumab when administered is usually dosed at 200 mg intravenously every 3 weeks 
for most of its indications.  It has a geometric mean (CV) elimination half-life of 22 days 
(CV 35%) and its geometric mean volume of distribution is 6.0 L (CV =20%), being 
primarily distributed in the vascular compartment.  Steady-state concentrations of 
pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week 
regimen and the systemic accumulation was 2.1-fold.  The peak concentration (Cmax), 
trough concentration (Cmin), and area under the plasma concentration versus time curve at 
steady state (AUCss) of pembrolizumab increases dose proportionally in the dose range of 
2 to 10 mg/kg.  Pembrolizumab clearance (CV%) is approximately 23% lower [geometric 
mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)].  
The elimination of IgG based monoclonal antibodies such as pembrolizumab in humans is 
complex including target mediated drug disposition with non-linear and linear components 
and protease mediated degradation processes.1  
Population pharmacology analyses for pembrolizumab suggested that the following factors 
had no clinically important effect on the its clearance (CL): age (range: 15 to 94 years), 
sex, race (89% White), renal impairment (eGFR ≥ 15 mL/min/1.73 m2), mild hepatic 
impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total 
bilirubin between 1 and 1.5 times ULN and any AST), or tumor burden.51,1 
This pharmacokinetic substudy is predicated on the primary hypotheses that:  
a) In the older adult population of non-small cell cancer patients the time varying 
clearance of pembrolizumab is > 40% decrease from initial clearance when 
pembrolizumab is administered as monotherapy or in combination with cytotoxic 
chemotherapy.  
b) The profile of decreasing pembrolizumab clearance over time extends beyond the 
defined pembrolizumab time to steady state (16 weeks).  
14.2.5 Methods 
Venous blood samples will be obtained in 5ml in red top tubes and allowed to clot for at 
least 30 minutes at room temperature, centrifuged and serum aliquots stored at -80°C until 
shipped.  Serum pembrolizumab trough concentrations (C0) will be obtained at baseline 
(pre-treatment i.e. pre infusion cycle 1, and then pre infusion on cycles 2, 3 and 6 and on 
one later cycle if the patient is still being treated with pembrolizumab (e.g pre-infusion on 
cycle 9 or cycle 12). See Section 6.2 and the CSM for additional instructions. These 
samples will have the time of day they were obtained documented in the case report forms 
in Medidata Rave. At clinic follow up visits where PK samples for pembrolizumab are 
being obtained drug pre-infusion details of the time and day of last dose of study drug will 
be documented in Medidata Rave as well.  
Serum pembrolizumab concentrations will be measured using an ELISA assay based on 
that developed by researchers at NCI. This assay has a limit of detection of ~ 1 -2 ng/mL 
and is similar to the assay described by Pluim et al52.  
The trough concentrations (Cmin) of pembrolizumab will be analyzed using the Cmin model 
in NONMEM to derive the relevant PK parameters of AUC, Clearance (CL) and apparent 
volume of distribution (Vdss).  
14.2.6 Analyses 
The Alliance Statistics and Data Center (SDC) A171901 Statistician to prepare analysis 
datasets in conjunction with clinical/outcome data. Analyses will be conducted using the 

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analysis dataset used for the analysis of the clinical endpoints to ensure consistent data is 
reported for the primary and secondary endpoints (e.g. data associated with censoring, 
proper inclusion of crossover data, and data to be excluded in cases of consent withdrawals 
for follow-up and correlative studies). 
Objective 1: To determine the intrapatient (pembrolizumab time dependent clearance) and 
interpatient variability in clearance in older adult (≥70 years) patients with non-small cell 
lung cancer receiving pembrolizumab monotherapy or combined with cytotoxic 
chemotherapy 
Objective 2:  To explore the relationship between Pembrolizumab exposure (AUC) and 
immune related toxicities when pembrolizumab is administered as monotherapy or when 
combined with cytotoxic chemotherapy in non-small cell lung cancer patients ≥70 years of 
age. 
 
 

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15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
15.1 
Geriatric Assessment Training  
At each participating site, a research nurse or clinical research professional (CRP) (person who 
intends to administer the geriatric assessment) will receive training on administration of the 
geriatric assessment using the online video training module through the Compliance, Learning, 
and SOP Solutions (CLASS) website, hyperlink below. Per Section 4.2.2, at least one staff 
member must complete this training for the site to receive site registration approval. 
Note: Site staff should only attempt to access the training if a) their site has commenced the site 
registration process for the study and there is an IRB/CIRB approval on file with the CTSU, and 
b) they are on a participating organization roster at the site. If these conditions are not met, users 
will be unable to access the training module.  
 
By going to the web address above, staff will be brought to the CTEP-IAM Single Sign On page, 
where they must enter their CTEP-IAM account username and password. After logging in to 
CLASS, staff will be brought to the CLASS Dashboard. By clicking the Catalog tile, a list of 
available courses will be displayed. The Alliance Geriatric Assessment training is provided in 
the list of available courses. To gain access to the course and begin training, click the Enroll 
button associated with the course.  
Once the first site member has completed their training, CLASS will automatically 
communicate with the Regulatory Support System (RSS) and the protocol-specific training 
requirement will be complied. Assuming all other regulatory requirements have been satisfied, 
the site will receive site registration approval.  
Alliance Geriatric Assessment training completed in CLASS will be valid for five years. Site 
staff whose training has expired will receive an email to retake the training. Site staff who have 
taken the same Alliance Geriatric Assessment training in CLASS for a different study within 
five years will not need to take it again for A171901. 
Any questions or concerns regarding accessing the training module in CLASS may be directed 
to the CLASS Help Desk at 
  
Any further questions or concerns regarding administering the geriatric assessment may be 
directed to the study chair. 
 
 

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Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
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Freeman M, Weber J. Subset analysis of the safety and efficacy of nivolumab in elderly patients 
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Moerbeek M, Teerenstra S. Power analysis of trials with multilevel data. Chapman and 
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Lachin JM. Statistical considerations in the intent-to-treat principle. Controlled clinical trials. 
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Tallarico M, Foster J, Seisler D, et al. Toxicities and related outcomes of elderly patients (pts)(≥ 
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Jatoi A, Foster NR, Egner JR, et al. Older versus younger patients with metastatic 
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Schild SE, Stella PJ, Brooks BJ, et al. Results of combined‐modality therapy for limited‐stage 
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Hurria A, Lichtman SM, Gardes J, et al. Identifying vulnerable older adults with cancer: 
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19. 
Hurria A. Geriatric assessment in oncology practice. Journal of the American Geriatrics Society. 
Nov 2009;57 Suppl 2:S246-9. doi:10.1111/j.1532-5415.2009.02503.x 

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20. 
Hurria A, Cirrincione CT, Muss HB, et al. Implementing a geriatric assessment in cooperative 
group clinical cancer trials: CALGB 360401. Journal of clinical oncology. 2011;29(10):1290.  
21. 
Hurria A, Mohile S, Gajra A, et al. Validation of a prediction tool for chemotherapy toxicity in 
older adults with cancer. Journal of Clinical Oncology. 2016;34(20):2366.  
22. 
Berger AM, Mooney K, Alvarez-Perez A, et al. Cancer-related fatigue, version 2.2015. Journal of 
the National Comprehensive Cancer Network. 2015;13(8):1012-1039.  
23. 
Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a 
potential mechanism of immune evasion. Nature medicine. 2002;8(8):793.  
24. 
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-
cell proliferation and interleukin-10 secretion. Nature medicine. 1999;5(12):1365.  
25. 
Yan Y, Cao S, Liu X, et al. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that 
withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight. Apr 19 
2018;3(8)doi:10.1172/jci.insight.97828 
26. 
Pereira G, Prestes J, Tibana R, Shiguemoto G, Navalta J, Perez S. Acute resistance training 
affects cell surface markers for apoptosis and migration in CD4+ and CD8+ lymphocytes. Cellular 
immunology. 2012;279(2):134-139.  
27. 
Bellmunt J, De Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced 
urothelial carcinoma. New England Journal of Medicine. 2017;376(11):1015-1026.  
28. 
Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-
cell carcinoma. New England Journal of Medicine. 2016;374(26):2542-2552.  
29. 
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. New 
England Journal of Medicine. 2015;372(26):2509-2520.  
30. 
Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and 
bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. The Lancet 
Oncology. 2017;18(11):1493-1501.  
31. 
Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced 
melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study 
(KEYNOTE-006). The Lancet. 2017;390(10105):1853-1862.  
32. 
Lemery S, Keegan P, Pazdur R. First FDA approval agnostic of cancer site—when a biomarker 
defines the indication. The New England journal of medicine. 2017;377(15):1409-1412.  
33. 
Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients 
with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. The Lancet. 
2011;377(9779):1749-1759.  
34. 
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in 
Metastatic Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2018;378(22):2078-2092. 
doi:10.1056/NEJMoa1801005 
35. 
Shumway D, Griffith KA, Jagsi R, Gabram SG, Williams GC, Resnicow K. Psychometric 
properties of a brief measure of autonomy support in breast cancer patients. BMC medical informatics and 
decision making. 2015;15(1):51.  
36. 
Immune-mediated adverse reactions have been reported in patients receiving MK-3475.  Adverse 
events potentially related to MK-3475 may be manifestations of immune-mediated adverse events. In 
clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions 
of MK-3475, administration of corticosteroids and supportive care. 
37. 
Accessed July 27, 2019. http://www.cas.usf.edu/~jacobsen/HANDOUT.FSI&MFSI.pdf; 
38. 
Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-
related fatigue: a randomized, double-blind trial, N07C2. Journal of the National Cancer Institute. 
2013;105(16):1230-1238.  
39. 
Motl RW, Bollaert RE, Sandroff BM. Validation of the Godin Leisure-Time Exercise 
Questionnaire classification coding system using accelerometry in multiple sclerosis. Rehabilitation 
psychology. 2018;63(1):77.  

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40. 
Jean-Pierre P, Figueroa-Moseley CD, Kohli S, Fiscella K, Palesh OG, Morrow GR. Assessment 
of cancer-related fatigue: implications for clinical diagnosis and treatment. The Oncologist. 
2007;12(Supplement 1):11-21.  
41. 
Hyland ME, Sodergren SC. Development of a new type of global quality of life scale, and 
comparison of performance and preference for 12 global scales. Quality of Life Research. 1996;5(5):469-
480.  
42. 
Sriwatanakul K, Kelvie W, Lasagna L, Calimlim JF, Weis OF, Mehta G. Studies with different 
types of visual analog scales for measurement of pain. Clinical Pharmacology & Therapeutics. 
1983;34(2):234-239.  
43. 
Locke DE, Decker PA, Sloan JA, et al. Validation of single-item linear analog scale assessment 
of quality of life in neuro-oncology patients. Journal of pain and symptom management. 2007;34(6):628-
638.  
44. 
Hocking R, Leslie R. Selection of the best subset in regression analysis. Technometrics. 
1967;9(4):531-540.  
45. 
Dronca RS, Liu X, Harrington SM, et al. T cell Bim levels reflect responses to anti-PD-1 cancer 
therapy. JCI Insight. May 5 2016;1(6)doi:10.1172/jci.insight.86014 
46. 
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting 
adaptive immune resistance. Nature. Nov 27 2014;515(7528):568-71. doi:10.1038/nature13954 
47. 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-
Cell Carcinoma. The New England journal of medicine. Sep 25 2015;doi:10.1056/NEJMoa1510665 
48. 
Liu X, Gibbons RM, Harrington SM, et al. Endogenous tumor-reactive CD8 T cells are 
differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor 
growth. Oncoimmunology. Jun 1 2013;2(6):e23972. doi:10.4161/onci.23972 
49. 
Gros A, Robbins PF, Yao X, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive 
repertoire infiltrating human tumors. The Journal of clinical investigation. May 1 2014;124(5):2246-59. 
doi:10.1172/JCI73639 
50. 
Gros A, Parkhurst MR, Tran E, et al. Prospective identification of neoantigen-specific 
lymphocytes in the peripheral blood of melanoma patients. Nat Med. Apr 2016;22(4):433-8. 
doi:10.1038/nm.4051 
51. 
Product label for Pembrolizumab (KEYTRUDA®). Accessed November 11, 2019. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287  
52. 
Pluim D, Ros W, van Bussel MT, Brandsma D, Beijnen JH, Schellens JH. Enzyme linked 
immunosorbent assay for the quantification of nivolumab and pembrolizumab in human serum and 
cerebrospinal fluid. Journal of pharmaceutical and biomedical analysis. 2019;164:128-134.  
53. 
Fillenbaum GG, Smyer MA. The development, validity, and reliability of the OARS 
multidimensional functional assessment questionnaire. J Gerontol. Jul 1981;36(4):428-34.  
54. 
Stewart AL, & Ware, J.E. Jr. Measuring functioning and well-being: The Medical Outcomes 
Study approach.  . Duke University Press; 1992. 
55. 
Loprinzi CL, Laurie JA, Wieand HS, et al. Prospective evaluation of prognostic variables from 
patient-completed questionnaires. North Central Cancer Treatment Group. J Clin Oncol. Mar 
1994;12(3):601-7.  
56. 
Therneau TM. How many stratification factors are &#x201c;too many&#x201d; to use in a 
randomization plan? Controlled Clinical Trials. 1993;14(2):98-108. doi:10.1016/0197-2456(93)90013-4 
57. 
Koenig H, Parkerson GR, Jr., Meador KG. Religion index for psychiatric research. Letter. The 
American journal of psychiatry. Jun 1997;154(6):885-6.  
58. 
Mahoney J, Drinka TJ, Abler R, et al. Screening for depression: single question versus GDS. 
Research Support, Non-U.S. Gov't. Journal of the American Geriatrics Society. Sep 1994;42(9):1006-8.  
59. 
Karnofsky D, Burchenal J. The clinical evaluation of chemotherapeutic agents in cancer. In: 
Macleod CM, ed. Evaluation of chemotherapeutic agents. Columbia University Press; 1948:191-205. 
60. 
Podsiadlo D, Richardson S. The timed "Up & Go": a test of basic functional mobility for frail 
elderly persons. Journal of the American Geriatrics Society. Feb 1991;39(2):142-8.  

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APPENDIX I: COMPREHENSIVE GERIATRIC ASSESSMENT  
GERIATRIC ASSESSMENT SURVEY 
To be completed by Physician, Nurse, or CRA: 
Responsible person name (Physician, Nurse, or CRA) ______________________________________________ 
Assessment Period (as applicable to this study) □ Pre-treatment   □□ Cycle #   □ End of Treatment 
 
 
PATIENT QUESTIONNAIRE 
 
Patient Instructions:  If you are unable to complete the questionnaire, a member of your health care team will assist you. Please 
do not have a family member complete the questionnaire for you. 
□ Mark box with an “X”, if form was not completed at specified timepoint and specify reason:  
   (Mark one with an X.) 
□ Patient refused  □ Patient withdrew consent □ Not done 
 
 
 
□ Other, specify ______________________________________________________ 
 
 
 
 
 
(For assessment date, record approximate date form was to be completed.) 
A. BACKGROUND INFORMATION 
 
1. 
What is the highest grade you finished in school? (Mark one with an X.) 
□ 8th grade or less 
□ Vocational/ technical school 
 
□ 9-11th grade 
□ Bachelor’s degree 
□ High school graduate/GED 
□ Advanced degree 
 
□ Associate degree/some college 
□ I prefer not to answer 
 
2. 
What is your marital status? (Mark one with an X.) 
□ Married 
□ Divorced 
□ I prefer not to answer 
□ Domestic partnership 
□ Separated 
 
□ Widowed 
□ Never married 
 
 
 
3. 
With whom do you live? (Mark all that apply with an X.) 
□ Spouse / partner  
 
□ Parent(s)/parent(s)-in-law 
□ Girlfriend / boyfriend 
 
□ Live alone 
□ Children aged 18 years or younger □ Others, specify: ________________ 
□ Children aged 19 years or older 
 
□ Other relative, specify: ________________ 
 
 

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4. 
What is your current employment status?  (Mark one with an X.) 
□ Employed 32 hours or more per week  
 
□ Unemployed 
□ Employed less than 32 hours per week 
 
□ Retired 
□ Homemaker 
 
 
 
 
□ Full-time student 
□ Disabled 
 
 
 
 
□ Part-time student  
□ On medical leave 
 
 
 
□ Other, specify: ________________ 
B. DAILY ACTIVITIES* 
 
PATIENT INSTRUCTIONS: Indicate your response by marking an X in one box per question. 
 
1. 
Can you use the telephone… 
□ without help, including looking up and dialing; 
□ with some help (can answer phone or dial operator in an emergency, but need a special phone or help in getting the 
phone number or dialing); or  
□ are you completely unable to use the telephone? 
 
2. 
Can you get to places out of walking distance… 
□ without help (can travel alone on buses, taxis, or drive your own car); 
□ with some help (need someone to help you or go with you when traveling); or 
□ are you unable to travel unless emergency arrangements are made for a specialized vehicle like an ambulance? 
 
 

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3. 
Can you go shopping for groceries or clothes (assuming you have transportation) … 
□ without help (taking care of all shopping needs yourself, assuming you have transportation); 
□ with some help (need someone to go with you on all shopping trips); or 
□ are you completely unable to do any shopping? 
 
4. 
Can you prepare your own meals… 
□ without help (plan and cook full meals yourself); 
□ with some help (can prepare some things but unable to cook full meals yourself); or 
□ are you completely unable to prepare any meals? 
 
5. 
Can you do your housework… 
□ without help (can clean floors, etc); 
□ with some help (can do light housework but need help with heavy work); or  
□ are you completely unable to do any housework? 
 
6. 
Can you take your own medicines… 
□ without help (in the right doses at the right time); 
□ with some help (able to take medicine if someone prepares it for you and/or reminds you to take it); or 
□ are you completely unable to take your medicines? 
 
7. 
Can you handle your own money… 
□ without help (write checks, pay bills, etc.); 
□ with some help (manage day-to-day buying but need help with managing your checkbook and paying your bills); or 
□ are you completely unable to handle money? 
 
* OARS IADL53 
 

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C. PHYSICAL ACTIVITIES*  
 
1. 
The following items are activities you might do during a typical day. Does your health limit you in these activities?  (Mark 
an X in the box on each line that best reflects your situation.) 
 
 
Activities 
Limited  
a lot 
Limited  
a little 
Not limited  
at all 
a. 
Vigorous activities such as: running, lifting heavy objects, participating 
in strenuous sports 
□ 
□ 
□ 
b. 
Moderate activities such as: moving a table, pushing a vacuum cleaner, 
bowling, or playing golf 
□ 
□ 
□ 
c. 
Lifting or carrying groceries 
□ 
□ 
□ 
d. 
Climbing several flights of stairs 
□ 
□ 
□ 
e. 
Climbing one flight of stairs 
□ 
□ 
□ 
f. 
Bending, kneeling, or stooping 
□ 
□ 
□ 
g. 
Walking more than a mile 
□ 
□ 
□ 
h. 
Walking several blocks 
□ 
□ 
□ 
i. 
Walking one block 
□ 
□ 
□ 
j. 
Bathing or dressing yourself 
 
□ 
□ 
□ 
 
 
* MOS, Physical Functioning Scale54 

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D. CURRENT HEALTH RATING* 
 
  Which one of the following phrases best describes you at this time? (Mark one with an X.) 
□ Normal, no complaints, no symptoms of disease 
□ Able to carry on normal activity, minor symptoms of disease 
□ Normal activity with effort, some symptoms of disease 
□ Care for self, unable to carry on normal activity or do active work 
□ Require occasional assistance but able to care for most of personal needs 
□ Require considerable assistance for personal care 
□ Disabled, require special care and assistance 
□ Severely disabled, require continuous nursing care 
 
* Patient KPS55 
 
 
E. FALLS 
How many times have you fallen in the last 6 months?  □□□ 
 
 
F. YOUR HEALTH  
1. 
Your General Health* 
Patient Instructions: Do you have any of the following illnesses at the present time, and if so, how much does it interfere with 
your activities: Not at all, Somewhat or A Great Deal? (Mark an X in the box that best reflects your answer.) 
 
 
 
If you have this illness:  
How much does it interfere with your activities? 
Illness 
No 
Yes 
 
Not  
at all 
A little 
A great 
deal 
a. 
Other cancers or leukemia 
□ 
□ 
→ 
□ 
□ 
□ 
b. 
Arthritis or rheumatism 
□ 
□ 
→ 
□ 
□ 
□ 

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If you have this illness:  
How much does it interfere with your activities? 
Illness 
No 
Yes 
 
Not  
at all 
A little 
A great 
deal 
c. 
Glaucoma 
□ 
□ 
→ 
□ 
□ 
□ 
d. 
Emphysema or chronic bronchitis 
□ 
□ 
→ 
□ 
□ 
□ 
e. 
High blood pressure 
□ 
□ 
→ 
□ 
□ 
□ 
f. 
Heart disease 
□ 
□ 
→ 
□ 
□ 
□ 
g. 
Circulation trouble in arms or legs 
□ 
□ 
→ 
□ 
□ 
□ 
h. 
Diabetes 
□ 
□ 
→ 
□ 
□ 
□ 
i. 
Stomach or intestinal disorders 
□ 
□ 
→ 
□ 
□ 
□ 
j. 
Osteoporosis 
□ 
□ 
→ 
□ 
□ 
□ 
k. 
Liver disease 
□ 
□ 
→ 
□ 
□ 
□ 
l. 
Kidney disease 
□ 
□ 
→ 
□ 
□ 
□ 
m. Stroke 
□ 
□ 
→ 
□ 
□ 
□ 
n. 
Depression 
□ 
□ 
→ 
□ 
□ 
□ 
 
 
* OARS IADL53 
 
 

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2. 
How is your eyesight (with glasses or contacts)?  (Mark one with an X.) 
□ Excellent 
 
□ Good 
 
□ Fair 
 
 
□ Poor 
 
 
□ Totally blind 
 
3. 
How is your hearing (with a hearing aid, if needed)? (Mark one with an X.) 
□ Excellent 
 
□ Good 
 
□ Fair 
 
 
□ Poor 
 
 
□ Totally deaf 
 
4. 
Do you have any other physical problems or illnesses (other than listed in questions 1-4) at the present time that seriously 
affect your health? 
□ No 
 
□ Yes, specify:  
 
If yes, how much does this interfere with your activities?  (Mark one with an X.) 
 
 
□ Not at all 
 
□ Somewhat 
 
□ A great deal 
  
 
 
* OARS IADL53  
 
 
 
 

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G. NUTRITIONAL STATUS 
1.  Have you lost weight involuntarily over the past 6 months?   
 
□ No 
 
□ Yes 
 
 
 
If yes, how much? 
 
 
 
□□□ pounds 
2.  What is your weight now? 
  
 
 □□□ pounds 
3. 
What was your weight 6 months ago? 
  □□□ pounds 
H. HEALTH QUESTIONNAIRE* 
INSTRUCTIONS: These questions are about how you have been feeling within the past month. Please mark an “X” in 
the box on each line that best reflects your situation. 
 
 
How much of the time during the past 
month: 
All  
of the 
Time 
Most 
of the 
Time 
A Good 
Bit of the 
Time 
Some  
of the 
Time 
A Little 
of the 
Time 
None 
of the 
Time 
1. 
has your daily life been full of things that 
were interesting to you? 
□ 
□ 
□ 
□ 
□ 
□ 
2. 
did you feel depressed? 
□ 
□ 
□ 
□ 
□ 
□ 
3. 
have you felt loved and wanted? 
□ 
□ 
□ 
□ 
□ 
□ 
4. 
have you been a very nervous person? 
□ 
□ 
□ 
□ 
□ 
□ 
5. 
have you been in firm control of your 
behavior, thoughts, emotions, feelings? 
□ 
□ 
□ 
□ 
□ 
□ 
6. 
have you felt tense or high-strung? 
□ 
□ 
□ 
□ 
□ 
□ 
7. 
have you felt calm and peaceful? 
□ 
□ 
□ 
□ 
□ 
□ 
8. 
have you felt emotionally stable? 
□ 
□ 
□ 
□ 
□ 
□ 
9. 
have you felt downhearted and blue? 
□ 
□ 
□ 
□ 
□ 
□ 
10. have you felt restless, fidgety, or 
impatient? 
□ 
□ 
□ 
□ 
□ 
□ 
11. have you been moody, or brooded about 
things? 
□ 
□ 
□ 
□ 
□ 
□ 

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12. have you felt cheerful, light-hearted? 
□ 
□ 
□ 
□ 
□ 
□ 
13. have you been in low or very low spirits? 
□ 
□ 
□ 
□ 
□ 
□ 
14. were you a happy person? 
□ 
□ 
□ 
□ 
□ 
□ 
15. did you feel you had nothing to look 
forward to? 
□ 
□ 
□ 
□ 
□ 
□ 
16. have you felt so down in the dumps that 
nothing could cheer you up? 
□ 
□ 
□ 
□ 
□ 
□ 
17. have you been anxious or worried? 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
* MHI-1754 - Stewart, A.L. and Ware, J.E., 1992 
 
 
 
 

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I. SOCIAL ACTIVITIES* 
 
1. 
During the past 4 weeks, how much time has your physical health or emotional problems interfered with your social 
activities (like visiting with friends, relatives, etc.)? (Mark one with an X.) 
 
□ All of the time 
□ Most of the time 
□ Some of the time 
□ A little of the time 
□ None of the time 
 
2. 
Compared to your usual level of social activity, has your social activity during the past 6 months decreased, stayed the same, 
or increased because of a change in your physical or emotional condition?  (Mark one with an X.) 
 □ Much less socially active than before 
□ Somewhat less socially active than before 
□ About as socially active as before 
□ Somewhat more socially active as before 
□ Much more socially active than before 
 
3. 
Compared to others your age, are your social activities more or less limited because of your physical health or emotional 
problems? (Mark one with an X.) 
 □ Much more limited than others 
□ Somewhat more limited than others 
□ About the same as others 
□ Somewhat less limited than others 
□ Much less limited than others 
 
 
 
* MOS, Social Activities54 
 

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J. SOCIAL SUPPORT* 
 
INSTRUCTIONS: People sometimes look to others for companionship, assistance or other types of support. How often is 
each of the following kinds of support available to you if you need it? (Mark an X in the box on each line that best reflects 
your situation.) 
 
 
None  
of the 
Time 
A Little 
of the 
Time 
Some  
of the 
Time 
Most  
of the 
Time 
All  
of the 
Time 
1. 
Someone to help you if you were confined to bed. 
□ 
□ 
□ 
□ 
□ 
2. 
Someone you can count on to listen to you when you 
need to talk. 
□ 
□ 
□ 
□ 
□ 
3. 
Someone to give you good advice about a crisis. 
□ 
□ 
□ 
□ 
□ 
4. 
Someone to take you to the doctor if needed. 
□ 
□ 
□ 
□ 
□ 
5. 
Someone to give you information to help you understand 
a situation. 
□ 
□ 
□ 
□ 
□ 
6. 
Someone to confide in or talk to about yourself or your 
problem. 
□ 
□ 
□ 
□ 
□ 
7. 
Someone to prepare your meals if you were unable to do 
it yourself. 
□ 
□ 
□ 
□ 
□ 
8. 
Someone whose advice you really want. 
□ 
□ 
□ 
□ 
□ 
9. 
Someone to help you with daily chores if you were sick. 
□ 
□ 
□ 
□ 
□ 
10. Someone to share your most private worries and fears 
with. 
□ 
□ 
□ 
□ 
□ 
11. Someone to turn to for suggestions about how to deal 
with a personal problem. 
□ 
□ 
□ 
□ 
□ 
12. Someone who understands your problems. 
□ 
□ 
□ 
□ 
□ 
 
 
* MOS Social Support Survey 56 
 

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K.  SPIRITUALITY/RELIGION* 
 
Directions: Please answer the following questions about your religious beliefs and/or involvement. (Please mark an “X” in 
the box on each line that best reflects your situation.) 
 
1. 
How often do you attend church, synagogue, or other religious meetings? (Mark one with an X.) 
 □ More than once per week 
□ Once a week 
□ A few times a month 
□ A few times a year 
□ Once a year or less 
□  Never 
 
2. 
How often do you spend time in private religious activities, such as prayer, meditation, or Bible study? (Mark one with an 
X.) 
 □ More than once a day 
□ Daily 
□ Two or more times per week 
□ Once a week 
□ A few times a month 
□  Rarely or never 
 
The following section contains 3 statements about religious belief or experience. Please mark the extent to which each statement 
is true or not true for you. 
 
3.  In my life, I experience the presence of the Divine (i.e., God). (Mark one with an X.) 
 
□ Definitely true of me 
□ Tends to be true 
□ Unsure 
□ Tends not to be true 
□ Definitely not true 
 
4.    My religious beliefs are what really lie behind my whole approach to life. (Mark one with an X.) 
 
□ Definitely true of me 
□ Tends to be true 
□ Unsure 
□ Tends not to be true 
□ Definitely not true 

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5.   I tried hard to carry my religion over into all other dealings in my life. (Mark one with an X.) 
 
□ Definitely true of me 
□ Tends to be true 
□ Unsure 
□ Tends not to be true 
□ Definitely not true 
 
*DUREL: Duke University ReligionIndex57– Koenig et al., 1997 
 
L.  YOUR FEELINGS* 
1.  Do you often feel sad or depressed? (Mark one with an X.) 
 
□ No 
□ Yes 
 
2.  How would you describe your level of anxiety, on average? Please circle the number (0-10) best reflecting your  
 
response to the following that describes your feelings during the past week, including today. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No anxiety  
 
 
 
 
 
 
 
 
Anxiety as bad as 
It can be 
*Mahoney et al., 1994; LASA58 
 
M.  QUESTIONS CONCERNING THE QUESTIONNAIRE 
 
1. 
Were there any questions difficult to understand?  □ No     □ Yes 
If Yes, which questions were they? 
 
 
 
 
2. 
Was the time it took to answer all the questions too long, just right or too short? 
□ Too short  →  How long would you have liked the questionnaire to be?   □□ minutes 
□ Just right 
□ Too long →  How long would you have liked the questionnaire to be?   □□ minutes 
 
 
Which items would you remove? 
 

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3. 
Did you find any of the questions upsetting?  
□ No     □ Yes 
 
If Yes, which questions were they? 
 
 
 
 
 
Could you tell me why they were upsetting? 
 
 
 
 
 
4. 
Do you think the questionnaire left out any questions that were important to ask? 
 
 
 
 
 
Thank you for your participation. 
 
 

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Geriatric Assessment: Healthcare Professional Questionnaire  
 
 
To be completed by Physician, Nurse, or CRA 
I. This form completed by: (Mark all that apply with an X.) 
Assessment Period (as applicable to this study) 
□ Physician 
    □ Nurse 
   □ CRA 
         □ Pre-treatment   □□ Cycle #   □ End of Treatment 
 
 
□ Mark box with an “X”, if form was not completed at specified timepoint and specify reason:  
   (Mark one with an X.) 
□ Patient refused  □ Patient withdrew consent □ Not done 
 
 
 
□ Other, specify ______________________________________________________ 
 
 
 
 
 
(For assessment date, record approximate date form was to be completed.) 
 
II.  FUNCTIONAL STATUS 
A. KPS  (Healthcare professional rated*) 
Please rate your assessment of patient’s Karnofsky Performance Status as of date this form is completed. (Scale is listed 
below.) 
□□□ % 
% 
CRITERIA 
100 
Normal: no complaints; no evidence of disease. 
90 
Able to carry on normal activity; only minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, but unable to carry on normal activity or do active work. 
60 
Requires occasional assistance, but is able to care for most personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospitalization is indicated although death not imminent. 
20 
Very sick; hospitalization necessary; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
* Physician KPS59  
 
 

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B. 
Timed “Up and Go”* 
 
INSTRUCTIONS: The timed “Up and Go” measures, in seconds, the time it takes for an individual to  stand up from a 
standard arm chair (approximate seat height of 46 cm [approximately 1.5 ft]), walk a distance of 3 meters (approximately 10 
feet), turn, walk back to the chair, and sit down again. The subject wears his/her regular footwear and uses their customary 
walking aid (none, cane, walker, etc.) No physical assistance is given. The subject starts with his back against the chair, his 
arm resting on the chair’s arm, and his walking aid in hand.  He is instructed that on the word “go”, he is to get up and walk 
at a comfortable and safe pace to a line on the floor 3 meters (approximately 10 feet) away, turn, and return to the chair and 
sit down again. The subject walks through the test once before being timed in order to become familiar with the test. Either a 
wrist watch with a second hand or a stop-watch can be used to time the performance. 
 
 
Time to perform “Up and Go”  □□.□ seconds 
 
* Timed “Up and Go”60  
 
 
 
III.  COGNITION This section is only completed Pretreatment and at the end of treatment 
 
6-ITEM ORIENTATION-MEMORY-CONCENTRATION TEST** 
 
Patient’s 
Response 
Maximum 
errors 
                                         Final 
Score          Weight          score 
1. 
What year is it now? 
[without looking at a calendar] 
□□□□ 
1 
□□  x               4        =      □□ 
2. 
What month is it now? 
[without looking at a calendar] 
□□ 
1 
□□   x               3        =      □□ 
Memory Phrase: 
Repeat this phrase after me:  
‘John Brown, 42 Market Street, Chicago’ 
 
 
 
3. 
About what time is it? 
[ within 1 hour – without looking at 
your watch] 
□□:□□ 
1 
□□   x               3        =      □□ 
4. 
Count backwards 20 to 1. 
 
2 
□□   x               2        =      □□ 
5. 
Say the months in reverse order. 
 
2 
□□   x               2        =      □□ 
6. 
Repeat the Memory Phrase. 
 
5 
□□   x               2        =      □□ 
 
 
 
 
                  TOTAL SCORE:     □□ 
 

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Scoring: For items 1 to 3, the response is either correct (score 0) or incorrect (score 1). For items 4 to 6, add one point for each 
error (item 4 and 5 maximum error is 2; for item 6, maximum error is 5); total all scores in “Final Score” column. Data from 
participants found to have gross cognitive impairment as determined by the Orientation-Memory-Concentration Score ≥11 will 
be excluded from the analysis. Maximum score = 28. 
 
** OMC – Katzman, R., et al., 1983; Kawas, C., et al., 1995 
 
 

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IV.  SCORING This section is only applicable if OMC-Test is completed Pretreatment and Post treatment 
 
Did the patient score ≥11 on the 6-Item Orientation-Memory-Concentration Test? 
 
□ No 
□ Yes (If yes, notify the patient’s treating physician.) 
 
This question is only applicable to question #1 in “Section K. Your Feelings” from the Patient Questionnaire. 
 
1. How did the patient answer the question “Do you often feel sad or depressed?” in the Patient 
 
Questionnaire (Section K)? 
 No 
 Yes (If yes, notify the patient’s treating physician.) 
 
 
 
V. NUTRITION 
 
What is the patient’s height? (from patient’s chart)    □□□ cm 
 
What is the patient’s current weight? (from patient’s chart)    □□□ kg 
 
What was the patient’s weight approximately 6 months ago? (from patient’s chart or patients self report)  □□□ kg 
 
Calculated Body Mass Index: □□.□ 
 
Percent Unintentional Weight Loss:  □□.□% 
 
 
 
VI. QUESTIONS REGARDING THE QUESTIONNAIRES 
 
A. Were any of the questionnaires in the “Geriatric Assessment – Healthcare Professional Questionnaire” difficult for you to 
administer? 
 
□Yes     □No 
 

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If no, please proceed to the next question. 
If yes, please indicate which questionnaire was difficult to administer? (Mark all that apply with an X.) 
□ KPS Healthcare Professional Rated (page 1) 
□ Timed Up and Go (page 2) 
□ 6-Item Orientation-Memory-Concentration Test (page 2) 
□ Other: Please specify _________________________________ 
 
 
B. 
Were any of the questionnaires in the “Geriatric Assessment – Patient Questionnaire” difficult for the patient to complete? 
 
□Yes     □No 
 
B.    If no, please proceed to the next question. If yes, please indicate which questionnaire(s) was difficult for the patient to 
complete? (Mark all that apply with an X.) 
 
□ Background Information (page 1) 
□ Daily Activities (page 2-3) 
□ Physical Activities (page 3) 
□ Current Health Rating (page 4) 
□ Falls (page 4) 
□ Your Health (page 4-5)  
□ Nutritional Status (page 7-8) 
□ Health Questionnaire (page 9) 
□ Social Activities (page 10) 
□ Social Support (page 11) 
□ Spirituality or religion (page 12) 
□ Your Feelings (page 13) 
 
C. 
Was the patient able to complete “Geriatric Assessment – Patient Questionnaire” on his/her own? 
 
□Yes     □No 
 
If no, why? (Mark all that apply with an X.) 
□ Not literate (does not read or write) 
□ Visual problem 
□ Fatigue 
□ Questions too difficult (above the patient’s reading ability) 

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□ Other: specify_________________________________________________ 
 
D. Length of time to complete both the Patient and Healthcare Professional Questionnaires 
 
Length of time to complete healthcare professional questionnaire □□□ minutes 
 
Length of time to complete patient questionnaire  
 
□□□ minutes 
 
Total length of time to complete both questionnaires 
 
 
□□□ minutes 
 
 
Completed by: ____________________________ 
Date form completed: □□ / □□ / □□□□ 
 
(Last name, First name) 
 
 
 
        M M         D  D         Y   Y   Y  Y 
 
 
 
 
 
 
 

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APPENDIX II: MFSI-SF  
 
 
 

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APPENDIX III: GODIN LEISURE-TIME EXERCISE QUESTIONNAIRE  
Godin Leisure-Time Exercise Questionnaire 
 
1. During a typical 7-Day period (a week), how many times on the average do you do the following kinds of 
exercise for more than 15 minutes during your free time (write on each line the appropriate number). 
  
Times Per 
Week 
a) STRENUOUS EXERCISE 
 
(HEART BEATS RAPIDLY) 
__________ 
 
(e.g., running, jogging, hockey, football, soccer, 
 
squash, basketball, cross country skiing, judo, 
 
roller skating, vigorous swimming, 
 
 vigorous long distance bicycling) 
 
b) MODERATE EXERCISE 
 
(NOT EXHAUSTING) 
__________ 
 
(e.g., fast walking, baseball, tennis, easy bicycling, 
 
volleyball, badminton, easy swimming, alpine skiing, 
 
popular and folk dancing) 
 
c) MILD EXERCISE 
 
(MINIMAL EFFORT) 
__________ 
 
(e.g., yoga, archery, fishing from river bank, bowling, 
 
horseshoes, golf, snow-mobiling, easy walking) 
 
 
2. During a typical 7-Day period (a week), in your leisure time, how often do you engage in any regular activity long 
enough to work up a sweat (heart beats rapidly)? 
 
 
OFTEN  
SOMETIMES  
NEVER/RARELY 
 
1. |_| 
2. |_| 
3. |_| 
 
 

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APPENDIX IV: LINEAR ANALOGUE SELF-ASSESSMENT (LASA) 
LINEAR ANALOGUE SELF ASSESSMENT 
  
Directions: Please circle the number (0-10) best reflecting your response to the following 
 
  
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well being? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
7. the frequency of your pain? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain  
 
 
 
 
 
 
 
 
Constant pain 
 
8. the severity of your pain, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain  
 
 
 
 
 
 
 
 
Pain as bad as  
 
 
 
 
 
 
 
 
 
 
 
you can imagine 
9. your level of fatigue, on the average? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No fatigue 
 
 
 
 
 
 
 
 
Constant tiredness 
 
10. your level of support from friends and family? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No support 
 
 
 
 
 
 
 
 
 
Highest level of  
 
 
 
 
 
 
 
 
 
 
 
 
support 
 

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11. your financial concerns? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns  
 
 
 
 
 
 
 
No concerns 
 
12. your legal concerns (will, advanced directives, etc.)? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Constant concerns  
 
 
 
 
 
 
 
No concerns 
13. Did you experience trouble sleeping? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not at all  
 
 
 
 
 
 
 
as bad as it can be 
 
© 1996  Mayo Foundation for Medical Research 
 
 

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APPENDIX V ELECTRONIC PATIENT-REPORTED OUTCOMES (EPRO) INSTRUCTIONS 
1.0 
Introduction 
Electronic collection of patient-reported outcomes is preferred but not mandatory.  Patients will need 
to use their own device (IOS or Android phone or tablet), or a device provided by their institution.  
Short term data will only appear on the patient’s/site device until responses are completed.  The 
patient data will import directly into the database once the patient clicks the submit button and will 
no longer be on the device.  
Sites can use a site-specific tablet for different study participants.  If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users.   
Site staff access 
Site users of ePRO and the Patient Cloud require the same access as those using Rave. Access to the 
trial in the Patient Cloud is granted through the iMedidata application to all persons with the 
appropriate roles assigned in Regulatory Support System (RSS). To access the Patient Cloud via 
iMedidata, the site user must have an active CTEP-IAM account and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login using their CTEP-IAM user name and password, and click 
on the “accept” link in the upper right-corner of the iMedidata page. Please note, site users will not 
be able to access the study in the Patient Cloud until all required Medidata and study specific trainings 
are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed 
by clicking on the link in the upper right pane of the iMedidata screen.  
Users who have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Rave tab at 
or by contacting the 
   
2.0 
Security 
All data are encrypted on the device (128 bit on file +https transfer) and the app requires a user to 
have a username and password.  If the user is idle for too long (5 minutes inactivity time), the app 
will time out and the user will need to log in again. 
The data will only reside on the device for a short period of time.  Once the user clicks “submit,” the 
data is securely transferred over https between the device and internal relay.  No identifying 
information is stored in iMedidata (only email address is stored). 
The Patient information (email/password) does not reside in Medidata Rave EDC and the patient 
accounts are hidden in iMedidata from sites and sponsors in the Patient Cloud Relay. 
The ePRO application is Part 11 compliant and acts as a gateway between device and Medidata 
Clinical Cloud (MCC).   
Messages and information communicated to and from the Patient Cloud are encrypted and therefore 
this information cannot be read if intercepted while in transit. 
 
 

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3.0 
CRP Training for ePRO 
Please visit the Medidata Learning Tool for reference information on Patient Cloud for CRAs. 
4.0 
Checklist for activities prior to consenting a patient 
• 
Site staff must have already completed required eLearning for the Patient Cloud application. 
See last bullet with hyperlink to training video library. See Section 1.0  of this Appendix for 
instructions on site staff access.  
• 
Accept study invitation at
 
Note: you must be rostered in RSS and have received an invitation to Patient Cloud ePRO 
• 
Verify the IOS or Android operating system is using the most current version 
• 
Verify Patient Cloud app is using the most current version 
• 
Refer to 
 
to review Quick reference guides  
5.0 
Instructions for ePRO patient registration 
Please visit the Medidata Learning Tool for additional screen shots and video tutorials on how to 
register participants to the study. 
i. 
The patient registration process starts in iMedidata.  Begin by clicking on the Patient Cloud 
Registration link for this study. 
ii. 
The patient management app will display, select your STUDY and SITE from the drop downs 
and click Launch. 
iii. Now the first patient can be registered. (Please note that the patient must have already been 
registered in OPEN to generate a patient ID).  Select subject ID (patient ID) and select a Country 
/ Language from the drop down, (these are the only required data fields). The patient initials are 
optional, but may help in identifying which subject ID maps with which activation code. When 
finished, click Add. 
iv. The patient added will appear at the top of the table and will include the date the patient was 
added, the subject ID, initials, (if included) and a unique auto-generated activation code. The 
activation code is unique for each patient and linked to the subject ID, it is not interchangeable. 
In addition, there is a status section, which determines if the patient has registered. When the 
patient has registered the status will change from invited to registered. 
 
 

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6.0 
Patient Users 
To use the Patient Cloud app, patients will need to use their own device (IOS, Android phone or 
tablet) (for those who choose to use their own device).  Short term data will only appear on the 
patient’s device until responses are completed and submitted.  The patient data will import directly 
into the database once the patient selects the “Submit” button and will no longer be visible on the 
patient's device. 
Patient compliance: The patient data imports directly from her/his device into the Rave database.  
There are no documents to audit.  The electronic responses are the source documentation. 
Patient Instructions for Accessing the Patient Cloud App using their personal device 
Downloading the Patient Cloud App: 
Please ensure that the patient downloads the following app from the app store, and not Patient cloud 
ePRO (which is the legacy app).   
 
If you are using your personal device, and you do not have the Patient Cloud app, use the following 
instructions. When downloading the app, you must use the Apple ID or Google account associated 
with the device. If the Patient Cloud app is already on the device, or if you are using a provider's 
device, you can skip this section. 
You will need an email address that you agree to use for this purpose. The e-mail address is needed 
to identify you on the Patient Cloud Application and for you to receive notifications to let you know 
when forms are due. Your e-mail address will only be used for this survey study, and will not be used 
for mail or marketing purposes. 
If you decide to use the electronic method to complete the questionnaires, and do not have an e- mail 
address, you may sign up for one at no charge at many different websites. A few sites that are 
commonly used and will allow you to create an email address very easily are Yahoo, Gmail, and 
Outlook. 
For iOS: 
1. 
An Apple ID is required for downloading the Patient Cloud app. 
2. 
Tap the App Store icon. 
3. 
Search for Medidata Patient Cloud and follow the installation instructions. 
Note: Patient Cloud is listed as an iPhone App in the App store. When using an iPad, please view the 
search results under iPhone apps. 
For Android: 
1. 
A Google account is required for downloading the Patient Cloud app. 
2. 
Tap the Play Store icon. 
3. 
Search for Medidata Patient Cloud and follow the installation instructions. 

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Registering on the App: 
You must register in order to complete and submit your study forms. When you register, you will 
create a username, which is your email address, and a password that allows you to log in to the Patient 
Cloud app. 
Note: You must have an activation code to begin this process. If you do not have an activation 
code, please contact your provider. 
There are two possible ways to register. Your provider may have sent you a link to a web address 
where you may register from any web browser, including the one on your device. The other way to 
register is on the Patient Cloud app. 
1. 
If registering from the Patient Cloud app, tap Register on the bottom of the log in page. If 
registering on the web, open the URL 
 on a web browser. 
2. 
Enter your activation code and tap Activate. 
3. 
On the next page, read the instructions and tap Next. 
4. 
Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. 
Enter and confirm your email address. Tap Next. 
6. 
Enter and confirm your password. Tap Next. 
7. 
Choose a security question by scrolling through the dropdown menu to display the question of 
your choice. 
8. 
Enter your security question response. 
9. 
Tap Create my account to complete your registration. 
If you registered on the Patient Cloud app, it automatically logs you out. If you registered on the web, 
you are presented with the option to download the Patient Cloud app. You can then proceed to log in 
with the credentials you created. 
Logging in to the App after registration: 
1. 
Enter your Email and Password that you created during the registration process. (If you 
previously set a PIN code, just enter your four-digit PIN.) 
2. 
Tap Log in. 
Note: If you do not remember your password, tap Forgot Password, and follow the instructions 
provided. 
Setting a PIN Code: 
The first time you log in to the Patient Cloud app, you are given the option to create a PIN code. A 
PIN code allows you to bypass the step of entering your email and password every time you need to 
log in to the Patient Cloud app. Instead, you can enter a four-digit PIN. 
1. 
If you wish to set a PIN code the first time you log in, tap Yes when prompted. 
2. 
Note: You can also set your PIN at a later time by tapping the options menu on the top left of 
most pages and selecting Set PIN. 
3. 
Enter a four-digit PIN. 
4. 
Re-enter the four-digit PIN to confirm. 

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If you forget your PIN code, tap Forgot PIN and you can access the app using your email and 
password. You may reset your PIN by tapping the options menu on the top left of most pages and 
selecting Set PIN. 
Resetting Your Password: 
You can reset your password by using the options menu at the top left of most pages. 
1. 
Tap the options menu icon. 
2. 
Tap Reset Password. 
3. 
Follow the instructions to reset your password. 
Completing and Submitting Forms: 
Once logged in, forms related to your study display on the Tasks page. If you are enrolled in multiple 
studies, select the appropriate study first, and then select a form. New forms can appear on the Tasks 
page at any time, depending on how the study is designed. 
There are two types of forms displayed on the Task List page: 
• 
Scheduled Forms (with a 
 icon): These forms have a "Due Date" indicator in them so you are 
aware of the last day by which you will need to complete the form. If the form is due in less than 
one day, you will see the due time in hours. 
• 
Anytime Forms (with a 
 icon): These forms have "Last Completed Time" indicator on them 
which tells the most recent date or time when you completed the form. If you start a form, but 
do not complete it, you will see an 'Incomplete" status beneath the form name, along with a half-
moon icon 
1. 
Select the appropriate form. 
2. 
Follow the on-screen instructions until you reach the end of the form where you are given the 
opportunity to review and change your responses prior to submitting. 
3. 
Review your responses by scrolling down the list. 
4. 
If you need to change an answer, tap the question to go back and change the answer. 
5. 
When you are ready to submit, tap Submit Your Data. 
Note: Once a form is submitted, you will be unable to edit any of your responses. In some cases, you 
may be asked to acknowledge your submission by entering your password. 
 
 

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APPENDIX VI EPRO INSTRUCTION FLOW CHART FOR PATIENTS  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Download the Patient Cloud app 
 
Create a username and password for the Patient 
Cloud app by selecting the ‘Have an Activation Code?’ 
option on the login screen. Use the activation code 
from your clinic. 
Log in to the Patient Cloud app 
See your forms on the main screen 
Complete, review, and submit your 
forms 
Tip: When a form is due, 
you will see the alarm clock 
with the date and time the 
form will close. 
 
For help with the Patient Cloud app, please ask your 
study team! 
 
Tip: Your username must be 
in email format (for example, 
jodiesmith20@email.com). 

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APPENDIX VII PATIENT INFORMATION SHEETS 
PATIENT INFORMATION SHEET 
BASELINE 
 
Patient Completed Quality of Life Booklet (Baseline/Week 1) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet is to be completed before you start study treatment. 
 
2. The booklet contains 4 set of questions: 
a. Comprehensive Geriatric Assessment questionnaire  
b. Multidimensional Fatigue Symptom Inventory Short form (MFSI-SF) 
c. Godin Leisure Time Exercise Questionnaire 
d. Linear Analogue Self-Assessment  
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. Please return your booklet, in the envelope provided or in person when you are finished. 
 
 
Thank you for taking the time to help us. 
 
 

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PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet (Weeks 2-9) and End of treatment 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet is to be completed once every 3 weeks for the first 9 weeks after the study begins, 
and at the end of study treatment. If you have a clinic visit at this time, please complete it on that 
day, before you receive any treatment. 
 
2. The booklet contains 3 set of questions: 
a. Multidimensional Fatigue Symptom Inventory Short form (MFSI-SF) 
b. Godin Leisure Time Exercise Questionnaire 
c. Linear Analogue Self-Assessment  
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. You may call a member of the study team to answer any questions you might have.  You will be 
given a name and telephone number.  You can call anytime with any concerns or questions. A 
nurse/research coordinator will also call you at the end of every week and they can answer 
questions you might have.  
 
5. It is very important that you return the booklet to us, whether you finish the study or not. 
 
6. When the booklet is complete, return it in the provided envelope. 
 
 
Thank you for taking the time to help us.  
 
 

Alliance A171901 
Version date 05/032022 
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Update #03 
 
APPENDIX VIII PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
 
 
 

Alliance A171901 
Version date 05/032022 
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Update #03 
 
APPENDIX IX PATIENT THANK YOU LETTERS 
 
Guidance for Disseminating 
Thank You Letters to Trial Participants 
 
Trial Participant Thank You Letter  
We ask that the physician use the template to prepare a letter thanking the participant for 
enrolling in this Alliance trial. The template is intended as a guide and can be downloaded from 
the study page on the Alliance website at 
 As this is a personal letter, 
physicians may elect to further tailor the text to their situation.  
This small gesture is a part of a broader program being undertaken by Alliance and the NCI to 
increase awareness of the importance of clinical trials and improve accrual and follow-through.  
We appreciate your help in this effort.  
____________________________________________________________________  
Sample Template 
[PARTICIPANT NAME] [DATE] [PARTICIPANT ADDRESS]  
Dear [PARTICIPANT SALUTATION],  
Thank you for agreeing to take part in this important research study. With the help of people like 
you who participate in clinical trials, we will achieve our goal of effectively treating and ultimately 
curing cancer.  
There are many reasons why individuals choose to participate in a clinical trial. Sometimes it is 
because they want access to a specific medication or because they want to do whatever they 
can to help someone else with cancer.  Whatever your reason for participating, you are making 
a contribution towards finding better treatments and ultimately eliminating this disease for future 
patients. 
You will receive high quality care while participating in this clinical trial. My research staff and I 
will maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other participants.  
On behalf of [INSTITUTION] and the Alliance for Clinical Trials in Oncology, we thank you again 
for your participation in this clinical trial and look forward to partnering with you.  
Sincerely, [PHYSICIAN NAME]