Clinical trial NCT04964960
Conditions: Lung Cancer Lung Cancer Metastatic Brain Cancer Cancer
Sponsor: John L. Villano, MD, PhD
Start date: 2022-05-19; Completion date: 2023-12-19
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this study is to evaluate whether providing Pembrolizumab prolongs survival and preserves quality of life while minimizing side effects for patients with NSCLC with untreated asymptomatic brain metastasis.

Detailed description:

Arms: arm 1: Patients will receive 200mg or 400mg of Pembrolizumab (standard of care dosing at the discretion of treating physician) over thirty minutes on day 1 every three or six weeks with standard of care chemotherapy treatment (carboplatin, pemetrexed, paclitaxel, nab-paclitaxel).
Interventions: intervention 1: Pembrolizumab intervention 2: Nab paclitaxel intervention 3: Paclitaxel intervention 4: Pemetrexed intervention 5: Carboplatin
Intervention descriptions: intervention 1: Pembrolizumab is an immunotherapy that can help fight certain cancers. intervention 2: Nab-paclitaxel is a taxane derivative that is an albumin-bound paclitaxel nanoparticle formulation that promotes microtubule assembly. intervention 3: Paclitaxel is a taxane derivative that promotes microtubule assembly by enhancing the action of tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly, interfering with the late G2 mitotic phase, and inhibiting cell replication. intervention 4: Pemetrexed is an antifolate agent that disrupts folate-dependent metabolic processes essential for cell replication. intervention 5: Carboplatin is a platinum compound alkylating agent which covalently binds to DNA and interferes with the function of DNA by producing interstrand DNA cross-links.

Protocol documents:
Prot_SAP_000.pdf: 
Document Coversheet 
 
 Study Title: Phase II Investigation of Use of CNS Active Pembrolizumab and Chemotherapy for 
Asymptomatic Brain Metastasis From Non-small Cell Lung Cancer (NSCLC) 
Institution/Site:  
University of Kentucky 
Document (Approval/Update) Date: 
2/8/2022 
NCT Number: 
NCT04964960 
IRB Number 
67945 
Coversheet created: 
6/18/2024 
 
 


 
 
MCC Protocol #: MCC-21-NEURO-11 
 
ClinicalTrials.gov #:  TBD 
 
 
 
Phase II Investigation of Use of CNS Active Pembrolizumab and Chemotherapy for Asymptomatic 
Brain Metastasis from NSCLC 
 
Short Title: CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC 
 
 
PROTOCOL FACE PAGE FOR 
MCC INTERVENTIONAL THERAPEUTIC PROTOCOL 
 
 
Study Site:  
 
Markey Cancer Center  
 
Funding Source: Markey Cancer Center CCSG internal research grant and supplemental funding from Markey IIT Executive 
Steering Committee (PI, Villano) 
 
 
FDA Status:    Study Exempt from IND Requirements per 21 CFR 312.2(b). 
 
Commercial Agents: 
Pembrolizumab (Merck) 
Carboplatin    
Pemetrexed  
Paclitaxel  
Nab-paclitaxel  
Investigational Agent:  None (study is evaluating the timing of systemic therapy in advanced CNS-involved NSCLC) 
 
 
Protocol Type / Version # / Version Date: Amendment / Version 1 / 15 December 2021 
 
 
Amendment / Version 2  /  8 February 2022 
 
 
ROLE 
NAME 
DEPARTMENT/DIVISION 
Principal Investigator 
John Villano, MD, PhD 
Professor, Director of Neuro-oncology 
Department of Medicine, Division of Oncology 
 
Co-Investigators:  
Reinhold Munker, MD 
Internal Medicine, Oncology, Hematology 
Alexander Kreimer, PharmD 
Clinical Pharmacist, Markey Cancer Center 
Heidi Weiss, PhD 
Statistician 
Susanne Arnold, MD 
Internal Medicine, Medical Oncology 
Ralph Zinner, MD 
Internal Medicine, Medical Oncology 
Zhonglin Hao, MD 
Internal Medicine, Medical Oncology 
William St Clair, MD, PhD 
College of Medicine, Radiation Medicine 
Tom Pittman, MD 
College of Medicine, Neuro-Surgery 
 
Collaborators:  
Leigh Anne Faul, PhD 
Director, Investigator-Initiated Trials Office 
April Bramel  
Senior IITs Project Manager, IITs Office 
Jennifer Land 
Senior Clinical Data Manager 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         2 
 
 
Protocol Development History –  
         Original Version to Current Version, w/ major Summary of Changes noted 
Original 
1/20/2021 
 Original protocol for concept review, version date 20JAN2021.  
1/29/2021 
PRMC Review of concept.  
Resolution: Conditional approval, pending edits. 
2/8/2021 
FRC full review of Original protocol version date 20JAN2021.  
   Resolution:  One edit and a few clarifications requested by FRC.  
Revision 1 
2/16/2021 
Protocol revised in response to PRMC and FRC reviews.  
New Version date 16FEB2021.  
3/8/2021 
PRMC Approval    
5/11/2021 
IRB Approval    
 
Revision 2 
9/10/2021 
Protocol version date 16FEB2021 was revised. Revisions comprisie the following:  
     Clarification of correlatives as 4 collections; clarification of Pembro vs. Pembro 
    maintenance; added MOCA and QOL to calendar (corrected their omission);  
    clarified PFS window as 6-mos in study calendar.  
New protocol version date 10SEP2021.  
12/07/2021 
Open to Accrual 
Amendment 1 
12/15/2021 
Administrative changes only. 
Amendment 2 
         02/08/2022 
The 15DEC2021 protocol was modified; Revised protocol version date, 02/08/2022.  
Protocol edits comprise the following: clarified pts whose mutation status is unknown are 
eligible (3.1.5, 3.2.1); expanded eligibility to include select pts with nonmeasurable disease 
(delete 3.2.2; add new 3.1.2); moved other inclusion criteria re: lesions (size, count) up to 
appear beneath new 3.1.2; Section 12.0: Patients with nonmeasurable disease by 
traditional RANO-BM enrolled on-study will be assessed by RANO-BM UK MOD. 
Amendment 3 
Add date 
Placeholder for a future amendment 
 
 


 
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         3 
 
 
 
PROTOCOL ABBREVIATIONS 
 
ABC 
ATP Binding Cassette 
ALK 
Anaplastic lymphoma kinase 
BOIN 
Bayesian optimal interval 
CA125 
Cancer Antigen 125 
DFS 
Disease free survival 
EGFR 
Epidermal growth factor receptor 
FDA 
U.S. Food and Drug Administration 
IND 
Investigational New Drug 
Mg 
Milligrams 
MTD 
Maximum tolerated dose 
NSCLC 
Non-small cell lung cancer 
OS 
Overall Survival 
P-gp 
P-Glycoprotein 
RANO 
Response assessment in neuro-oncology  
ROS-1 
ROS Proto-Oncogene 1 
RP2D 
Recommended Phase 2 Dose 
TKI 
Tyrosine Kinase Inhibitors 


MCC Protocol #: MCC-21-NEURO-11
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SCHEMA
Target N = 25 for interim, with expansion to 45 patients (based on results of interim analysis) 
Initiate Pembrolizumab ± chemotherapy*
Evaluation every 3 wks (clinical), 6-12 wks (imaging- phys. discretion), 1 cycle= 6 wks
Clinical and radiographic monitoring:
Primary Endpoint: Intracranial benefit defined as stable disease, partial response and 
complete response for 6 months.
Secondary Endpoints: OS, systemic disease control (PFS), Quality of life
Stable Disease: Continuation of study 
treatment
Disease Progression by RANO-BM 
criteria
Standard of care: WBRT or 
SRS or surgery
Single-arm, Phase II trial
NSCLC w/ untreated asymptomatic brain metastasis, lacking known EGFR, ALK & ROS mutations
Major Inclusion criteria: ages 18 - 85
-
Absence of neurological symptoms; ECOG Performance Status 0-2 and PRnths life expectancy
-
Measurable disease per RANO, OR presence of 3 lesions that can be followed, OR Presence of one lesion 
PHDVXULQJPP3/86DVHFRQGOHVLRQWKDWFDQEHIROORZHG
-
Less than 10 intracranial lesions; no lesion larger than 3cm
Major Exclusion criteria: 
-
Midline shift; known leptomeningeal involvement 
-
Lesions located within 10mm of optic chiasm or optic nerve, or within the brainstem
-
Not eligible for Pembrolizumab; TKI-sensitive tumors are excluded


 
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Legend from Schema (figure on previous page):  
 
* Pembrolizumab ± chemotherapy at investigator’s discretion will select one of the following: 
a. Squamous NSCLC receives carboplatin plus paclitaxel/nab-paclitaxel plus pembrolizumab for 4  
 
treatments and then pembrolizumab maintenance to continue 
 
b. Adenocarcinoma lung receives carboplatin plus pemetrexed plus pembrolizumab for 4 treatments  
 
and then pemetrexed plus pembrolizumab maintenance to continue 
 
c. If PDL1 Tumor Proportion Score >50%, may receive single agent pembrolizumab (up to 2 yrs) 
 


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TABLE OF CONTENTS
SCHEMA ...........................................................................................................................................4
1.
OBJECTIVES.........................................................................................................................9
Primary Objective........................................................................................................9
Secondary Objectives..................................................................................................9
Exploratory/Correlative Endpoint ..................................................................................9
2.
BACKGROUND....................................................................................................................10
Non-Small Cell Lung Cancer......................................................................................10
Brain Metastasis and Current Treatment .....................................................................10
Pembrolizumab and Systemic Chemotherapy in NSCLC ..............................................11
Pembrolizumab.........................................................................................................11
Concurrent Carboplatin-plus Regimens that are FDA approved.....................................12
Rationale..................................................................................................................13
Correlative Studies....................................................................................................14
3.
PATIENT SELECTION..........................................................................................................15
Eligibility Criteria .......................................................................................................15
Exclusion Criteria......................................................................................................16
Inclusion of Women and Minorities .............................................................................18
4.
INVESTIGATOR REQUIREMENTS AND REGISTRATION PROCEDURES ..............................19
Trial Registration required by National Cancer Institute.................................................19
Protocol Review and Monitoring Committee and Institutional Review Board ...................19
Investigator and Research Associate Registration with MCC Enrollment Guidelines........19
Overview and Informed Consent Guidelines................................................................20
Eligibility Confirmation and Enrollment ........................................................................21
5.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................................22
Summary Table for Specimen Collection.....................................................................22
5.2
Specimen Collection and Processing..........................................................................22
6.
TREATMENT PLAN..............................................................................................................23
Overview of Pembrolizumab and Concurrent Chemotherapy Regimens.........................23
General Concomitant Medication and Supportive Care Guidelines ................................28
Duration of Therapy...................................................................................................29
Duration of Follow-Up................................................................................................29
7.
PHARMACEUTICAL INFORMATION .....................................................................................29
7.1
Drug Ordering and Accountability ...............................................................................29
7.2
Pembrolizumab.........................................................................................................30
Commercial Agents: Carboplatin, Pemetrexed, Paclitaxel and Nab-paclitaxel.................33
8.
DOSING DELAYS/DOSE MODIFICATIONS............................................................................35


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9.
STATISTICAL CONSIDERATIONS ........................................................................................39
Study Design/Endpoints and Sample Size/Accrual Rate...............................................39
Sample Size and Accrual Rate...................................................................................39
Stratification Factors..................................................................................................39
Interim Analysis ........................................................................................................39
Statistical Analysis Plan for Primary Endpoint..............................................................40
Statistical Analysis Plan for Secondary Endpoints........................................................40
Statistical Analysis Plan for Correlative Endpoint..........................................................41
Reporting and Exclusions ..........................................................................................41
10.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS.............................................42
Expected Toxicities for Pembrolizumab.......................................................................42
Adverse Event Characteristics....................................................................................43
MCC Expedited Adverse Event Reporting Guidelines...................................................43
Expedited Reporting to External Agencies...................................................................45
Expedited Reporting to Hospital Risk Management......................................................45
Routine Adverse Event Reporting...............................................................................45
Pregnancy................................................................................................................46
Secondary Malignancy ..............................................................................................46
Second Malignancy...................................................................................................46
11.
STUDY CALENDAR..............................................................................................................47
12.
MEASUREMENT OF EFFECT...............................................................................................49
Antitumor Effect (CNS/brain):  RANO-BM Criteria ........................................................49
Antitumor Effect (systemic) – Immune-Related RECIST Criteria (iRECIST) ....................51
Other Response Parameters – Quality of Life and Neurocognitive Functioning...............58
CORRELATIVE STUDIES .........................................................................................60
13.
STUDY APPROVAL, OVERSIGHTAND DATA REPORTING / REGULATORY 
REQUIREMENTS.................................................................................................................61
Protocol Review and Monitoring Committee and Institutional Review Board Review........61
Quality Assurance.....................................................................................................61
Data and Safety Monitoring Committee.......................................................................62
Data Reporting .........................................................................................................62
Data Management.....................................................................................................63
Compliance with Laws and Regulations ......................................................................63
14.
REFERENCES.....................................................................................................................64
APPENDIX A. PERFORMANCE STATUS CRITERIA ..........................................................................68
APPENDIX B. FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM CREATININE.................69
APPENDIX C. CONTRACEPTION GUIDANCE AND PREGNANCY TESTING.......................................70
APPENDIX D. LAB MANUAL FOR PROCESSING CORRELATIVES....................................................72


 
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APPENDIX E. BRAIN CANCER (FACT-Br) Questionnaire ....................................................................74 
APPENDIX F. FATIGUE (FACIT-Fatigue, V4) Questionnaire ................................................................81 
APPENDIX G. COGNITIVE FUNCTIONING (FACT-cog) Patient Questionnaire .....................................83 
APPENDIX H. MONTREAL COGNITIVE ASSESSMENT (MoCA) – Staff-Administered ..........................88 
 
 
 
 
 
 


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1.
OBJECTIVES
Primary Objective
Single-arm, Phase II single arm non-inferiority trial to assess intracranial benefit of systemic therapy with 
pembrolizumab, with or without chemotherapy, defined as disease control rate (DCR) which includes stable 
disease (SD), partial response (PR), and complete response (CR) at 6 months.  
Secondary Objectives
Evaluate Overall Survival at 12-months post study enrollment
Evaluate systemic disease control (6-month systemic Progression-Free Survival).
Assess changes in quality of life, via patient self-report on validated measures (FACT-Cog, FACT-Brain 
Cancer and FACIT-F Fatigue questionnaires) every 3 mos. 
Evaluate changes in patients’ neurocognitive functioning, via repeated assessment using the Montreal 
Cognitive Assessment (MoCA) pre- and 1-, 3-, 6-, 9- and 12-mos.
Assess changes in performance status as rated by physician – defined as latency to increase in ECOG 
performance status greater than 2 and scores on the Montreal Cognitive Assessment (MoCA)
  Exploratory/Correlative Endpoint
Evaluation of immune based biomarker activity: e.g., PD-1 expression and activation of cytotoxic 
T-cells.


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2.
BACKGROUND
Non-Small Cell Lung Cancer 
Lung cancer is the leading cause of cancer mortality in the United States (U.S.). More than 80 percent of lung cancers 
are classified as non-small cell lung cancer (NSCLC) and include adenocarcinoma, squamous cell, bronchioalveolar 
and adenosquamous histologies.
When metastatic, the disease is treated palliatively and cure is generally not an option. The goal of treatment is to 
prolong survival and preserve quality of life while minimizing the side effects due to treatment. When oncogenic driver 
mutations like EGFR, ALK, ROS1, BRAF mutations are present in metastatic NSCLC, targeted specific inhibitors are 
the preferred treatment option.1 In tumors lacking known oncogenic drivers, NSCLC treatment includes
Pembrolizumab with or without chemotherapy based on PDL1 expression status.
Brain Metastasis and Current Treatment
The incidence of metastatic lesions to the brain is increasing.2,3 The estimated incidence is as high as 200,000 
metastatic cancers to the brain per year in the United States and lung cancer represents 40-50% of these.4 The 
increasing frequency of metastatic lesions to the brain is attributable to earlier detection using superior imaging 
modalities and to patients living longer with more effective treatment of systemic disease.  
Current care for patients with metastatic disease to the brain for the majority of cancers remains focused on symptom 
management and/or therapeutic strategies. Symptomatic therapies include the use of corticosteroids and, if needed, 
antiepileptic medications, as well as supportive care.  
Therapeutic measures include the use of radiation therapy administered as whole brain radiotherapy (WBRT) or 
stereotactic radiosurgery (SRS) and possibly surgery for single metastatic lesions.5 WBRT involve repeated 
administration of small doses of radiation to the whole brain to achieve killing of tumor cells. However, administration 
of WBRT is associated with an increased risk of decline in neurocognitive function. Stereotactic radiation surgery 
delivers single or very limited number of fractions of high-dose radiation directed specifically at the tumor while 
avoiding normal tissue. The Gamma Knife System is a commonly used technique of SRS, employing an array of 
radioactive sources to target the tumor with increased accuracy. 
Due to the high risk of decline in cognitive function with WBRT, SRS is currently preferred in patients with 1 to 3 brain 
metastases.6 Prospective non-randomized data in patients with newly diagnosed brain metastases have expanded 
the use of SRS to up to 10 brain lesions.7 Despite the reduced dose outside target tissue with SRS, close proximity 
to cranial nerves can often lead to radiation neurotoxicity. 
Median survival is in the range of 2.4–4.8 months with treatment via whole-brain radiation therapy (WBRT) alone and 
do not offer survival benefit compared to optimal supportive care.8,9 The two-year relapse rates at initial and new sites 
range from 59% and 42% respectively with surgery, and 31% and 48% with SRS alone.10 Median overall survival for 
patients with 2-4 brain metastasis who received SRS was 6.4 months.11


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Pembrolizumab and Systemic Chemotherapy in NSCLC
Multiple resistance mechanisms, including systemic dysfunction in T-cell signaling12-15 and exploitation of immune 
checkpoints16 evolve in tumors, helping them evade specific immune responses despite the presentation of tumor 
antigens to the immune system. Recent understanding of these host-tumor immune interactions has given rise to 
novel antibodies directed against immune checkpoint proteins.17,18
Pembrolizumab is also a human immunoglobulin (Ig) G4 programmed cell death (PD) 1 immune checkpoint inhibitor 
antibody via intravenous infusion with FDA approval in numerous cancers. The drug is involved in PD1 (ligand) and 
PDL1 (receptor) signaling.  PDL1 is a transmembrane protein that binds to its receptor, PD-1, found on activated T 
cells, B cells, and myeloid cells to modulate activation or inhibition during particular events such as pregnancy, tissue 
allografts, autoimmune disease and severe infections.   Drugs targeting PD1 and PDL1, checkpoint inhibitors, are 
associated with fewer high-grade treatment-related adverse events than systemic cytotoxic chemotherapy.  
Pembrolizumab as a single agent showed significant PFS/OS benefit in a subset of frontline NSCLC patients [as 
determined as a tumor proportion score (TPS) >50% staining of tumor cells for PDL1] relative to standard of care. 
When TPS score is 0-50%, Pembrolizumab is used in conjunction with carboplatin and pemetrexed in non-squamous 
histologies and carboplatin and paclitaxel (or nab-paclitaxel) in squamous histology. 
Pembrolizumab
Pembrolizumab is a highly selective anti-PD-1 humanized monoclonal antibody which inhibits PD-1 activity by binding 
to the PD-1 receptor on T-cells to block PD-1 ligands from binding. Blocking the PD-1 pathway inhibits the negative 
immune regulation caused by PD-1 receptor signaling. This reverses T-cell suppression and induces anti-tumor 
responses. Pembrolizumab is given at a dose of 200mg IV over 30 minutes once on Day 1 every 3 weeks or 400mg 
IV over 30 minutes once on Day 1 every 6 weeks. Selection of q3 weeks or q6 weeks dosing will be at the discretion 
of the treating physician, while all subjects will be seen in clinic every 3 weeks. Administration every 3-weeks versus 
every 6-weeks will be based on patient/physician preference and insurance approval. Pembrolizumab administration 
every 6 weeks was granted accelerated FDA approval in April 2020 based on pharmacokinetic modeling and 
exposure-response analyses in the KEYNOTE-555 trial.19
Pembrolizumab is cleared from the circulation through non-specific catabolism and no studies were done on routes 
of elimination. There are no clinically important effects on the clearance based on age, sex, race, renal impairment, 
mild hepatic impairment, or tumor burden. The impact on moderate or severe hepatic on the pharmacokinetics of 
pembrolizumab is unknown. No metabolic drug interactions are expected.
Pembrolizumab safety and efficacy has been proven in multiple clinical trials in various cancers. In an open-label, 
phase 3 trial pembrolizumab was compared with standard of care platinum-based chemotherapy for patients with 
previously untreated advanced NSCLC with PDL1 expression on at least 50% of tumor cells and no sensitizing 
mutation of the EGFR or ALK gene. At the time of first analysis, median PFS was 10.3 months for the pembrolizumab 
arm versus 6 months for the chemotherapy arm. Estimated median OS at 6 months was also improved, 80.2% vs. 
72.4%, respectively. Safety evaluation also favored the pembrolizumab arm.20 At a median follow up of 24.2 months, 
the updated analysis continued to demonstrate benefit with pembrolizumab monotherapy with an OS of 30 months 
vs. 14.2 months for the chemotherapy arm.21
The safety and efficacy of Pembrolizumab in combination with pemetrexed and platinum chemotherapy was 
investigated in KEYNOTE-189, a randomized, multicenter, double-blind, active controlled trial in patients with 
metastatic nonsquamous NSCLC, regardless of PDL1 tumor expression status, who had not previously received 


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systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. The 
addition of pembrolizumab to standard chemotherapy (pemetrexed plus a platinum-based drug) resulted in 
significantly longer survival and progression-free survival than chemotherapy alone with similar frequency of adverse 
events.22 At a median follow-up of 24.1 months, median OS was 22 months in the pembrolizumab-combination arm 
versus 10.7 months in the placebo-combination arm and median PFS was 9 months vs. 4.9 months, respectively. OS 
and PFS benefits were observed regardless of the PDL1 expression. Similar benefit for OS and PFS was also seen 
in patients with or without brain metastases.23
The safety and efficacy of pembrolizumab in combination with carboplatin and investigator’s choice paclitaxel or 
paclitaxel protein-bound was investigated in KEYNOTE-407, a randomized, multicenter, double-blind, placebo 
controlled trial in patients with metastatic squamous NSCLC, regardless of PDL1 tumor expression status, who had 
not previously received systemic therapy for metastatic disease. The addition of pembrolizumab to standard 
chemotherapy (carboplatin plus paclitaxel or paclitaxel protein-bound) resulted in significantly longer OS and PFS 
than chemotherapy alone with similar frequency of adverse events.24 At a median follow-up of 14.3 months, median 
OS was 17.1 months in the pembrolizumab combination arm versus 11.6 months in the placebo-combination arm 
and median PFS was 8 months vs. 5.1 months, respectively. OS and PFS benefits were observed regardless of PDL1
expression.24
Concurrent Carboplatin-plus Regimens that are FDA approved
Carboplatin with Pemetrexed
Carboplatin is a platinum compound alkylating agent which covalently binds to DNA and interferes with the function 
of DNA by producing interstrand DNA cross-links. Carboplatin is apparently not cell-cycle specific. Per standard of 
care carboplatin can be used in combination pemetrexed with/without pembrolizumab for non-squamous histologies.
Pemetrexed is an antifolate agent that disrupts folate-dependent metabolic processes essential for cell replication. 
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. Per standard of care 
and FDA approval pemetrexed is used in combination with carboplatin for non-small cell lung cancer with non-
squamous histology. Standard of care supplementation with folic acid, vitamin B12, and corticosteroids are used to
help reduce toxicities from pemetrexed.25 In a phase III trial, carboplatin and pemetrexed were compared against a 
standard of care regimen for advanced non-small cell lung cancer, docetaxel and carboplatin. Carboplatin and 
pemetrexed combination was found to have improved survival without treatment-emergent grade 3/4 toxicity and 
similar overall survival.26 Another phase III study looked at combination therapy with pemetrexed/carboplatin versus 
standard of care, gemcitabine/carboplatin. Pemetrexed/carboplatin combination was found to have similar health-
related quality of life and survival when compared to the standard regimen for advanced non-small cell lung cancer.27
These studies utilized standard of care dosing, intravenous pemetrexed 500mg/m2 plus carboplatin area under the 
curve (AUC) of 5 on day 1 of an every 3 week cycle. Treatment delays and dose-reductions for toxicities were based 
on standard of care recommendations. 
Carboplatin with Paclitaxel or Nab-paclitaxel
Paclitaxel is a taxane derivative that promotes microtubule assembly by enhancing the action of tubulin dimers, 
stabilizing existing microtubules, and inhibiting their disassembly, interfering with the late G2 mitotic phase, and 


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inhibiting cell replication. Per standard of care, paclitaxel can be used in combination with carboplatin for non-small 
cell lung cancer with squamous cell histology. Due to risk of hypersensitivty reactions with paclitaxel, premedications 
based on standard of care must be given to reduce the risk of reactions. Efficacy with carboplatin/paclitaxel was 
compared in a randomized trial with standard of care cisplatin/paclitaxel and two other regimens, 
cisplatin/gemcitabine and cisplatin/docetaxel. Carboplatin/paclitaxel found to have a similar response rate and 
survival when compared to the other regimens with a lower rate of toxic effects.28
Nab-paclitaxel is a taxane derivative that is an albumin-bound paclitaxel nanoparticle formulation with a mechanism 
similar to paclitaxel. Due to the protein binding, drug delivery is optimized by utilizing the reversible binding affinity of 
paclitaxel to promote transport across the endothelial cell and concentrates the drug within the tumor cell. Per 
standard of care nab-paclitaxel can be used in combination with carboplatin for advanced non-small cell lung cancer 
with squamous cell histology. Nab-paclitaxel can be utilized first line or substituted for paclitaxel in patients who have 
experienced hypersensitivity reactions after receiving paclitaxel despite premedication or if standard premedications 
are contraindicated. Efficacy of nab-paclitaxel/carboplatin was shown in a phase 3 trial comparing against standard 
paclitaxel/carboplatin. Nab-paclitaxel was found to have significantly improved objective overall response rate with 
significantly less grade 3 toxicities, specifically neuropathy. Progression free survival and overall survival were non-
inferior and comparable to historical results in non-small cell lung cancer patients. This study utilized standard of care 
dosing for these agents. Nab-paclitaxel was administered intravenously (IV) 100mg/m2 over 30 minutes on days 1, 
8, and 15 followed by carboplatin IV AUC 6 on day 1 of an every 3 week cycle. Paclitaxel was administered IV 
200mg/m2 over 3 hours on day 1 followed by carboplatin IV AUC 6 on day 1 of an every 3 week cycle. Treatment 
delays and dose-reductions for toxicities were based on standard of care recommendations.29
Rationale
Although WBRT, SRS and surgery are established in the treatment for those patients with symptomatic brain 
metastases, the management of asymptomatic or controlled brain metastases is not as straight forward. Radiation 
therapy confers significant side effects, especially the potential risk of cognitive decline.30   Brain radiation necrosis 
can also cause significant toxicities, generally occurring from 6 months to several years after treatment.31 With regards 
to patients with NSCLC with brain metastatic disease with poorer performance status for surgery or stereotactic 
radiosurgery (SRS), the non-inferiority QUARTZ phase III trial evaluated dexamethasone and supportive care with or 
without WBRT and found no overall survival difference (HR 1.06) as well as no overall quality of life difference.32 This 
suggests that this population may derive minimal benefit from WBRT. 
In the treatment of CNS metastases, chemotherapy was previously thought to be inferior to radiation and/or surgery 
due to concerns of poor penetration of systemic agents via the blood-brain barrier.33  Gerstner et al. established that 
tumor neovasculature is similar to extracranial vessels in relation to permeability.34 Further, due to improvement in 
systemic therapy, there is evidence to support efficacy in treating brain metastasis from NSCLC with systemic therapy. 
Lee et al. described a similar response rate between NSCLC patients with absent or controlled neurologic symptoms 
treated with primary chemotherapy versus WBRT administered as initial therapy. There was no statistically significant 
difference in overall response rate which was 28% vs 39%, progression-free survival, 3.6 months vs 4.4 months, and 
overall survival, 9.1 months vs 9.9 months.35 Further, in the WBRT-first arm, grade 3 or 4 neutropenia was more 
frequent (79% vs 40%) during chemotherapy and 4 patients (17.4%) did not receive further chemotherapy because 
of early death or worsening performance status after WBRT. Robinet et al examined early versus delayed WBRT in 
NSCLC in phase III trial where 86 patients who had chemotherapy alone had RR of 27% and those with chemotherapy 
with WBRT had RR of 33%.36 An additional trial examined 26 chemotherapy -naïve patients with metastatic NSCLC 


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to brain who received cisplatin/paclitaxel and either vinorelbine on D1 and D15 or gemcitabine D1 and D8 and found 
that 38% had intracranial responses.37
With the advent of immunotherapy for the treatment of metastatic non-small cell lung cancer, improved disease 
response in regard to CNS metastases has been observed.  Crino et al. included 409 of 1588 patients with 
asymptomatic or controlled brain metastases in their non-squamous NSCLC study evaluating the use of Nivolumab 
as subsequent therapy. The disease control rate was 39% among these patients. However, of these 409 patients, 
118 were receiving corticosteroids and 74 were undergoing concomitant radiotherapy.38  A phase III trial completed 
by Brahmer, et al. demonstrated the effect of Nivolumab, an anti-PD-1 monoclonal antibody, on patients with CNS 
disease from NSCLC. This trial included 37 patients with treated and stable brain metastases. The disease control 
rate was 49% among patients with CNS metastasis and the objective response rate was 7/37 (19%). Further the 
overall survival rate at 12 months was 35% for CNS metastatic patients compared to 39% for all patients.39 Two 
phase II trials evaluated the use of Pembrolizumab in untreated non-small cell with brain metastases. The first study
included 18 NSCLC patients without associated neurologic symptoms or need for steroids and tissue demonstrating 
PDL1 expression (>1%).  Brain metastasis response rate was 33% for patients with NSCLC with durable response, 
ranging from 3 to 7 months.40 The second study enrolled 42 patients with similar characteristics and were treated with 
pembrolizumab 10mg/kg every 2 weeks. On median follow up of 8.3 months, 29.7% of patients with PD-L1 expression 
DFKLHYHGEUDLQPHWDVWDWLFUHVSRQVHLQGLFDWLQJSHPEUROL]XPDEKDVDFWLYLW\LQEUDLQPHWDVWDVLV41 Borghaei et al 
found that Nivolumab improved overall survival versus docetaxel in advanced non-squamous non-small cell lung 
cancer after failure of platinum therapy (12.2 months for nivolumab versus 9.4 months for docetaxel [HR 0.73, 
p=0.002]). However, of those with CNS metastases (n=68) the hazard ratio did not favor nivolumab.42
Given the risks of brain radiation and the above data that supports brain metastasis response to systemic 
chemotherapy and immunotherapy, we propose a trial providing up-front therapy for non-mutated EGFR, ALK and 
ROS1 (wild-type) NSCLC patients with asymptomatic brain metastases using Pembrolizumab +/- chemotherapy 
(Carboplatin/Pemetrexed for nonsquamous and Carboplatin/Paclitaxel or Nab-paclitaxel for squamous).  It is 
reasonable that the initial treatment of CNS metastasis with systemic chemotherapy and immunotherapy will have 
similar disease control to lung disease alone.  This study would add onto the Goldberg investigation, but include the 
improved benefit of allowing chemotherapy to improve disease control, and hopefully improved clinical outcomes with 
early systemic treatment.40
Correlative Studies 
This exploratory study assesses the T-cell subsets and monitors PD-1 expression along with activation and will 
correlate with therapy. Multiplex immunofluorescence will be used to evaluate spatial relationships between 
immunologic factors in the tumor microenvironment. The study is based on peripheral blood to assess immune 
activation. The following steps for processing and cryopreservation of blood samples will be performed in Flow 
Cytometry and Immune Monitoring (FCIM) SRF. FCIM SRF provides flow cytometric analysis and cell sorting as well 
as human immune monitoring services.  These services include blood processing and cryopreservation of PBMC.  


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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         15
3.
PATIENT SELECTION
Eligibility Criteria 
Non-small cell lung cancer with untreated asymptomatic brain metastases 
Measurable disease as defined by as defined by the Response Assessment in Neuro-Oncology (RANO) 
group criteria. Per RANO, Measurable disease is defined as at least one brain lesion that can be accurately 
measured in at least one dimension with WKHORQJHVWUHFRUGHGGLDPHWHUPP
OR
Presence of 3 lesions that can be followed*
OR
Presence of one lesion measuring 5 mm PLUS a second lesion that can be followed*
*RANO criteria considers these “nonmeasurable” leasions, which is terminology used in sections 9.2 and 12  
Presence of fewer than 10 intracranial lesions
Each lesion measures 3cm or less.
Absence of known oncogenic driver mutations, i.e., EGFR, ALK, or ROS-1. 
NOTE: IF a mutation is discovered after the patient enrolls to this trial, then the patient will be 
                    taken off-study and considered “non-evaluable” for analysis. 
Absence of new onset neurological symptoms (includes increased intracranial pressure, uncontrolled nausea
or vomiting, Grade 3 headache, epilepsy, or focal motor deficit attributed to the metastatic lesions).
Eligible for treatment with immune checkpoint inhibitor. Note that no limit is placed on prior systemic 
treatment. 
Ages 18-85 years. 
ECOG SHUIRUPDQFHVWDWXV 2 (see Appendix A).
/LIHH[SHFWDQF\RIPRQWKV
Patients must have adequate organ and marrow function as defined below:

absolute neutrophil count
000/mm3

platelets
75,000/mm3

total bilirubin
1.5 x ULN

AST and ALT if no hepatic metastasis
 2.5 × ULN

AST and ALT with hepatic metastasis
[8/1
-
Creatinine
1.5 x ULN and 5HTXLUHV&U&O0ml/min 
(per 24-hr urine collection or calculated via Cockcroft-Gault 
           formula, see Appendix B)


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         16
Steroid dose maintenance is allowed, however no more than 10 mg of prednisone or equivalent per day or 
inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day.
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable 
viral load within 6 months are eligible for this trial.
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be 
undetectable on suppressive therapy, if indicated.
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients 
with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral 
load.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential 
to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic 
agents, should have a clinical risk assessment of cardiac function using the New York Heart Association 
Functional Classification.  To be eligible for this trial, patients should be class 2B or better.
The effects of Pembrolizumab on the developing human fetus are unknown. The other chemotherapy agents 
used in this trial are known to be teratogenic. Hence, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry 
and for the duration of study participation.  Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating physician immediately.
Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for 
the duration of study participation, and 120 days after completion of Pembrolizumab administration.
Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria
Presence of known oncogenic driver mutations, such as EGFR, ALK and/or ROS-1, at study pre-screening.
Measurable lesion located within 10mm of the optic chiasm or optic nerve, or within the brainstem.
Known leptomeningeal involvement.
Midline shift.


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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         17
Pregnant and/or lactating women expecting to conceive or father children within the projected duration of 
the study, starting with the screening visit and extending through 120 days after the last dose of the trial 
treatment. Female subjects of childbearing potential must not be pregnant at screening. Female subjects 
are considered to be of childbearing potential unless one of the following criteria is met in Appendix C.
Active clinically serious infection > CTCAE Grade 2.
Serious non-healing wound, ulcer or bone fracture.
Baseline inability to participate or complete neurocognitive testing, e.g. having developmental disabilities.
Ineligible for immune checkpoint inhibitors based on package insert of the chosen immune checkpoint 
inhibitor (e.g., uncontrolled immunologic disorders, active hepatitis, active colitis, active pneumonitis, 
uncontrolled/active hormone gland problems - including thyroid, pituitary, adrenal glands and pancreas).
Major surgical procedure (including craniotomy and open brain biopsy) or significant traumatic injury within 
14 days prior to registration. 
Receipt of a non-CNS minor surgical procedure (e.g. core biopsy or fine needle aspiration) within 3 days prior 
to registration. There is no waiting period for central line placement. 
History of allergic reactions attributed to monoclonal antibodies (mAb), compounds of similar chemical or 
biologic composition to Pembrolizumab. Severe hypersensitivity to Pembrolizumab or any of its excipients. 
Clinically significant cardiovascular disease, for example cerebrovascular accidents (less than 6 months, 
CVA) /stroke, myocardial infarction (also less than 6 months), unstable angina pectoris, New York Heart 
Association class 3 or 4 congestive heart failure, or serious cardiac arrhythmia requiring medication. 
Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 90mm Hg 
diastolic despite optimal antihypertensive treatment.
QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 
days before first dose of study treatment. 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at 
intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of 
WKHVHWKUHHFRQVHFXWLYHUHVXOWVIRU47F)ZLOOEHXVHGWRGHWHUPLQHHOLJLELOLW\LHLIWKHDYHUDJHLVPV
the patient is eligible). 
Patients with uncontrolled intercurrent illness.


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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         18
Patients with psychiatric illness/social situations that would limit compliance with study requirements.
Patients who received prior radiation (WBRT, SRS or Stereotactic radiotherapy) within the past 3 years at 
the discretion of the treatment team.
Patients who have a RET or MET driver mutation that can be targeted with an FDA-approved TKI (tyrosine 
kinase inhibitor) that is expected to generate a high response.
Inclusion of Women and Minorities
NIH policy requires that women and members of minority groups and their subpopulations be included in all NIH-
supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and 
compelling rationale and justification establishes that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research. 


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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         19
4.
INVESTIGATOR REQUIREMENTS AND REGISTRATION PROCEDURES
Trial Registration required by National Cancer Institute
The National Cancer Institute requires that interventional treatment trials be registered in clinicaltrials.gov and on 
NCI’s CTRP (Clinical Trials Reporting Program) prior to patient enrollment. The Regulatory Group within MCC’s 
Clinical Research Office and Investigator-Initiated Trials Office at Markey will provide assistance in completing these 
required registrations/renewals. 
Protocol Review and Monitoring Committee and Institutional Review Board
Before implementing this study, the protocol must be reviewed by the Markey Cancer Center’s Protocol Review and 
Monitoring Committee (PRMC). Additionally, the protocol, the proposed informed consent form and other information 
to subjects, must be reviewed by the University of Kentucky Institutional Review Board (IRB). A signed and dated UK 
IRB initial review approval memo must be maintained in the Markey Cancer Center Clinical Research Office (MCC 
CRO) regulatory binder. Any amendments to the protocol, other than administrative ones, must be reviewed and 
approved by the PRMC, and UK IRB. 
Investigator and Research Associate Registration with MCC Enrollment Guidelines
All investigators must be qualified by education, training and experience to assume responsibility for the proper 
conduct of human subject research.  Investigators are responsible for being able to provide evidence of such 
qualifications through up-to-date curriculum vitae and/or other relevant documentation and training per institutional, 
state and federal guidelines.  All investigators conducting MCC trials will register with the MCC Clinical Research 
Office and complete all requisite training and registrations per MCC SOPs.  
Delegation of Tasks Log (DTL)
All MCC studies require a Delegation Task Log which is maintained by the MCC Regulatory Unit of the Clinical 
Research Office. The DTL for this study has training requirements as follows: In order to be added to the DTL for a 
given study, each staff member must have appropriate training to conduct assigned duties including but not limited 
to protocol specific training. The DTL log will identify the protocol version on which each staff member was trained 
when being added to a study. 
The Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the 
ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse events; 
reporting of expedited adverse events; and accumulation of reported adverse events from other trials testing the same 
drug(s). The Principal Investigator and Statistician have access to the study data at all times through OnCore.  All 
decisions regarding dose modifications require consultation with the Principal Investigator. 


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Overview and Informed Consent Guidelines
Brief Overview of Enrollment Process
Eligible patients will be identified by the principal investigator and co-investigators of this study. Potentially eligible 
patients will be screened in the University of Kentucky Markey Cancer Center clinics by the investigators and study 
personnel with oversight by the Principal Investigator (PI). The consenting professional will explain in detail the study 
to the patient and will review the informed consent with the patient (Section 4.4.2). Broadly, patients will be made 
aware of the protocol, its specific aims and objectives, and the potential risks and benefits the patient may incur. A 
copy of the signed informed consent form is provided to the patient. Upon obtaining consent, study staff will register 
potentially eligible patients in the trial’s database in OnCore, Markey’s Clinical Trials Management System. During 
the screening and enrollment process, registering individuals (study staff and PI) will be required to complete a 
protocol-specific Eligibility Checklist for each patient. The PI or treating physician signing the Eligibility Checklist is 
confirming whether or not the patient is eligible to enroll in the trial. Upon confirmation of eligibility, the patient will be 
enrolled into the study as a participant via the entry of an on-study date. See Section 4.5 for details. 
Informed Consent
The goal of the informed consent process is to provide people with sufficient information so they can make informed 
choices about whether to begin or continue participation in clinical research.  The process involves a dynamic and 
continuing exchange of information between the research team and the participant throughout the research 
experience.  It includes discussion of the study's purpose, research procedures, risks and potential benefits, and the 
voluntary nature of participation.
The informed consent document provides a summary of the clinical study and the individual's rights as a research 
participant.  The document acts as a starting point for the necessary exchange of information between the investigator 
and potential research participant.  Also, research participants and their families may use the consent document as 
an information resource and reference throughout participation in the trial.  The informed consent document is often 
considered the foundation of the informed consent process; it does not, however, represent the entirety of the process.  
Nor is the informed consent document a risk-management tool for the investigator and/or institution.
The investigator must explain to each subject (or legally authorized representative) the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort 
it may entail. Each subject must be informed that participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in non-technical language. 
The subject should read and consider the statement before signing and dating it, and should be given a copy of the 
signed document. If the subject cannot read or sign the documents, oral presentation may be made or signature given 
by the subject’s legally appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her informed consent has 
been obtained.  The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with the protocol at the time of IRB review.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         21
Screening and Enrollment Guidelines
Prior to any study-required tests, subjects must first provide written informed consent to participate in this study. 
Eligibility Confirmation and Enrollment
The following information should be reviewed by the Clinical Research Nurse (CRN) / Clinical Research Associate 
(CRA) with the study physician per MCC SOPs to confirm eligibility:
x
Copy of required laboratory tests
x
Pathology reports
x
Physician dictations
x
Imaging reports
x
Signed patient consent form and HIPAA authorization form
x
Referring physician records as available
x
Other required screening procedures when applicable
x
Eligibility Checklist
Once eligibility is confirmed, the CRN/CRA will complete subject enrollment to the trial in the OnCore database. To 
complete the enrollment process, the CRN/CRA will complete the OnCore on-study form, which comprises the 
following: 
x
assignment of a patient study number
x
enter diagnosis and date of diagnosis
x
enter histology
x
enter the on-study date in OnCore


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         22
5.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Summary Table for Specimen Collection
Timepoint
Specimen
Send Specimens To:
Baseline (pre-treatment)
x
15 mL blood in whole blood tube w/ anticoagulant , BD 
Vacutainer™ CPT™ Tube with Sodium Citrate (mandatory)
Markey FCIM
6 weeks after treatment initiation (r2-weeks)
x
15 mL blood in whole blood tube w/ anticoagulant , BD 
Vacutainer™ CPT™ Tube with Sodium Citrate (mandatory)
Markey FCIM
12 weeks after treatment initiation (r2-weeks)
x
15 mL blood in whole blood tube w/ anticoagulant , BD 
Vacutainer™ CPT™ Tube with Sodium Citrate (mandatory)
Markey FCIM
18 weeks after treatment initiation (r2-weeks)
x
15 mL blood in whole blood tube w/ anticoagulant , BD 
Vacutainer™ CPT™ Tube with Sodium Citrate (mandatory)
Markey FCIM
5.2
Specimen Collection and Processing
All samples cryopreserved by FCIM are then banked and managed by Biospecimen and Tissue Procurement (BSTP) 
SRF until all samples for a subject have been collected.  Once all samples are collected, all stored samples for a 
subject will be thawed and analyzed simultaneously by FCIM to obtain correlative endpoints as described above.  
Data analysis will be performed by Dr. Cohen with members of his laboratory along with review and discussion of 
data with Drs. Subbarao Bondada, Val Adams, and John L. Villano.
The correlative studies are based on peripheral blood to assess immune activation. The following steps for processing 
and cryopreservation of blood samples listed below are to be performed in Flow Cytometry and Immune Monitoring 
(FCIM) SRF. FCIM provides flow cytometric analysis and cell sorting as well as human immune monitoring services. 
These services include blood processing and cryopreservation of PBMC. All samples cryopreserved by FCIM are 
then banked and managed by Biospecimen and Tissue Procurement (BSTP) SRF until all samples for a subject have 
been collected. Once all samples are collected, all stored samples for a subject will be thawed and analyzed 
simultaneously by FCIM to obtain correlative endpoints as described below. Data analysis will be performed by Dr. 
Don Cohen with members of his FCIM laboratory along with review and discussion of data with Drs. Subbarao 
Bondada, Val Adams, and John L. Villano.
At each time-point, 15 ml of blood will be collected from patients at indicated times (Whole Blood tube w/ 
Anticoagulant, BD Vacutainer™ CPT™Tube with Sodium Citrate). This collection is performed in clinics and 
handed to Markey FCIM. There will be a total of 4 collection times as mentioned and should yield approximately 16 
million PBMCs for each blood draw that will be analyzed by flow cytometry.
Lab manual for processing of the liquid specimen is provided in Appendix D.


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6.
TREATMENT PLAN
Prior to any study-required tests, subjects must first provide written informed consent to participate in this study.  
Section 11 (Study Calendar) details windows for completion of baseline scans and labs to verify eligibility. 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks are described 
in Section 10.  Appropriate dose modifications are described in Section 7.  No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the patient's malignancy.
Overview of Pembrolizumab and Concurrent Chemotherapy Regimens
Pembrolizumab with Carboplatin/Pemetrexed Regimen
Carboplatin/Pemetrexed/Pembrolizumab Regimen Description (C1-4)
Agent
Premedications; 
Precautions; 
Postmedications
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
200 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Carboplatin 
Aprepitant 130mg IV,
Ondansetron 16mg PO,
Dexamethasone 8mg IV
(if PO dexamethasone has 
not been administered at 
home) prior to 
chemotherapy on day1
Dexamethasone 4mg BID 
day before chemotherapy 
and on days 1, 2, and 3
AUC 5  
(diluted in 
250mL 0.9% 
sodium 
chloride) 
IV over 30 
minutes 
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Pemetrexed 
500 mg/m2
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 10 
minutes 
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Pembrolizumab/Pemetrexed Maintenance (after C1-4)
Pembrolizumab
Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
200 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter 
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Pemetrexed
Anti-emetics per 
institutional guidelines
500 mg/m2
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 10 
minutes 
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         24
Pembrolizumab with Paclitaxel and Carboplatin Regimen
                                                                           
Carboplatin/Paclitaxel/Pembrolizumab Regimen Description (C1-4)
Pembrolizumab 
Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
200 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Carboplatin 
Aprepitant 130mg IV, 
Dexamethasone 12mg PO,
Ondansetron 16mg PO,
Cetirizine 10mg PO,
Famotidine 20mg PO
prior to chemotherapy on 
day 1
Dexamethasone 8mg PO 
once daily on days 2,3,4
Give paclitaxel prior to 
carboplatin
Monitor for hypersensitivity 
reactions
*See additional precautions 
below
AUC 6  
(diluted in 
250mL 0.9% 
sodium 
chloride) 
IV over 30 
minutes 
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Paclitaxel
200mg/m2
(diluted in 
500mL 0.9% 
sodium 
chloride)
Non-PVC 
tubing with 
0.22 micron 
filter
IV over 3 
hours
Day 1
Q3 weeks
21 days 
(3 weeks)
Maintenance Pembrolizumab (After C1-4)
Pembrolizumab 
Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
400 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter
Day 1,  
Q6 weeks 
42 days
(6 weeks)


MCC Protocol #: MCC-21-NEURO-11
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Pembrolizumab with Nab-Paclitaxel and Carboplatin Regimen
Carboplatin/Nab-Paclitaxel/Pembrolizumab Regimen Description (C1-4)
Pembrolizumab 
Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
200 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Carboplatin 
Aprepitant 130mg IV,
Dexamethasone 12mg PO,
Ondansetron 16mg PO
prior to chemotherapy on 
day 1
Dexamethasone 8mg PO 
on days 2,3,4
Ondansetron 16mg PO 
prior to chemotherapy on 
day 8 and 15
Give nab-paclitaxel prior to 
carboplatin on day 1
Monitor for hypersensitivity 
reactions
AUC 6  
(diluted in 
250mL 0.9% 
sodium 
chloride) 
IV over 30 
minutes 
Day 1,  
Q3 weeks 
21 days  
(3 weeks) 
Nab-paclitaxel
100mg/m2
(undiluted)
IV over 30 
minutes
Day 1, 8, 
15
Q3 weeks
21 days
(3 weeks)
Maintenance Pembrolizumab (After C1-4)
Pembrolizumab 
Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
400 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter
Day 1,  
Q6 weeks 
42 days
(6 weeks)


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         26
Pembrolizumab Alone Regimen
Pembrolizumab Regimen Description
Pembrolizumab 
Monitor for hypersensitivity 
reactions (refer to section 
6.1.1)
Give prior to chemotherapy
400 mg
(diluted in 
100mL 0.9% 
sodium 
chloride)
IV over 30 
minutes
with 0.22 
micron 
filter
Day 1,  
Q6 weeks 
42 days
(6 weeks)
Pembrolizumab Administration
Pembrolizumab Infusion Requirements and Guidance 
First Infusion
Subsequent Infusions:
• No premedication is permitted.
• Vital signs (blood pressure, respiratory rate, 
pulse, and temperature) should be recorded 
within 60 min prior to the infusion.
• Pembrolizumab should be infused over 30 min 
(-5 min/+10 min).
• If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, and 
60 min (± 5 min for all time points) during the 
infusion and at 30 (± 10) min after the infusion.
• Subjects should be informed about the 
possibility of delayed post-infusion symptoms 
and instructed to contact their physician 
• If the subject experienced an infusion-related 
reaction with any previous infusion, premedication 
with antihistamines, antipyretics, and/or analgesics 
may be administered for subsequent doses at the 
discretion of the investigator.
• Vital signs should be recorded within 60 min prior to 
the infusion.
• Pembrolizumab should be infused over 30 (± 15) 
min if the previous infusion was tolerated without an 
infusion-related reaction, or 60 (± 15) min if the 
subject experienced an infusion-related reaction with 
the previous infusion.
• If the subject experienced an infusion-related 
reaction with the previous infusion or if clinically 
indicated, vital signs should be recorded during the 
infusion and at 30 (± 5) min after the infusion.
Administration of Other Commercial Agents
Carboplatin Administration
x
Premedications per institutional standard 
x
Administer after pembrolizumab and chemotherapy (pemetrexed, paclitaxel, nab-paclitaxel) on day 1


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         27
x
For dosing please refer to institution carboplatin dosing guideline
o
Calvert Formula 

Carboplatin dose (mg) = (Target AUC) X (GFR + 25) 
x
Maximum GFR of 125 ml/min
o
Cockcroft-Gault to estimate GFR 

CrCl (ml/min) = (140-age) x Actual* Body Weight (kg) 
Serum Creatinine (mg/dL) x 72 
x
2EHVHSDWLHQWV%0,XVH$GMXVWHG%RG\:HLJKW
x
Multiply by 0.85 if female 
x
Minimum SCr of 0.7 mg/dL
o
AdjXVWHG%RG\:HLJKW,I%0,

Estimate Ideal body weight (IBW) 
x
Males: IBW = 50kg + 2.3kg for each inch over 5 feet 
x
Females: IBW = 45.5kg + 2.3kg for each inch over 5 feet 

Adjusted body weight: IBW + 0.4 (ABW - IBW)
   Pemetrexed Administration
x
Premedications (in conjunction with carboplatin):
x
Administer aprepitant 130mg IV prior to chemotherapy on day 1 to prevent nausea
x
Administer ondansetron 16mg PO prior to chemotherapy on day 1 to prevent nausea
x
Administer dexamethasone 8mg IV (if PO dexamethasone has not been administered at home) 
prior to chemotherapy on day 1 to prevent nausea and rash
x
Administer dexamethasone 4mg PO BID day before chemotherapy and on days 1, 2, and 3 to 
prevent nausea and rash
x
No NSAIDs 2 days prior, day of, and 2 days after pemetrexed
x
Should not be administered in the presence of ascites or pleural effusions
x
Confirm patient has taken the following: 
x
Folic acid 1mg PO daily starting 7 days prior to initial dose of pemetrexed and continue until 21 
days after the last dose
x
Vitamin B12 (cyanocobalamin) 1,000 mcg IV every 3 months beginning 1-2 weeks prior to 
pemetrexed
x
Dexamethasone 4mg PO twice daily the day prior to pemetrexed
x
Administer after pembrolizumab and prior to carboplatin on day 1
x
For dosing utilize actual body weight and Dubois formula for body surface area 
x
Monitor for hypersensitivity reactions; refer to institution hypersensitivity protocol
Paclitaxel Administration
x
Premedications (in conjunction with carboplatin):
x
Administer aprepitant 130mg IV prior to chemotherapy on day 1 to prevent nausea
x
Administer dexamethasone 12mg PO prior to chemotherapy on day 1 to prevent nausea and 
minimize hypersensitivity reactions
x
Administer ondansetron 16mg PO prior to chemotherapy on day 1 to prevent nausea


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         28
x
Administer cetirizine 10mg PO prior to chemotherapy on day 1 to minimize hypersensitivity 
reactions
x
Administer famotidine 20mg PO prior to chemotherapy on day 1 to minimize hypersensitivity 
reactions
x
Administer dexamethasone 8 mg PO on days 2,3, and 4 to prevent nausea
x
Administer after pembrolizumab and prior to carboplatin on day 1
x
For dosing utilize actual body weight and Dubois formula for body surface area 
x
Monitor for hypersensitivity reactions; refer to institution hypersensitivity protocol
Nab-paclitaxel Administration 
x
Premedications (in conjunction with carboplatin):
x
Administer aprepitant 130mg IV prior to chemotherapy on day 1 to prevent nausea
x
Administer dexamethasone 12mg PO prior to chemotherapy on day 1 to prevent nausea and 
minimize hypersensitivity reactions
x
Administer ondansetron 16mg PO prior to chemotherapy on day 1 to prevent nausea
x
Administer dexamethasone 8 mg PO on days 2,3, and 4 to prevent nausea
x
Premedications (single agent nab-paclitaxel day 8 and 15):
x
Administer ondansetron 16mg PO prior to chemotherapy on day 8 and day 15
x
Administer after pembrolizumab and prior to carboplatin on day 1
x
For dosing utilize actual body weight and Dubois formula for body surface area 
x
Monitor for hypersensitivity reactions; refer to institution hypersensitivity protocol
General Concomitant Medication and Supportive Care Guidelines
Because there is a potential for interaction of Pembrolizumab with other concomitantly administered drugs, the case 
report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  
The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential for 
drug interactions. The chemotherapy pharmacist will review all medications (concurrent use of other all other drugs, 
over the counter medications or alternative therapies) for interactions at the start of therapy and new medications will 
be reviewed if started. The study team should check a frequently updated medical reference for a list of drugs to 
avoid or minimize use of.  
Participants should receive appropriate supportive care measures as deemed necessary by the treating investigator.  
Suggested supportive care measures for the management of AEs with potential immunologic etiology are outlined 
along with the Pembrolizumab dose modification guidelines.  Where appropriate, these guidelines include the use of 
oral or IV treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased.  For each disorder, attempts should be made to rule out other 
causes such as metastatic disease or bacterial or viral infection, which might require additional supportive care.  The 
treatment guidelines are intended to be applied when the Investigator determines the events to be related to 
pembrolizumab. 


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         29
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following 
criteria applies:
x
Disease progression
x
Intercurrent illness that prevents further administration of treatment
x
Unacceptable adverse event(s)
x
Patient decides to withdraw from the study
x
General or specific changes in the patient's condition render the patient unacceptable for further treatment 
in the judgment of the investigator
x
Clinical progression, defined as a worsening ECOG performance status or disease-related pain or 
symptoms as determined by physician evaluation
x
Patient non-compliance
x
Pregnancy
o
All women of child-bearing potential should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation.
o
The investigator must immediately be notified of a confirmed pregnancy in a study participant.
x
Termination of the study by sponsor
x
The drug manufacturer can no longer provide the study agent
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).
Duration of Follow-Up
Survival and treatment response: Patients will be followed for at least 12 months and up to 12 months after treatment 
initiation or death, whichever occurs first. 
Patients removed from study treatment for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event.
7.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with Pembrolizumab (investigational, timing) and SOC 
chemotherapy (commercial agents) can be found in Section 10. 
7.1
Drug Ordering and Accountability
7.1.1
Procurement of medications: 
All of the study drugs are commercially available agents. Prescriptions for medications will be written by the treating 
physician, preferably the medical oncologist, using study-approved standardized Markey Cancer Center order sets.  
The clinical research pharmacist of the MCC-CRO will review and approve these orders per published MCC polices. 
Drug accountability will be maintained on a Drug Accountability Report Form (DARF).


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         30 
 
7.2 
Pembrolizumab 
 
Consult the package insert and investigator brochure for the most current and complete information.  
 
 
7.2.1 
Pembrolizumab Product Dosing:  
 
The recommended dose of KEYTRUDA in adults is either:  
- 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks  
                              or  
- 400mg administered as an intravenous infusion over 30 minutes every 6 weeks 
 
This recommended dose of Pembrolizumab is administered on the Q3 or A6 weeks schedule until disease 
progression, unacceptable toxicity, or up to 24 months in patients without disease progression. 
 
Formulation  
For injection: 50mg white to off-white lyophilized powder in a single-dose vial for reconstitution 
Injection: 100 mg/4mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in single-dose vial 
 
Reconstitution: 
Add 2.3 mL of sterile water for injection, USP by injecting the water along the walls of the vial and not directly on the 
lyophilized powder (resulting concentration 25 mg/mL). 
Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial. 
 
Preparation for intravenous infusion: 
Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, 
colorless to slightly yellow. Discard the vial if visible particles are observed. 
Dilute the pembrolizumab injection (solution) or reconstituted lyophilized powder prior to intravenous administration. 
Withdraw the required volume from the vial(s) of pembrolizumab and transfer into an intravenous (IV) bag 
containing 0.9% sodium chloride injection, USP. Mix diluted solution by gentle inversion. The final concentration of 
the diluted solution should be between 1mg/mL to 10mg/mL. 
Discard any unused portion left in the vial.  
 
Storage:  
The product does not contain a preservative.  
Store the reconstituted and diluted solution from the pembrolizumab 50mg vial either: 
x At room temperature for no more than 6 hours from the time of reconstitution. This includes room 
temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion.  
x Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. 
If refrigerated, allow the diluted solution to come to room temperature prior to administration.  
Store the diluted solution from the pembrolizumab 100mg/4mL vial either: 
x At room temperature for no more than 6 hours from the time of dilution. This includes room temperature 
storage of the diluted solution, and the duration of infusion. 
x Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If 
refrigerated, allow the diluted solution to come to room temperature prior to administration. 
Discard after 6 hours at room temperature or after 24 hours under refrigeration.  


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         31
Do not freeze.
Pembrolizumab Administration 
Refer to the treatment section for specific administration instructions. 
Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-
pyogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
Do not co-administer other drugs through the same infusion line. 
Drug Interactions 
      None
Herb/Nutraceutical Interactions:
    None
Pharmacokinetics 
Distribution: the geometric mean value (CV%) for volume of distribution at steady state is 6L (20%).
Elimination: terminal half-life (t½) is 22 days (32%).
Excretion: Clearance: First dose 252 mL/day; steady state: 195 mL/day
Adverse Events for Pembrolizumab
Consult the package insert for the most current and complete information.
>10%:
Cardiovascular: Peripheral edema (11% to 15%), cardiac arrhythmia (11%)
Dermatologic: Pruritus (11% to 28%), skin rash (13% to 24%), vitiligo (13%)
Endocrine & metabolic: Hyperglycemia (19% to 59%), hyponatremia (10% to 46%), hypoalbuminemia (24% to 
44%), hypertriglyceridemia (33% to 43%), hypophosphatemia (19% to 29%), hypocalcemia (15% to 27%), 
hyperkalemia (13% to 23%), decreased serum bicarbonate (22%), hypercalcemia (14% to 22%), 
hypercholesterolemia (20%), hypokalemia (15% to 20%), hypoglycemia (13% to 19%), hypothyroidism (9% to 
18%), hypomagnesemia (16%), weight loss (10% to 15%)
Gastrointestinal: Diarrhea (12% to 28%), decreased appetite (15% to 25%), constipation (12% to 22%), abdominal 
pain (13% to 22%), nausea (11% to 22%), vomiting (11% to 19%)
Genitourinary: Hematuria (12% to 19%), urinary tract infection (12% to 19%)
Hematologic & oncologic: Lymphocytopenia (24% to 54%; grades 3/4: 1% to 25%), anemia (17% to 54%; grades 
3/4: 1% to 24%), leukopenia (35%; grades 3/4: 9%), neutropenia (7% to 30%; grades 3/4: 1% to 11%), 
thrombocytopenia (12% to 27%; grades 3/4: 4%), increased INR (19% to 21%), hemorrhage (19%; grades 
3/4: 5%), prolonged partial thromboplastin time (14%)
Hepatic: Increased serum alkaline phosphatase (17% to 42%), increased serum transaminases (27% to 34%), 
increased serum aspartate aminotransferase (20% to 34%), increased serum alanine aminotransferase (9% 
to 33%), increased liver enzymes (13%)
Immunologic: Graft versus host disease (followed by allogeneic hematopoietic stem cell transplantation: 26%)
Infection: Infection (16%)
Nervous system: Fatigue (23% to 43%), pain (22%), headache (11% to 14%)
Neuromuscular & skeletal: Musculoskeletal pain (19% to 32%), arthralgia (10% to 18%), myalgia (12%), back pain 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         32 
(11% to 12%), asthenia (10% to 11%) 
Renal: Increased serum creatinine (11% to 35%) 
Respiratory: Upper respiratory tract infection (13% to 28%), cough (14% to 26%), dyspnea (10% to 23%), 
pneumonia (12%), flu-like symptoms (11%) 
Miscellaneous: Fever (10% to 28%) 
 
1% to 10%: 
Cardiovascular: Facial edema (10%), pericarditis (4%), pericardial effusion (2%) 
Endocrine & metabolic: Hyperth\URLGLVPWRWK\URLGLWLV 
Gastrointestinal: Dysphagia (8%), stomatitis (3% to 4%; grades 3/4: 1%), colitis (2%) 
Hepatic: Hyperbilirubinemia (10%), hepatic sinusoidal obstruction syndrome (followed by allogeneic hematopoietic 
stem cell transplDQWDWLRQDVFLWHVJUDGHVKHSDWLWLV 
Immunologic: Antibody development (2%; neutralizing: <1%) 
Nervous system: Peripheral neuropathy (2% to 10%), insomnia (7%), dizziness (5%), peripheral sensory 
neuropathy (1%) 
Neuromuscular & skeletal1HFNSDLQDUWKULWLVP\RVLWLV 
2SKWKDOPLF8YHLWLV 
Renal: Acute renal failure (2%) 
Respiratory: Nasopharyngitis (10%), pneumonitis (2% to 8%) 
0LVFHOODQHRXV,QIXVLRQUHODWHGUHDFWLRQ 
 
Frequency not defined: 
Cardiovascular: Acute myocardial infarction, cardiac failure, cardiac tamponade, edema, pulmonary embolism, 
septic shock 
Dermatologic: Cellulitis, dermatitis, erythematous rash, follicular rash, maculopapular rash 
Genitourinary: Uterine hemorrhage 
Hematologic & oncologic: Rectal hemorrhage 
Infection: Candidiasis, Clostridioides difficile associated diarrhea, herpes zoster infection, sepsis 
Nervous system: Confusion, polyneuropathy 
Neuromuscular & skeletal: Osteomyelitis 
Respiratory: Epistaxis, hemoptysis, pleural effusion, respiratory failure 
Miscellaneous: Fistula, physical health deterioration 
 
<1%, postmarketing, and/or case reports: Adrenocortical insufficiency, anaphylaxis, chronic inflammatory 
demyelinating polyneuropathy, diabetic ketoacidosis, encephalitis, Guillain-Barré syndrome, hemolytic 
anemia, hypersensitivity reaction, hypophysitis, myasthenia gravis, myelitis, myocarditis, nephritis, organ 
transplant rejection (solid), pancreatitis, sarcoidosis, subacute cutaneous lupus erythematosus, type 1 
diabetes mellitus, vasculitis 
 
Nursing Guidelines 
Infuse through a 0.2 micron to 5 micron sterile, nonpyogenic, low-protein binding inline or add-on filter. 
Do not infuse other medications through the same infusion line.  
Assess laboratory values prior to drug administration, especially CBC, platelets, liver enzymes, creatinine 
Administer antiemetic therapy pre- and post-treatment if indicated.  
Monitor for signs and symptoms of hypersensitivity reactions during and post-infusion. 
 
 


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         33
7.2.3
Immune-Related Adverse Events - Pembrolizumab
AEs associated with Pembrolizumab exposure may represent an immunologic etiology. These irAEs may occur 
shortly after the first dose or several months after the last dose of Pembrolizumab treatment and may affect more 
than 1 body system simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of Pembrolizumab, administration of corticosteroids, and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, or skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue Pembrolizumab and administer corticosteroids. 
7.2.4
Management of Adverse Reactions to Pembrolizumab dose holds or discontinuation
As per guidelines established by FDA (package insert)
Commercial Agents: Carboplatin, Pemetrexed, Paclitaxel and Nab-paclitaxel
Carboplatin
Product description: Supplied as aqueous solution in multi-dose vials as 10mg/mL concentration 
(50mg/5mL, 150mg/15mL, 450mg/45mL, 600mg/60mL)
Solution preparation: refer to the package insert for standard preparation instructions
Route of administration: 
x Infuse intravenously over 30 minutes per protocol
x When administered as a part of a combination chemotherapy regimen, sequence of 
administration may vary by regimen. Refer to specific protocol.
Agent Ordering: agent is commercially available
Expected Toxicities/Adverse Events: 
o
Myelosuppression (anemia, thrombocytopenia, neutropenia)
o
Nausea/vomiting
o
Hypersensitivity reactions
o
Refer to the package insert for the comprehensive list of adverse events
Pemetrexed 
Product description:
x Pemetrexed for injection, is a white-to-light yellow or green-yellow lyophilized powder supplied 
in single-dose vials for reconstitution for intravenous infusion.
x Supplied as single-dose vial: 100mg or 500mg
Solution preparation: refer to the package insert for standard preparation instructions
Route of administration: 
x
Infuse intravenously over 10 minutes per protocol.
x
When administered as a part of a combination with platinum-based therapy (ie. carboplatin), 
administer pemetrexed prior to the platinum.
x
When administered with pembrolizumab, administer after pembrolizumab if on the same day.


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         34
Agent Ordering: agent is commercially available
Expected Toxicities/Adverse Events: 
o
Fatigue
o
Myelosuppression (anemia, neutropenia)
o
Nausea/vomiting
o
Rash
o
Refer to the package insert for the comprehensive list of adverse events
Paclitaxel 
Product description: Supplied as a nonaqueous solution intended for dilution in multidose vials at 
6mg/mL concentration (30mg/5mL, 100mg/16.7mL, 150mg/25mL, 300mg/50mL)
Solution preparation: refer to the package insert for standard preparation instructions
Route of administration: 
x Infuse intravenously over 3 hours per protocol.
x Infuse through a 0.22 micron in-line filter and polyethylene-lined (non-PVC) administration set. 
x Ensure per protocol pre-medications are administered to reduce risk of infusion related reactions
x When administered as a part of a combination chemotherapy regimen, sequence of
administration may vary by regimen. Refer to specific protocol.
Agent Ordering: agent is commercially available
Expected Toxicities/Adverse Events: 
o
Hypersensitivity reactions
o
Myelosuppression (anemia, thrombocytopenia, neutropenia)
o
Peripheral neuropathy
o
Nausea/vomiting
o
Alopecia
o
Refer to the package insert for the comprehensive list of adverse events
Nab-paclitaxel 
Product description: Supplied as a lyophilized powder in a single-use vial (100mg)
Solution preparation: refer to the package insert for standard preparation instructions
Route of administration: 
x
Infuse intravenously over 30 minutes per protocol
x
When administered as a part of a combination chemotherapy regimen, sequence of administration 
may vary by regimen. Refer to specific protocol. If administered concurrently with carboplatin, 
administer nab-paclitaxel first, followed immediately by carboplatin. 
Agent Ordering: agent is commercially available
Expected Toxicities/Adverse Events: 
o
Myelosuppression (anemia, thrombocytopenia, neutropenia)
o
Peripheral neuropathy
o
Nausea/vomiting
o
Alopecia
o
Hypersensitivity reactions
o
Refer to the package insert for the comprehensive list of adverse events


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         35 
 
8. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
KUV 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug intervention 
Participant may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
Pembrolizumab with: 
Diphenhydramine 50 
mg po (or equivalent 
dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
 
Stop Infusion. 
  
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
intervention. 
 
 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 
 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         36 
Dose modifications and toxicity management guidelines for immune-related AEs associated with Pembrolizumab 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.  
2. 
Pembro must be permanently discontinued if the irAE does not resolve or the corticosteURLGGRVHLVQRW mg/day within 12 weeks of the last Pembro treatment.  
3. 
7KHFRUWLFRVWHURLGWDSHUVKRXOGEHJLQZKHQWKHLU$(LV*UDGHDQGFRQWLQXHDWOHDVWZHHNV 
4. 
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased WR Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
Action with 
Pembro 
Corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
x 
Administer corticosteroids (initial 
dose of 1 - 2 mg/kg prednisone 
or equivalent) followed by taper 
x 
Add prophylactic antibiotics for 
opportunistic infections 
 
x 
Monitor participants for signs and symptoms of pneumonitis 
x 
Evaluate participants with suspected pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
 
Grade 3 or 4, 
or recurrent 
Grade 2  
 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
x 
Administer corticosteroids (initial 
dose of 1 - 2 mg/kg prednisone 
or equivalent) followed by taper 
 
x 
Monitor participants for signs and symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus) 
x 
3DUWLFLSDQWVZLWK*UDGHGLDUUKHDVXVSHFWLQJFROLWLVVKRXOGFRQVLGHU*,
consultation and performing endoscopy to rule out colitis 
x 
Participants with diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
x 
Administer corticosteroids (initial 
dose of 0.5 - 1 mg/kg 
prednisone or equivalent) 
followed by taper 
x 
Monitor with liver function tests (consider weekly or more frequently until liver 
enzyme value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
x 
Administer corticosteroids (initial 
dose of 1 - 2 mg/kg prednisone 
or equivalent) followed by taper 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         37 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyper-
glycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
E-cell failure 
Withhold d 
x 
Initiate insulin replacement 
therapy for participants with 
T1DM 
x 
Administer anti-hyperglycemic 
in participants with 
hyperglycemia 
 
x 
Monitor participants for hyperglycemia or other signs and symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
x 
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated 
x 
Monitor for signs and symptoms of hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyper-
thyroidism  
Grade 2 
Continue 
x 
Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
x 
Monitor for signs and symptoms of thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypo-
thyroidism 
Grade 2, 3, or 
4 
Continue 
x 
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care 
x 
Monitor for signs and symptoms of thyroid disorders 
Nephritis 
and renal 
dysfunction: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
 
Grade 2 
Withhold 
x 
Administer corticosteroids 
(prednisone 1 – 2 mg/kg or 
equivalent) followed by taper 
x 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         38 
Myocarditis 
Grade 1 or 2 
Withhold 
x 
Based on severity of AE 
administer corticosteroids 
x 
Ensure adequate evaluation to confirm etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-
related AEs 
Intolerable/pers
istent Grade 2 
Withhold 
x 
Based on severity of AE 
administer corticosteroids 
x 
Ensure adequate evaluation to confirm etiology or exclude other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e.  
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline 
abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. For participants with Grade 3 or 4 immune-
UHODWHGHQGRFULQRSDWK\ZKHUHZLWKKROGRISHPEUROL]XPDELVUHTXLUHGSHPEUROL]XPDEPD\EHUHVXPHGZKHQ$(UHVROYHVWR*UDGH2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM) 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
 
 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / surgical events or logistical reasons not related to study 
therapy. Participants should be placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The 
reason for interruption should be documented in the patient's study record. 
 
 
Other Grade 3 or 4 toxicities not outlined above. Hold all treatment until toxicities resolve to < Grade 2 and discuss with PI prior to restarting.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         39
9.
STATISTICAL CONSIDERATIONS
Study Design/Endpoints and Sample Size/Accrual Rate
A single arm, phase II, single arm non-inferiority trial is proposed.  The primary endpoint is disease control rate,
which includes intracranial benefit defined as stable disease, partial response, and complete response at 6 
months. 
Sample Size and Accrual Rate
Based on prior studies we assume an 85% disease control rate in the lung for this regimen and will assume a 
similar rate in the brain.22,24,43 A sample size of 45 patients achieves 90% power to detect a non-inferiority 
difference of -0.0500 using a one-sided Z-test with a continuity correction at 0.05 significance level. 
For enrolled patients with RANO-BM-defined measurable disease: Response will be assessed by traditional 
RANO-BM criteria for measurable disease using gadolinium-enhanced MRI.
For enrolled patients with nonmeasurable disease (as noted in 3.1.2): Response will also be assessed via 
gadolinium-enhanced MRI, using the following definitions of response: 
a. Presence of 3 lesions that can be followed: 
               Response will be assessed as presence/absence of the identified lesions
b. Presence of one lesion measuring t5mm PLUS a second lesion that can be followed: 
Response will be assessed by: 
i.
the presence/absence of the two identified lesions post-treatment
ii.
if either of the two lesions doubled in size from baseline
iii.
if either of the two identified lesions measure t5mm post-treatment
We expect to accrue 1-2 patients per month and thus, accrual is projected to be completed in 45 months. 
Stratification Factors
            None.
Interim Analysis
An initial set of 25 patients is proposed for internal funding atMCC. Interim analysis will be performed after 25 patients 
have been enrolled in the trial prior to proceeding to accrual of 45 patients.  Specifically, Bayesian posterior 
probability will be calculated to assess if disease control rate is within the non-inferiority threshold of 80%. A futility 
rate ൑80% will be assumed and the probability for stopping for futility will be set at 80%. The beta distribution for 
the efficacy/success rate is utilized with a non-informative Jeffrey’s prior equal to beta (0.5, 0.5). Bayesian posterior 
probability will be calculated after 25 patients are enrolled. The stopping bound for futility is shown in the table below 
(https://trialdesign.org). If at least 19 out of 25 patients exhibit disease control rate, we will proceed to accrue a total 
of 45 patients. We will then proceed with performing a hypothesis test of non-inferiority in disease control rate after 


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         40
a total of 45 patients.
Statistical Analysis Plan for Primary Endpoint 
Disease control rate will be estimated along with 95% exact binomial confidence interval. After 45 patients have 
been enrolled, test for non-inferiority will be performed using the Z-test.  The primary analysis will be an intent-to-
treat analysis on all patients who received treatment.    Evaluable patients will be defined as those receiving at least 
1 cycle of treatment. Patients who are non-evaluable will not be replaced.  
Statistical Analysis Plan for Secondary Endpoints
Overall Survival at 12-months post-enrollment
Kaplan-Meier estimates will be calculated for overall survival along with estimates of median survival time and 
proportion of surviving at specific time points (6 and 12 months).  
Evaluate extracranial disease control (6-month PFS)
Kaplan-Meier estimates will be calculated for progression-free survival along with estimates of median survival time 
and proportion of surviving at specific time points (6 and 12 months).  
Assess changes in Quality of Life (FACT-Cog, FACT-Brain, FACIT-Fatigue)
Quality of life (QOL) measures (FACT-Cog, FACT-Brain and FACIT-Fatigue) will be summarized at baseline and 
follow-up time points (every 3 months coinciding with routine clinic visits).  Changes in scores will be analyzed using 
paired t-test as well as linear mixed models for multiple repeated measurements. Exploratory comparisons of these 
three QOL measures with disease control status will be performed using two-group comparison tests.
Evaluate changes in Neurocognitive Functioning (MoCA) 
Neurocognitive functioning (MoCA) will be summarized at baseline and follow-up time points (3-, 6-, 9- and 12-
months coinciding with routine clinic visits).  Changes in scores will be analyzed using paired t-test as well as linear 
mixed models for multiple repeated measurements. Exploratory comparisons of the MoCA with disease control 
status will be performed using two-group comparison tests.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         41
Assess changes/decrements in ECOG Performance Status and MoCA 
ECOG Performance Status scores will be recorded at baseline and follow-up time points.  Changes in scores will be 
analyzed using non-parametric test for paired data as well as linear mixed models for multiple repeated
measurements. Correlations between ECOG PS scores and MoCA scores will be assessed using Pearson or 
Spearman’s correlation.  Exploratory comparisons of ECOG PS scores with disease control status will be performed 
using two-group comparison tests.
Statistical Analysis Plan for Correlative Endpoint 
Evaluate immune-based biomarker activity (PD-1 and activation of cytotoxic T-cells)
PD-1 and several immune-based markers, such as cytotoxic T cells, will be measured and summarized descriptively. 
Correlations with PD-1 and between markers will be estimated using Pearson or Spearman’s correlation coefficient.  
Exploratory association of these biological markers with DCR will be performed using two-group comparison tests.  
Adjustment for multiple testing due to several immune-based markers will be considered using Holm’s p-value 
adjustment method. 
Reporting and Exclusions
Evaluation of Toxicity
All patients will be evaluable for toxicity from the time of their first treatment with Pembrolizumab.
Evaluation of Response
All patients included in the study must be assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible.  Evaluable patients are defined as those who had at least 1 cycle of 
treatment. The primary analysis will be an intent-to-treat analysis on all patients who received treatment.  Sub-
analyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these sub-analyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported.  
Non-evaluable patients will not be replaced.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         42
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine whether the 
event requires expedited reporting to Overall PI and DSMC via the OnCore in addition to routine reporting.
Expected Toxicities for Pembrolizumab
Per standard of care, we will follow well-established AE reporting for all chemotherapy-immunotherapy 
combinations. In this trial we will limit the Adverse Events reporting to include: 
-
Adverse Events that are clinically significant
-
grade 4 and grade 5 AEs know to be associated with Pembrolizumab
-
all neurologic/CNS Adverse Events
Rare but serious known potential toxicities of Pembrolizumab, <1%: 
Adrenocortical insufficiency, anaphylaxis, chronic inflammatory demyelinating polyneuropathy, diabetic
ketoacidosis, encephalitis, Guillain-Barré syndrome, hemolytic anemia, hypersensitivity reaction, 
hypophysitis, myasthenia gravis, myelitis, myocarditis, nephritis, organ transplant rejection (solid), 
pancreatitis, sarcoidosis, subacute cutaneous lupus erythematosus, type 1 diabetes mellitus, vasculitis
Less Common known potential toxicities of Pembrolizumab, 1% - 10%: 
Cardiovascular: Facial edema (10%), pericarditis (4%), pericardial effusion (2%)
Immunologic: Antibody development (2%; neutralizing: <1%)
Nervous system: Peripheral neuropathy (2% to 10%), insomnia (7%), dizziness (5%), peripheral sensory 
neuropathy (1%)
2SKWKDOPLF8YHLWLV
Renal: Acute renal failure (2%)
0LVFHOODQHRXV,QIXVLRQUHODWHGUHDFWLRQ
Common known potential toxicities of Pembrolizumab, >10%: 
Cardiovascular: Peripheral edema (11% to 15%), cardiac arrhythmia (11%)
Genitourinary: Hematuria (12% to 19%), urinary tract infection (12% to 19%)
Hematologic & oncologic: Lymphocytopenia (24% to 54%; grades 3/4: 1% to 25%), anemia (17% to 54%; grades 
3/4: 1% to 24%), leukopenia (35%; grades 3/4: 9%), neutropenia (7% to 30%; grades 3/4: 1% to 11%), 
thrombocytopenia (12% to 27%; grades 3/4: 4%), increased INR (19% to 21%), hemorrhage (19%; grades 
3/4: 5%), prolonged partial thromboplastin time (14%)
Infection: Infection (16%)
Nervous system: Fatigue (23% to 43%), pain (22%), headache (11% to 14%)
Other potential toxicities/AEs of Pembrolizumab (frequency not defined):
Cardiovascular: Acute myocardial infarction, cardiac failure, cardiac tamponade, edema, pulmonary embolism, 
septic shock
Dermatologic: Cellulitis, dermatitis, erythematous rash, follicular rash, maculopapular rash
Genitourinary: Uterine hemorrhage
Hematologic & oncologic: Rectal hemorrhage


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         43
Infection: Candidiasis, Clostridioides difficile associated diarrhea, herpes zoster infection, sepsis
Nervous system: Confusion, polyneuropathy
Neuromuscular & skeletal: Osteomyelitis
Respiratory: Epistaxis, hemoptysis, pleural effusion, respiratory failure
Miscellaneous: Fistula, physical health deterioration
Adverse Event Characteristics 
x
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  
All treatment areas should have access to a copy of the CTCAE version 5.0.,  downloaded from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
x
For expedited reporting purposes only: 
o AEs for Pembrolizumab that are listed above in Section 10.1 should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity information which is 
provided. 
o Other AEs for the protocol that do not require expedited reporting are outlined in Section 10.3.3, 
under the heading, “Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions.”
x
Definitions of Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
MCC Expedited Adverse Event Reporting Guidelines
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC DSMC SOP and the University 
of Kentucky IRB reporting policy, as specified in the tables below.  Use the MCC protocol number and the protocol-
specific patient ID assigned during trial registration on all reports.
For MCC Investigator-Initiated Trials (IITs), investigators must report to the Overall PI any serious adverse event 
(SAE) that occurs after the initial dose of study treatment, during treatment, or within 90 days of the last dose of 
Pembrolizumab on the local institutional SAE form. This applies to the following categories: 
•Grade 3 (severe) Medical Events – Only events that are both Unexpected and Possibly, Probably or 
Definitely Related / Associated with Pembrolizumab (the Intervention). 
•ALL Grade 4 (life threatening or disabling) Medical Events – Unless expected AND specifically listed 
in protocol as not requiring reporting. 
•ALL Grade 5 (fatal) Events regardless of study phase or attribution.
Note: If subject is in Long Term Follow-Up, death is reported at continuing review.  
Note: Abnormal laboratory values are not considered medical events, unless determined to be
causative of SAE by the investigator or grade 5.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         44
Note:  A death on study requires both routine and expedited reporting, regardless of causality. 
          Attribution to treatment or other cause must be provided.
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. 
Required Forms and Reporting Structure for Clinical Trials
The following table outlines the required forms and reporting structure for MCC clinical trials. 
Study type 
Expedited reporting to MCC
Expedited reporting to 
External Agency
Non-expedited 
AE
Form
IRB
IIT by
MCC 
investigator
of 
commercially 
available
agent
(non-IND)
•Grade 3 – Unexpected AE 
PLUS Possibly, 
Probably or 
Definitely 
Related  
•ALL Grade 4 AEs, 
Unless AE is expected AND
listed in the protocol
as not requiring expedited 
reporting.
•ALL Grade 5 
(fatal) Events 
FDA: 
Suspected AE that is 
both serious and
Unanticipated 
(not listed in IDB or
in the consent) 
OnCore
and
DSMC
reporting
only
Voluntary 
Medwatch 
3500 for 
Serious and 
unanticipated
OnCore for 
all AEs, 
including 
SAEs
Per IRB
regulations
MCC Expedited Reporting Guidelines for MCC IITs 
Table 10.3.2 -- MCC Reportable AEs (expedited)
Attribution
Gr. 3 AE
Gr. 3 AE
Gr. 4 AE
Gr. 4 AE
ALL Gr. 5 AEs
Expected
Unexpected
Expected
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days #
5 calendar days
24 hours *
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days #
5 calendar days
24 hours *
NOTES: 
# If listed in protocol as expected and not requiring expedited reporting (Section 10.3.3), event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention,
          the AE should be reported within 24 business hours of learning of the event.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         45
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to the Overall PI or the MCC DSMC, 
however, these AEs still must be reported through the routine reporting mechanism (i.e., case report form) and to the UK
IRB (as outlined in IRB SOP: C2.0350). 
Adverse Event
Grade
Attribution
Alopecia
All
All causes
Laboratory abnormalities
1-2
Deemed not clinically significant by the treating MD
Rash
1-2
Deemed not clinically significant by the treating MD
Diarrhea
1-2
Deemed not clinically significant by the treating MD
All other AEs
1-2
Deemed not clinically significant by the treating MD
Expedited Reporting to External Agencies
Overall PI will comply with the policies of all external funding agencies, FDA and the UK IRB regarding expedited reporting, 
as per the UK IRB’s Mandated Reporting to External Agencies SOP C4.0150.  
Expedited Reporting to Hospital Risk Management
Participating investigators will report to the UK Office of Risk Management any participant safety reports or sentinel events
that require reporting according to institutional policy. 
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions with the exception of those listed in Section 
10.3.3.  AEs reported expeditiously to the Overall PI and DSMC via OnCore must also be reported in routine study 
data submissions.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         46
Pregnancy
Pregnancy is considered an unanticipated events and pregnancy as well as its outcome must be documented and 
reported to overall PI and DSMC and Office of Research Integrity, as well the FDA and sponsor in according to reporting 
requirements.  Any pregnancy occurring in a patient or patient’s partner from the time of consent to 90 days after the last 
dose of study drug must be reported and then followed for outcome.  Newborn infants should be followed until 30 days 
old.  
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial 
neoplasm.
All secondary malignancies that occur following treatment with an agent under an NCI IND/IDE must be reported to overall 
PI and DSMC and Office of Research Integrity, as well the FDA and sponsor in according to reporting requirements. 
Three options are available to describe the event: 
x
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
x
Myelodysplastic syndrome (MDS) 
x
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine 
reporting mechanisms outlined in each protocol. 
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial
malignancy).  Second malignancies require ONLY routine AE reporting unless otherwise specified.


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         47 
11. STUDY CALENDAR 
 
 
Pre-
enrollment 
Planned Treatment with Carboplatin + 
pemetrexed + pembrolizumab; 
or carboplatin + paclitaxel (or nab-
paclitaxel) + pembrolizumab; 
4 cycles of treatment Q3 weeks 
or pembrolizumab alone.  
2 cycles of treatment Q6 weeks* 
Maintenance Phase with 
pemetrexed + pembrolizumab;  
Treatment Q3 weeks *  
(if benefit, up to 13 additional cycles) 
or pembrolizumab alone 
Treatment Q6 week* 
 
Post-Treatment 
Follow-Up 
  Off - Treatment 
  Off - Study 
   Assessment: 
   
Screening  
 
Cycle 1 
   Cycles 2 - 4 
Cycles 5 & above 
(up to 13 cycles) 
120-Day 
Follow-Up 
1-year 
Follow-Up 
Visit Windows 
Day -30 to -1 
( ± 3 days) 
( ± 3 days) 
( ± 7 days) 
( +14 days) ( +14 days) 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
Demographics, 
Medical History 
 days 
 
 
 
 
 
 
 
Interval History 
      -----  
Day 1 of every cycle (C1 – C8) 
 
 
 
 
Physical Exam 
 days 
X /  Day 1 of every cycle 
X 
X 
 
 
Weight 
GD\V 
X /  Day 1 of every cycle 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
ECOG PS 
 days 
X /  Day 1 of every cycle 
X 
X 
 
 
MOCA 
GD\V 
X/ pre-treatment, and at 1-mos, 3-mos, 6-mos, 9-mos and 12-mos.  
 
 
 
 
QOL  
GD\V 
X / FACT-Cog, FACT-Brain Cancer and FACIT-Fatigue quality of life 
(QOL) measures every 3-months (same window at MOCA) through  
12-mos.  
 
 
 
 
 
Vital Signs 
 days 
X 
Day 1 of every cycle 
X 
X 
 
 
12-lead ECG 
ZHHNV 
As clinically indicated 
 
 
 
 
 
CBC w/ diff, 
Platelets, CMP 
GD\V 
X /  Day 1 of every cycle 
X 
X 
 
 
Pregnancy test** 
GD\V 
X 
 
 
 
 
 
 
TSH test 
GD\V 
X 
Q6 weeks at clinic visit 
 
 
 
 
Body 
Imaging: 
CT/PET scan 
Within 
4-8 weeks  
of 
treatment 
initiation 
CT of the chest, abdomen and pelvis or CT of the chest with MRI of the abdomen and pelvis or SOC radiographs 
will be performed in all subjects at screening or within 28-56 days of starting therapy.  
Then every 6-12 weeks after initiation of treatment as per SOC. 
 
Tumor imaging will continue until either 12-months post-treatment initiation OR until radiographic disease 
progression per RECIST 1.1 as determined by the investigator. PR or CR per RECIST 1.1 at a given time point 
PXVWEHFRQILUPHGE\UHSHDWDVVHVVPHQWV 4 weeks after the criteria for response are first met.  
 
 
Brain Imaging: 
MRI *** 
Within  
2 weeks of 
treatment 
initiation 
Initial MRI within 2 weeks of starting therapy; and then following 2 cycles, can then be done every 6 to 12 weeks.  
Tumor imaging will continue until either 12-months post-treatment initiation OR until radiographic disease 
progression per RANO-BM (and UK MOD that has been modified) as determined by the investigator. 
PR or CR per RANO-BM (and UK MOD to RANO-BM criteria) at a given timepoint must be confirmed with 
repeat scan ZHHNVDIWHUWKHFULWHULDIRUUHVSRQVHDUHILUVWPHW 
 
 
Correlative Blood 
Draws (2x Whole 
Blood Tube w/ 
Anticoagulant, 
ACD Sol A 8.5 cc 
Yellow top—BD 
product #364606) 
Within 1 week 
prior to 
treatment 
X / 15 mL blood in Whole blood tube w/ Anticoagulant, BD Vacutainer™ CPT™ Tube with Sodium Citrate.  
4 collection timepoints for each participant:  
     Initial collection within one week prior to treatment (or on the day of treatment);  
      and three additional collections every six weeks ±2 weeks after initiation of treatment (e.g., at 6-weeks,  
         12-weeks, and 18-weeks post treatment initiation).  
  
 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         48 
Tumor biopsy 
X, 
 if available 
 
 
 
 
 
 
 
Con Meds 
X 
 
 
 
 
 
 
 
Adverse Events 
GD\V 
X 
X 
X 
X 
X 
   
   
Pembrolizumab + 
chemotherapy  
(IV infusion) **** 
 
X* 
X* 
* Could continue 
 
 
 
 
Tumor Assessment 
to determine 
PFS and OS 
 
Imaging/scans will be assessed per RECIST and iRECIST and the results (PR, CR, etc.) will be noted in the eCRF 
to support interim analysis (initial 25 patients) and the final analysis if the trial is not stopped early for futility.   
 
 
Survival Status 
 
 
Interim analysis will be conducted after the first 25 patients are enrolled and will be followed for an event (disease 
progression, death).  
   Patients will be followed Until death or until 1-year post-treatment initiation.  
   NOTE: PFS at 6-months is study objective 1.2.2.  
 
 
Note reason for 
early discontin- 
uation of treatment 
(or the reason for 
removal from 
study participation) 
 
 
 
 
 
 
X 
 
X 
 
 
 
Screening 
 
Cycle 1 
 
Cycles 2 - 4 
 
Cycles 5 & above 
(up to 13 cycles) 
120-Day 
Post-TX 
Follow-Up 
1-year 
Post-TX 
Follow-Up 
  Off - Treatment 
  Off - Study 
 
NOTES for the STUDY CALENDAR:  
D= day; H&P= history and physical; ECOG PS= Performance Status; ECG= electrocardiogram; TSH= thyroid 
stimulating hormone test; CBC= complete blood count w/ differential, CMP=comprehensive metabolic panel; CT= 
Computerized Tomography, PET= Positron Emission Tomography, MRI= Magnetic Resonance Imaging; RANO-
BM= response criteria for brain metastases, PR=Partial Response, CR=Complete Response; mL=milliliter; Con 
Meds= concurrent medications; IV= intravenous; PFS=progression-free survival, OS=overall survival. 
 
 * Pembrolizumab Q6week can be considered as per treating physician. 
 
** Only in woman of reproductive potential. Women with amenorrhea for <2 years and who have not had a 
    hysterectomy and oophorectomy will only be considered not to be of reproductive potential if they have a 
    documented FSH value in the postmenopausal range. 
 
*** All effort to be done to obtain MRI. However, if not possible due to baseline reasons (e.g. Claustrophobia,   
     contrast intolerance), may obtain CT head with and without contrast. 
 
**** Standard of care chemo-immunotherapy regimens.  
 
 
 
 
 
 


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         49
12. MEASUREMENT OF EFFECT
Evaluable for Adverse Events.  All patients will be evaluable for adverse event evaluation from the time of their first 
treatment.
Evaluable for Response.  All patients who have received at least one cycle of therapy and have their disease re-
evaluated will be considered evaluable for response (exceptions will be those who exhibit objective disease 
progression prior to the end of Cycle 1 who will also be considered evaluable).  Patients on therapy for at least this 
period and who meet the other listed criteria will have their response classified according to the definitions set out 
below.
Patients with measurable disease will be assessed by iRECIST (for systemic) and RANO-BM criteria (for brain)
that has been modified for our study: RANO-BM UK MOD.44,45
Patients with nonmeasurable disease by traditional RANO-BM enrolled on-study will be assessed by RANO-BM 
UK MOD. 44,45
Antitumor Effect (CNS/brain):  RANO-BM Criteria
Only those participants who have measurable CNS disease present at baseline (per the UK Modified RANO-BM 
criteria), have received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for target disease response. These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable). Definitions of CNS treatment response and progression are based on RANO-
BM criteria that has been modified (RANO-BM UK MOD) as specified below.
Disease Parameters for Intracranial Disease Response
Measurable disease
RANO-BM has measurable lesions are defined as those that can be accurately measured in at least one dimension 
ORQJHVWGLDPHWHUWREHUHFRUGHGDVPPZLWK05,However, asymptomatic lesions identified on screening are 
RIWHQVPDOOHULQVL]H$OHVLRQRIPPZLOOEHFRQVLGHUHGDVRXU5$12-BM UK MOD for this trial. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
For multifocal intracranial disease, no more than 5 target measurable lesions (each >=5mm in diameter) should be 
selected for measurement. Target lesions should be selected on the basis of their size (lesions with longest 
diameter), be representative of other lesions and lend themselves to reproducible repeated measurements.
Non-measurable disease
Masses with margins not clearly defined, lesions with maximal diameter < 0.5cm, dural metastases, bony skull 
metastases, cystic-only lesions.
Target lesions
All measurable lesions up to a maximum of 5 lesions in total, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
and in addition should be those that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameter for all target lesions 
will be calculated and reported as the baseline sum diameters.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         50
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should 
be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout 
follow-up.
Methods of Evaluation of Disease
All measurements of the imaging-based evaluation should be taken and recorded in metric notation using a ruler, 
calipers, or a digital measurement tool. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of 
assessment and the same technique should be used to characterize each identified and reported lesion at baseline 
and during follow-up. Gadolinium-enhanced MRI is strongly encouraged as the default standard imaging technique, 
although CT with and without contrast could be considered in specific circumstances (e.g., severe claustrophobia, 
intolerance to contrast).
Response Criteria in Intracranial Disease
Complete Response (CR): Requires all of the following
•complete disappearance of all enhancing measurable and non-measurable disease sustained for at 
        least 4 weeks
•no new lesions
•stable or decreasing corticosteroids (the steroid dose at the time of the scan evaluation should be no 
       greater than the dose at time of baseline scan)
•stable or improved clinically
Partial Response (PR): All of the following criteria must be met:
•Greater than or equal to 30% decrease in the sum longest diameter of CNS target lesions compared to
      baseline sum of target lesions sustained for at least 4 weeks. In the absence of a confirming scan 
       4 weeks later, this scan will be considered only stable disease.
•no progression of non-measurable disease.
•no new lesions
•stable or reduced corticosteroid dose (the steroid dose at the time of the scan
•evaluation should be no greater than the dose at time of baseline scan)
•stable or improved clinically
Progressive Disease (PD): At least one of the following must be true:
•At least 20% increase in the sum of longest diameter of target lesions using the same techniques as 
baseline, taking as reference the smallest sum on study (this includes baseline if that is the smallest sum),
however if lesion initially at baseline is 5-9 mm in diameter, an increase by at least 5 mm in diameter is required.
•clear worsening of any non-measurable disease*
•appearance of any new enhancing lesion/site
•clear clinical worsening (unless clearly unrelated to this cancer, e.g. seizures, medication side effects, 
       complications of therapy, cerebrovascular events, infection)
•failure to return for evaluation due to death or deteriorating condition
*Progression of non-measurable CNS lesions is defined as follows:
- a lesion initially at baseline </=5mm in diameter that increases to >/= 10mm in diameter


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         51
Stable Disease (SD): All of the following criteria must be met:
•Does not qualify for CR, PR or progression
•All measurable and non-measurable sites must be assessed using the same techniques as baseline
•Stable clinically
Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend on the achievement of both measurement 
and confirmation criteria. If a response recorded at one scheduled MRI does not persist at the next regular scheduled 
MRI, the response will still be recorded based on the prior scan, but will be designated as a non-sustained response. 
If the response is sustained, i.e. still present on the subsequent MRI at least four weeks later, it will be recorded as 
a sustained response, lasting until the time of tumor progression.
Duration of Response
Duration of overall response: The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since the treatment 
started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that progressive disease is objectively documented, or death due to any cause. 
Participants without events reported are censored at the last disease evaluation.
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline 
measurements.
Antitumor Effect (systemic) – Immune-Related RECIST Criteria (iRECIST)
Definitions
Response and progression will be evaluated in this study using the ‘immune’-Revised International Criteria 
(iRECIST) which is based on RECIST version 1.1 proposed by the RECIST committee.46 Investigators should note 
the different requirements for confirmatory scans as well as follow up for the iRECIST criteria.
iRECIST Response and Evaluation Endpoints
Measurable Disease.  Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ metastases) 
are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) 
DVPPZLWKFKHVWX-ray and as mm with CT scan or clinical examination. Bone lesions are considered 
measurable only if assessed by CT scan and have an identifiable soft tissue component that meets these 
requirements (soft tissue component mm by CT scan). Malignant lymph nodes must be 15 mm in the short 
axis to be considered measurable; only the short axis will be measured and followed.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). Previously irradiated lesions are not considered 
measurable unless progression has been documented in the lesion.


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         52
Non-Measurable Disease.
All other lesions (or sites of disease), including small lesions are considered 
non-measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic 
involvement of lung or skin and abdominal masses followed by clinical examination are all non-measurable. Lesions 
in previously irradiated areas are non-measurable, unless progression has been demonstrated.
Target Lesions. When more than one measurable tumor lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, and be those that lend 
themselves to reproducible repeated measurements. Note that pathological nodes must meet the criterion of a short 
axis of mm by CT scan and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis PP but <15 mm) should be considered non-target lesions. Nodes 
that have a short axis <10 mm are considered non-pathological and should not be recorded or followed. At baseline, 
the sum of the target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall maximum of 
5) is to be recorded.
After baseline, a value should be provided on the CRF for all identified target lesions for each assessment, even if 
very small. If extremely small and faint lesions cannot be accurately measured but are deemed to be present, a 
default value of 5 mm may be used. If lesions are too small to measure and indeed are believed to be absent, a 
default value of 0 mm may be used.
Non-Target Lesions. All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not required but these lesions 
should be noted at baseline and should be followed as "present" or "absent."
Response Criteria  
All patients will have their best response from the start of study treatment until the end of treatment classified as 
outlined below:
Complete Response (CR): Disappearance of target and non-target lesions and normalization of tumor markers. 
Pathological lymph nodes must have short axis measures <10 mm (Note: continue to record the measurement even 
if <10 mm and considered CR). Residual lesions (other than nodes <10 mm) thought to be non-malignant should 
be further investigated (by cytology specialized imaging or other techniques as appropriate for individual cases
before CR can be accepted. Confirmation of response is only required in non-randomized studies.
Partial Response (PR): At least a 30% decrease in the sum of measures (longest diameter for tumor lesions and 
short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non target 
lesions must be non-PD. Confirmation of response is only required in non-randomized studies.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as 
reference the smallest sum of diameters on study.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of measured lesions taking as references 
the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of 5 mm. 
Appearance of new lesions will also constitute PD (including lesions in previously unassessed areas).  In exceptional 


 
MCC Protocol #: MCC-21-NEURO-11 
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         53 
circumstances, unequivocal progression of non-target disease may be accepted as evidence of disease progression, 
where the overall tumor burden has increased sufficiently to merit discontinuation of treatment or where the tumor 
burden appears to have increased by at least 73% in volume.  Modest increases in the size of one or more non-
target lesions are NOT considered unequivocal progression.  If the evidence of PD is equivocal (target or non-target), 
treatment may continue until the next assessment, but if confirmed, the earlier date must be used. 
 
 
Integration of target, non-target, and new lesions into response assessment 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response For This 
Category Also Requires 
Target lesions ± non target lesions  
CR 
CR 
No 
CR 
Normalization of tumor markers, 
tumor nodes <10 mm 
CR 
Non-CR/non-PD 
No 
PR 
Normalization of tumor markers, 
tumor nodes <10 mm 
CR 
Not all evaluated 
No 
PR 
  
PR 
Non-PD/not all 
evaluated 
No 
PR 
  
SD 
Non-PD/not all 
evaluated 
No 
SD 
'RFXPHQWHGDWOHDVWRQFH
weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
  
PD 
Any 
Any 
PD 
  
Any 
PD 
Any 
PD 
  
Any 
Any 
Yes 
PD 
  
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor markers, 
tumor nodes <10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/ 
non-PD 
  
No Target 
Not all evaluated 
No 
NE 
  
No Target 
Unequivocal PD 
Any 
PD 
  
No Target 
Any 
Yes* 
PD 
  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration." This is a reason for stopping therapy, but is NOT objective PD. Every effort should be 
made to document the objective progression even after discontinuation of treatment. 
 
*Investigators should record all new lesions separately.  If the new lesion is felt to be equivocal, 
treatment may be continued pending further assessments. 
 


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         54
iRECIST Response Assessment
Overall response will also be assessed using iRECIST.  Immunotherapeutics may result in infiltration of immune 
cells leading to transient increase in the size in malignant lesions, or undetectable lesions becoming detectable.  
The criteria are identical to those of RECIST 1.1 in many respects but have been adapted to account for instances 
where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression.
Key differences are described below.  All responses defined using iRECIST criteria are designated with a prefix.  
iRECIST time-point and best overall responses will be recorded separately.
Confirming progression:  iRECIST requires the confirmation of progression and uses the terms iUPD (unconfirmed 
progression) and iCPD (confirmed progression).  Confirmatory scans should be performed at least 4 weeks, but no 
longer than 8 weeks, after iUPD.
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen as evidenced by 
one or more of the following:
x
Continued increase in tumor burden (from iUPD) where definitions of progression had been met (from 
nadir) in target, non-target disease, or new lesions.
o
Progression in target disease worsens with an increase of at least 5 mm in the absolute value of 
the sum.
o
Continued unequivocal progression in non-target disease with an increase in tumor burden.
o
Increase in size of previously identified new lesion(s) (an increase of at least 5 mm in the absolute 
value of the sum of those considered to be target new lesions) or additional new lesions.
x
iRECIST criteria are met in lesions types (target or non-target or new lesions) where progression was not
previously identified, including the appearance of additional new lesions.
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned (iUPD if the 
criteria are still met, but no worsening, or iSD, iPR, or iCR if those criteria are met compared to baseline). The 
prior documentation of iUPD does not preclude assigning iCR, iPR, or iSD in subsequent time-point assessments 
or as best overall response (BOR) providing that iCPD is not documented at the next assessment after iUPD.
New lesions:  
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum of 5 lesions, 
no more than 2 per site, at least 10 mm in long axis [or 15 mm in short axis for nodal lesions]), and recorded as New 
Lesions - Target (NLT) and New Lesion - Non-Target (NLNT) to allow clear differentiation from baseline target and 
non-target lesions.
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the measurements of 
target lesions should NOT be included in the sum of measures of original target lesions identified at baseline. Rather, 
these measurements will be collected on a separate table in the case record form.
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 weeks (but not 
more than 8 weeks) after iUPD confirms further progression from iUPD with either an increase of at least 5 mm in 
the absolute value of the sum of NLT OR an increase (but not necessarily unequivocal increase) in the size of NLNT 
lesions OR the appearance of additional new lesions.


 
MCC Protocol #: MCC-21-NEURO-11 
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         55 
Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**, *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD with no 
change OR 
decrease 
from last TP 
iUPD with no 
change OR 
decrease from last 
TP 
Yes 
NA 
NLs confirms iCPD if NLs were 
previously identified and increase in 
VL]HPPLQ620IRU1/7RUDQ\
increase for NLNT) or number. If no 
change in NLs (size or number) 
from last TP, remains iUPD. 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based in further increase 
in size of NT disease (need not 
meet RECIST 1.1 criteria for 
unequivocal PD). 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in SOM of at least 5 mm, 
otherwise remains iUPD. 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in: 
x previously identified T lesion 
L83'620PPDQGRU 
x NT lesion iUPD (prior 
assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in: 
x previously identified T lesion 
L83'PPDQGRU 
x previously identified NT lesion 
iUPD (need not be unequivocal) 
and/or 


 
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         56 
Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**, *** 
x size or number of new lesions 
previously identified 
Non-iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD 
confirmed based on increase in 
size or number of new lesions 
previously identified. 
* Using RECIST 1.1 principles.  If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR, 
and SD would be the same.  
** in any lesion category.  
*** previously identified in assessment immediately prior to this TP. 
 
All patients will have their iBOR from the start of study treatment until the end of treatment classified as outlined 
below. 
 
 


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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         57
iRECIST best overall response (iBOR)
TPR 1
TPR 2
TPR 3
TPR 4
TPR 5
iBOR
iCR
iCR, iPR, 
iUPD, NE
iCR, iPR, 
iUPD, NE
iUPD
iCPD
iCR
iUPD
iPR, iSD, NE
iCR
iCR, iPR, 
iSD, iUPD, 
NE
iCR, iPR, 
iSD, iUPD, 
iCPD, NE
iCR
iUPD
iPR
iPR, iSD, 
iUPD, NE
iPR, iSD, 
iUPD, NE, 
iCPD
iPR, iSD, 
iUPD, NE, 
iCPD
iPR
iUPD
iSD, NE
PR
iPR, iSD, 
iUPD, NE
iPR, iSD, 
iUPD, iCPD, 
NE
iPR
iUPD
iSD
iSD, iUPD, 
NE
iSD, iUPD, 
iCPD, NE
iSD, iUPD, 
ICPD, NE
iSD
iUPD
iCPD
Anything
Anything
Anything
iCPD
iUPD
iUPD
iCPD
Anything
Anything
iCPD
iUPD
NE
NE
NE
NE
iUPD
Table assumes a randomized study where confirmation of CR or PR is not required.
x
NE = not evaluable that cycle.
x
Designation "I" for BOR can be used to indicate prior iUPD to aid in data interpretation.
x
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be 
assigned at each TPR but is not shown in the table for ease of presentation.
Response and Stable Disease Duration (iRECIST)
Response duration will be measured from the time measurement criteria for iCR/iPR (whichever is first recorded) 
are first met until the first date that recurrent or PD is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline). 
Stable disease duration will be measured from the time of start of treatment until the criteria for progression are met, 
taking as reference the smallest sum on study (including baseline).
Methods of Measurement
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up.  Assessments should be identified on a calendar schedule and 
should not be affected by delays in therapy.  While on study, all lesions recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  If it is the opinion of 
the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
(in this trial, this only applies to non-CNS metastases from lung cancer). For lesions which fragment/split add together 
the longest diameters of the fragmented portions; for lesions which coalesce, measure the maximal longest diameter 


MCC Protocol #: MCC-21-NEURO-11
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for the "merged lesion."
CT, MRI. CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans). Other specialized imaging or other techniques may also be appropriate for individual case.  For example, 
while PET scans are not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT (with 
IV and oral contrast).
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). When effusions are known to be a potential adverse effect of treatment (e.g., with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is 
advised to differentiate between response or SD and PD.
Other Response Parameters – Quality of Life and Neurocognitive Functioning
The trial will assess quality of life and cognition as an important secondary endpoint.
Quality of Life
Patient-reported outcomes will be assessed through use of the Functional Assessment of Cancer Therapy-Brain 
(FACT-Br) and the FACIT Fatigue Scale (FACIT-F) questionnaires. Assessments will be conducted every 3 months 
during interim visits.
The FACT-Br is a commonly used instrument measuring general quality of life (QOL) that reflects symptoms or 
problems associated with brain malignancies across 5 subscales.47 The measure yields information about total QOL, 
as well as information about the dimensions of physical well-being, social/family well-being, emotional well-being, 
functional well-being, and disease-specific concerns. The FACT-Br is written at the 4th grade reading level, and 
subjects can complete it in 5-10 minutes. FACT-Br questionnaire is found in Appendix E. 
The FACIT Fatigue Scale (FACIT-F) is a short, 13-item, easy to administer tool that measures an individual’s level 
of fatigue during their usual daily activities over the past week.48 The level of fatigue is measured on a four-point 
Likert scale (4 = not at all fatigued to 0 = very much fatigued). Subjects can complete the questionnaire in 2-3 
minutes. FACIT-Fatigue scale is found in Appendix F. 
Patient-Reported Cognitive Functioning 
The Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) questionnaire was developed to assess 
perceived cognitive function and impact on quality of life (QOL) in cancer patients. FACT-Cog has been widely 
administered across clinical settings and validated across different cultures and languages. Subjects can complete 
it in 5 minutes. FACT-Cog questionnaire and scoring is found in Appendix G. 


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Screener for Mild Cognitive Impairment – MoCA
In an effort to screen for significant cognitive decline and potential differences in the study population, a screening 
test of cognitive functioning will be employed, the Montreal Cognitive Assessment (MoCA). The MoCA is a ten-
minute cognitive test validated in >50 languages (including English, French, and Spanish). The MoCA will be 
administered to study participants every 3 months during routine clinic visits. The MoCA screener and instructions 
and scores are found in Appendix H. 
The MoCA is comprised of 15 items assessing multiple cognitive domains: 
DOMAIN
Task
Possible total 
points per item
Delayed Recall
Memory & 5-min recall
5 points
Visuospatial / Executive
Visuoconstructional - clock drawing
3 points
Visuoconstructional - Cube copy task
1 point
Alternative Trail making- part B
1 point
Naming
Phonemic fluency
3 points
Attention 
Target detection – letter A
1 point
Serial 7s (subtraction)
3 points
Digits forward
1 point
Digits backward
1 point
Language 
Sentence repetition
2 points
Semantic fluency – F words in one minute
1 point
Abstraction
Similarities
2 points
Orientation
Date, month, year, day, place & city
6 points 
The MoCA is scored to obtain an item total, scores can range from 0 to 30. One point is added for individuals who 
have 12 years or less of formal education (the number of years of education must actually be counted starting after 
kindergarten such that kindergarten is not included in the count). The total possible score is a maximum of 30 points. 
The MoCA has been found to be more sensitive than the Mini Mental State Examination (MMSE) in detecting mild 
cognitive impairment.49 In a prospective study, the MoCA exhibited excellent sensitivity (96%) and specificity (95%) 
when a cutoff score of 23 or below was utilized to define cognitive impairment.50 The MoCA has been prospectively 
evaluated in patients with brain metastases and found to be predictive of survival.51,52 The MoCA has also been 
prospectively evaluated in patients with resected brain metastases and greater than 90% of patients did not find the 
MoCA a burden.53


MCC Protocol #: MCC-21-NEURO-11
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CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         60
CORRELATIVE STUDIES
Identify the immunologic response profile with clinical response
Fluorescence-activated cell sorting (FACS) sorting to assess activated PD-1 positive immune T-cell subsets prior 
and during therapy with pembrolizumab and combination of chemotherapy and pembrolizumab.
Goal 
Identify the immunologic response profile with clinical response and mechanism of action of checkpoint blockade 
therapy in the CNS.
Burden to Subject
Minimal, extra 8.5 ml blood within seven days prior to treatment and every six weeks for three additional collection.
Overview
This exploratory study assesses the T-cell subsets and monitors PD-1 expression along with activation and will 
correlate with therapy. Multiplex immunofluorescence will be used to evaluate spatial relationships between 
immunologic factors in the tumor microenvironment. The study is based on peripheral blood to assess immune 
activation. The following steps for processing and cryopreservation of blood samples listed below are to be 
performed in Flow Cytometry and Immune Monitoring (FCIM) SRF. FCIM provides flow cytometric analysis and cell 
sorting as well as human immune monitoring services.  These services include blood processing and 
cryopreservation of PBMC.  All samples cryopreserved by FCIM are then banked and managed by Bio Specimen 
and Tissue Procurement (BSTP) SRF until all samples for a subject have been collected.  Once all samples are 
collected, all stored samples for a subject will be thawed and analyzed simultaneously by FCIM to obtain correlative 
endpoints as described above.  Data analysis will be performed by Dr. Cohen with members of his laboratory along 
with review and discussion of data with Drs. Subbarao Bondada, Val Adams, and John L. Villano.
Correlative endpoints
The correlative studies are based on peripheral blood to assess immune activation. The following steps for 
processing and cryopreservation of blood samples listed below are to be performed in Flow Cytometry and Immune 
Monitoring (FCIM) SRF. FCIM provides flow cytometric analysis and cell sorting as well as human immune 
monitoring services. These services include blood processing and cryopreservation of PBMC. All samples 
cryopreserved by FCIM are then banked and managed by Biospecimen and Tissue Procurement (BSTP) SRF until 
all samples for a subject have been collected. Once all samples are collected, all stored samples for a subject will 
be thawed and analyzed simultaneously by FCIM to obtain correlative endpoints as described below. Data analysis 
will be performed by Dr. Don Cohen with members of his FCIM laboratory along with review and discussion of data 
with Drs. Subbarao Bondada, Val Adams, and John L. Villano. Our investigation will have the following correlative 
endpoints.
Percentage of PD-1+ CD4+ T (helper) cells and PD-1+ CD8+ T (cytotoxic) cells prior to treatment versus with 
concurrent treatment: PD-1 can effectively inhibit functioning and proliferation of T-cells, reduce secretion of IL-2, 
IL-10 and IFN-Ȗ cytokines that can enhance effector T-cell function. An increase in the percentage of both PD-1+ 
CD4+ T and PD-1+ CD8+ T-cells is found in many advanced disease states (e.g., sepsis).
Percentage of CD8+ T-cells that are gamma-interferon positive during treatment. A significant change, an 
increase of 50% or more, may demonstrate an improved anti-tumor response.
PD-L1+ CD4+ and PD-L1+ CD8+ T-cell expression differences during treatment. PD-L1+ T-cells have been 
correlated with response to anti-PD-1 therapy and evaluation of this during concurrent treatment may provide more 
robust data. CD 3+ cells will also be analyzed in an exploratory manner.


MCC Protocol #: MCC-21-NEURO-11
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13. STUDY APPROVAL, OVERSIGHTAND DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 (Adverse Events: 
List and Reporting Requirements).
Protocol Review and Monitoring Committee and Institutional Review Board Review
Before implementing this study, the protocol must be reviewed by the Markey Cancer Center’s Protocol Review and 
Monitoring Committee and the protocol, the proposed informed consent form and other information to subjects, must 
be reviewed by the University of Kentucky Institutional Review Board (IRB). A signed and dated UK IRB initial review 
approval memo must be maintained in the Markey Cancer Center Clinical Research Office (MCC CRO) regulatory 
binder. Any amendments to the protocol, other than administrative ones, must be reviewed and approved by the 
PRMC, study sponsor and the UK IRB.  
Quality Assurance
The MCC places the highest priority on ensuring the safety of subjects participating in clinical trials and on the quality 
of data obtained from clinical and translation research.  The MCC Quality Assurance (QA) Office oversees the 
maintenance of quality standards in clinical cancer research through clinical data monitoring of Investigator Initiated 
Trials (IITs) and routine audits.
Data Monitoring
The MCC QA Office will collaborate with the PI, Biostatisticians and Lead OnCore® Data Management Specialist in 
creating a Clinical Data Monitoring Plan (CDMP) using a risk based approach. The CDMP will describe the scope,
communication plan, and frequency of monitoring visits. In addition, describe query submissions and resolutions, 
action items and monitoring reports. 
The QA monitor assigned to the trial will perform the monitoring tasks in accordance with the protocol specified 
CDMP. The monitoring process will provide research staff and PI with the opportunity to evaluate the progress of 
the study, verify the accuracy and completeness of the case report forms, assure that all protocol requirements, 
including applicable regulations and investigator’s obligations are being fulfilled, and prompt resolution of any 
inconsistencies in the study records.
Audit
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, the MCC Audit 
Committee will conduct a quality assurance audit. A minimum of 10% of patients enrolled in the study may be 
selected for review. The purpose of a MCC audit is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were recorded, analyzed, 
and accurately reported according to the protocol, Good Clinical Practice guidelines of the International Conference 
on Harmonization, and any applicable regulatory requirements. 


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Data and Safety Monitoring Committee
The MCC Data and Safety Monitoring Committee (DSMC) will oversee the conduct of this trial. The MCC DSMC 
performs routine real-time data monitoring and safety review of all trials, with a special focus upon investigator-
initiated trials (IITs). The MCC DSMC will conduct review of the trial on a schedule determined the MCC Protocol 
Review & Monitoring Committee (PRMC). The MCC DSMC will monitor the following elements of the trial: adverse 
event analysis, serious adverse events, protocol deviations/violations, and accrual. In addition, when applicable will 
review QA audits and monitoring reports, previous reviews by the DSMC, suggested actions by other committees, 
such as the IRB, UK Risk Management Committee, and other parameters and outcomes as determined by the 
DSMC. If appropriate, the DSMC will designate and monitor corrective action(s) based on review outcome. The MCC 
DSMC has the authority to amend, temporarily suspend, or terminate the trial based upon patient safety or 
compliance matters. 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 (Adverse Events: 
List and Reporting Requirements).
Data Reporting
Method
This study will require data submission and reporting via the OnCore Enterprise Research Clinical Trials 
Management System, which is the official database of the Markey Cancer Center.  Instructions for submitting data 
is listed in study-specific guidance documents authored by a member of the MCC Data Management Team. These
guidance documents may include any of the following, as appropriate for the scope of the study: eCRF Completion 
Guidelines, Data Management Specifications, Subject Console Guide, and Query Resolution Guide. These guidance 
documents will be approved and housed within OnCore to ensure access to approved versions to facilitate data 
submission. 
Responsibility for Data Submission
This trial will be monitored by the MCC Data and Safety Monitoring Committee (DSMC) on a schedule determined 
by the Protocol Review and Monitoring Committee at the initial PRMC review.  Study staff are responsible for 
submitting study data and/or data forms to OnCore as per the Markey Cancer Center SOPs.  Study staff are 
responsible for compiling and submitting data for all participants and for providing the data to the Principal 
Investigator for review.  


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Data Management
Data management will be performed by cross-team members at MCC.  These team members will include 
representatives from the Data Management Team, Biostatistics and Bioinformatics SRF, and the Quality Assurance 
Office.  They will work closely with study staff to ensure timely and accurate data submission.  A protocol specific 
Data Management Plan (DMP) will be authored by a senior data manager in collaboration with the biostatistician 
and Principal Investigator with each expected to review and approve the finalization of the DMP.  In order to maintain 
best clinical practices in data management, the DMP may include, but not be limited to CRF/eCRF design, database 
build and design, database training, edit check/validation specifications, study database testing/release, data and 
paper workflow, report, metrics, query/discrepancy management, management of external (including lab) data, 
medical coding, SAE handling/reconciliation, data transfers and database lock. The protocol specific DMP will 
additionally define the schedule at which data will be accessed by data management and study statistician to perform 
statistical programming for conduct of data quality, data control, data management, generation of interim reports and 
statistical analysis. Cross-team members will collaborate to establish procedures and timelines for quality control, 
audits, query resolution, annual reports, interim analysis and final data analysis. 
Compliance with Laws and Regulations
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and International 
Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the Declaration of Helsinki, any 
applicable local health authority, and Institutional Review Board (IRB) requirements.  The PI or designee will be 
responsible for obtaining continuing and not less than annual IRB re-approval throughout the duration of the study.  
Copies of the Investigator’s annual report to the IRB and copies of the IRB continuance of approval must maintained 
by the MCC CRO.  The PI or designee is also responsible for notifying the Data and Safety Monitoring Committee 
of the MCCC and the UK IRB of any significant adverse events that are serious and/or unexpected, as per SOP’s of 
those entities. DSMC will review all adverse events of this IIT as per its SOP.


 
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14. REFERENCES 
 
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Thavarajah N, Bedard G, Zhang L, et al. Psychometric validation of the functional assessment of cancer 
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Luis CA, Keegan AP, Mullan M. Cross validation of the Montreal Cognitive Assessment in community 
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Olson R, Tyldesley S, Carolan H, Parkinson M, Chhanabhai T, McKenzie M. Prospective comparison of 
the prognostic utility of the Mini Mental State Examination and the Montreal Cognitive Assessment in 


 
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patients with brain metastases. Support Care Cancer 2011;19(11):1849-55. DOI: 10.1007/s00520-010-
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Olson RA, Chhanabhai T, McKenzie M. Feasibility study of the Montreal Cognitive Assessment (MoCA) in 
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APPENDIX A. PERFORMANCE STATUS CRITERIA 
 
ECOG/WHO Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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APPENDIX B. FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM CREATININE
Formulas to estimate renal function using serum creatinine. 
Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft and Gault, 1976).
Followed by conversion to a value normalized to 1.73 m2 with the patient’s body surface area (BSA).
Cockcroft, D.W. and M.H. Gault.  (1976). Prediction of creatinine clearance from serum creatinine.  
Nephron.  16:31-41.


 
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APPENDIX C. CONTRACEPTION GUIDANCE AND PREGNANCY TESTING 
 
Woman of Childbearing Potential (WOCBP) 
 
A woman is considered fertile following menarche and until becoming post-menopausal unless permanently 
sterile (see below).  
 
Women in the following categories are not considered WOCBP: 
Ɣ 
Premenarchal 
 
Ɣ 
Premenopausal female with 1 of the following: 
ż Documented hysterectomy 
ż Documented bilateral salpingectomy 
ż Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview. 
 
Ɣ 
Postmenopausal female 
ż A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.  
ƒ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation 
with two FSH measurements in the postmenopausal range is required.  
ż 
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment 
 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they agree to one of 
the following:  
Ɣ Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term 
and persistent basis) and agree to remain abstinent 
Ɣ Use a male condom plus partner use of a contraceptive method as described in Table below when having 
penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant. 
ż Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration. 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use one of the 
contraception methods described in Table below consistently and correctly during the protocol-defined time 
frame.  
 
Pregnancy Testing  
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test. Pregnancy 
testing will be performed whenever an expected menstrual cycle is missed or when pregnancy is otherwise 
suspected. 


 
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Acceptable Contraceptive Methods   
Failure rate of >1% per year when used consistently and correctly.  
Ɣ 
Male or female condom with or without spermicide 
Ɣ 
Cervical cap, diaphragm or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
Ɣ Combined (estrogen- and progestogen- containing ) hormonal contraception b 
ż 
Oral  
ż 
Intravaginal  
ż 
Transdermal  
ż 
Injectable 
Ɣ Progestogen-only hormonal contraception b 
ż 
Oral  
ż 
Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
Ɣ 
Progestogen- only contraceptive implant b, c  
Ɣ 
Intrauterine hormone-releasing system (IUS) b  
Ɣ 
Intrauterine device (IUD) 
Ɣ 
Bilateral tubal occlusion 
 
Ɣ 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should 
be used.  
Ɣ 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies. 
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, condoms must be used in 
addition to the hormonal contraception during the treatment period and for at least 30 days [corresponding to time needed to 
eliminate study treatment plus 30 days for study treatments with genotoxic potential]ௗ after the last dose of study treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives 
are limited to those which inhibit ovulation.  
 
 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         72 
 
 
APPENDIX D. LAB MANUAL FOR PROCESSING CORRELATIVES 
 
Isolation of Mononuclear Cells from Peripheral Blood 
 
a. The FCIM group will perform the following steps to process for cryopreservation. 
x CPT blood tubes will be centrifuged at 400 x g for 30 minutes at room temperature 
x Aspirate buffy coat at interface, resuspend in sterile saline and wash by centrifugation. Repeat wash 
procedure twice. 
x Resuspend pellet containing PBMCs in ice cold 100% fetal calf serum (FCS) 
x Determine cell concentration and viability 
x Store on ice for cryopreservation by FCIM 
 
NOTE: PBMCs from all blood collections from each patient will be cryopreserved by FCIM and banked by BSTP 
SRF until all blood collections are completed.  Flow cytometric analysis by FCIM will be performed in bulk on all 
collected samples per patient. 
 
x Following determination of cell number and viability, PBMCs in FCS will be adjusted to a concentration 
of 2 x 106 viable cells/ml. 
x 2 x 106 viable cells will be added to cryopreservation vials containing DMSO to obtain a final 
concentration of 10% DMSO. 
x Vials will be transferred to cryopreservation containers for slow freezing in a -80°C freezer. 
x Following overnight freezing, vials will be transferred to liquid nitrogen freezers maintained by BSTP 
for banking until all patient blood samples are collected. 
 
 
b. Activation of Peripheral Blood Mononuclear Cell (PBMC) for Intracellular IFNȖ detection (performed by 
FCIM SRF). 
x Culture 2 x 106 freshly thawed PBMC will be incubated for 5 hours in 37oC incubator in complete RPMI 
medium containing PMA (50ng/ml) and Ionomycin (1ug/mL), plus Brefeldin A to activate cells 
x Cells will then be washed by centrifugation and then stained as follows for flow cytometry analysis:  
o Suspend cells in FACS buffer (PBS, 1% BSA, sodium azide [0.01%]) at a concentration of 107 
cells per ml 
o Add Fc Block to all tubes and incubate for 10 minutes on ice 
o Add all of the indicated fluorochome-labelled antibodies for surface membrane staining 
 CD4 FITC/CD8 PE/CD3 PerCP 
 PE-Cy7 Mouse anti-Human CD279 (PD-1) 
o Incubate on ice in the dark for 30 minutes 
o Wash cells twice with PBS+Azide to remove excess antibody 
o Fix and permeabilize cells (paraformaldehyde/saponin)  
o Stain cells for intracellular IFNȖ with fluorochrome-labeled anti-human IFNȖ antibody 
o Wash cells by centrifugation and resuspend in FACS buffer for flow cytometry analysis 
 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         73 
 
c. Flow cytometric analysis (performed by FCIM SRF). 
x Set the flow cytometer on the following gates 
o 
Live cell gate 
o 
Lymphocyte gate 
x Set the following fluorescent gates on the live lymphocyte population 
o 
CD3+, CD4+ to identify helper T-cells 
o 
CD3+, CD8+ to identify cytotoxic T-cells 
x Analyze both the helper T-cell and cytotoxic T-cell subpopulations for the following 
o 
Surface expression levels of PD-1 
o 
Intracellular expression levels of IFNȖ 
 
 
d. Analysis and storage of flow cytometric data (performed by FCIM SRF). 
x flow cytometric data will be analyzed using FlowJo analytical software to determine the 
percentage of T cell subsets (CD4+ and CD8+) which express PD-1 and/or IFNȖ 
x Calculated results for each patient and blood collection will be recorded in an Excel 
spreadsheet.  Note:  patients will be identified only with the unique code assigned for each 
patient.  
x Spreadsheet containing all results will be stored in a private folder on Dr. Cohen’s 
UK server site, which UK backs up daily. 
x Raw flow cytometry data and spreadsheet containing calculated results will also be submitted 
to the OnCore Database, the official database of the MCC CRO, as required. 
x Only the following individuals will have access to the results in the private folder of Dr. Cohen:  
Dr. Villano, Dr. Bondada, biostatistician assigned to the study. 
 
 
 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         74 
 
APPENDIX E. BRAIN CANCER (FACT-BR) QUESTIONNAIRE 
 
 
 
 
Questionnaire, instructions and scoring are found on the following pages.  
 
 
 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         75 
Below is a list of statements that other people with your illness have said are important. Please circle or mark one 
number per line to indicate your response as it applies to the past 7 days. 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble meeting the 
needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my illness 
0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my main support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please answer the 
following question. If you prefer not to answer it, please mark this box      
and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         76 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about dying 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quitea 
bit 
Very 
much 
 
GF1 
I am able to work (include work at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
0 
1 
2 
3 
4 
 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         77 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little bit Some-
what 
Quite 
a bit 
Very 
much 
Br1 
I am able to concentrate 
0 
1 
2 
3 
4 
Br2 
I have had seizures (convulsions) 
0 
1 
2 
3 
4 
Br3 
I can remember new things 
0 
1 
2 
3 
4 
Br4 
I get frustrated that I cannot do things I used to 
0 
1 
2 
3 
4 
Br5 
I am afraid of having a seizure (convulsion) 
0 
1 
2 
3 
4 
Br6 
I have trouble with my eyesight 
0 
1 
2 
3 
4 
Br7 
I feel independent 
0 
1 
2 
3 
4 
NTX6 
I have trouble hearing 
0 
1 
2 
3 
4 
Br8 
I am able to find the right word(s) to say what I 
mean 
0 
1 
2 
3 
4 
Br9 
I have difficulty expressing my thoughts 
0 
1 
2 
3 
4 
Br10 
I am bothered by a change in my personality 
0 
1 
2 
3 
4 
Br11 
I am able to make decisions and take responsibility 
0 
1 
2 
3 
4 
Br12 
I am bothered by the drop in my contribution to the 
family
 
0 
 
1 
 
2 
 
3 
 
4 
Br13 
I am able to put my thoughts together 
0 
1 
2 
3 
4 
Br14 
I need help in caring for myself (bathing, dressing, 
eating, etc.) 
 
0 
 
1 
 
2 
 
3 
 
4 
Br15 
I am able to put my thoughts into action 
0 
1 
2 
3 
4 
Br16 
I am able to read like I used to 
0 
1 
2 
3 
4 
Br17 
I am able to write like I used to 
0 
1 
2 
3 
4 
Br18 
I am able to drive a vehicle (my car, truck, etc.) 
0 
1 
2 
3 
4 
Br19 
I have trouble feeling sensations in my arms, 
hands, or legs 
 
0 
 
1 
 
2 
 
3 
 
4 
Br20 
I have weakness in my arms or legs 
0 
1 
2 
3 
4 
Br21 
I have trouble with coordination 
0 
1 
2 
3 
4 
An10 
I get headaches 
0 
1 
2 
3 
4 
 


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         78
FACT-Br Scoring Guidelines (Version 4) – Page 1
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the  
    number of items answered.  This produces the subscale score.
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT-Br). 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PHYSICAL
GP1
4
-
________
=________
WELL-BEING
GP2
4
-
________
=________
   (PWB)
GP3
4
-
________
=________
      
GP4
4
-
________
=________
      
GP5
4
-
________
=________
      
GP6
4
-
________
=________
      
GP7
4
-
________
=________
              Sum individual item scores: ________  
                      Multiply by 7: ________
Divide by number of items answered: ________=PWB subscale score
SOCIAL/FAMILY
GS1
0
+
________
=________
WELL-BEING
GS2
0
+
________
=________
    (SWB)
GS3
0
+
________
=________
      
GS4
0
+
________
=________
      
GS5
0
+
________
=________
   
GS6
0
+
________
=________
      
GS7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
    Divide by number of items answered: ________=SWB subscale score
EMOTIONAL
GE1
4
-
________
=________
WELL-BEING
GE2
0
+
________
=________
    (EWB)
GE3
4
-
________
=________
      
GE4
4
-
________
=________
     
GE5
4
-
________
=________
GE6
4
-
________
=________
             Sum individual item scores: ________  
                     Multiply by 6: ________
Divide by number of items answered: ________=EWB subscale score
Score range: 0-28
Score range: 0-28
Score range: 0-24


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         79
FUNCTIONAL  
GF1
0
+
________
=________
WELL-BEING 
GF2
0
+
________
=________
     (FWB)
GF3
0
+
________
=________
      
GF4
0
+
________
=________
      
GF5
0
+
________
=________
      
GF6
0
+
________
=________
      
GF7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
Divide by number of items answered: ________=FWB subscale score
FACT-Br Scoring Guidelines (Version 4) – Page 2
Subscale
         Item Code       Reverse item?            Item response        
Item Score
BRAIN 
Br1
0
+
________
=________
CANCER
Br2
4
-
________
=________
SUBSCALE
Br3
0
+
________
=________
  (BrCS)
Br4
4
-
________
=________
Br5
4
-
________
=________
Br6
4
-
________
=________
Br7
0
+
________
=________
Ntx6
4
-
________
=________
Br8
0
+
________
=________
Br9
4
-
________
=________
Br10
4
-
________
=________
Br11
0
+
________
=________
Br12
4
-
________
=________
Br13
0
+
________
=________
Br14
4
-
________
=________
Br15
0
+
________
=________
Br16
0
+
________
=________
Br17
0
+
________
=________
Br18
0
+
________
=________
Br19
4
-
________
=________
Br20
4
-
________
=________
Br21
4
-
________
=________
An10
4
-
________
=________
              Sum individual item scores:________  
                  Multiply by 23 : ________
Divide by number of items answered: ________=BrC Subscale score
Score range: 0-28
Score range: 0-92


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         80
To derive a FACT-Br Trial Outcome Index (TOI):
__________ + __________ + __________ =________=FACT-Br TOI
(PWB score)   (FWB score)   (BrCS score)  
To Derive a FACT-G total score:
__________ + __________ + __________ + __________=________=FACT-G Total score
(PWB score)    (SWB score)   (EWB score)  (FWB score)
To Derive a FACT-Br total score:
_________ + __________ + __________ + __________ + __________ =________=FACT-Br Total score
(PWB score)  (SWB score)   (EWB score)  (FWB score)   (BrCS score)
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring Guidelines 
in the manual or on-line at www.facit.org
To derive a FACT Br T
Score range: 0-148
To Derive a FACT G to
Score range: 0-108
To Derive a FACT B
Score range: 0-200


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         81 
APPENDIX F. FATIGUE (FACIT-FATIGUE, V4) QUESTIONNAIRE 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
 
HI7 
I feel fatigued 
0 
1 
2 
3 
4 
HI12 
I feel weak all over 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”) 
0 
1 
2 
3 
4 
An2 
I feel tired 
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired 
0 
1 
2 
3 
4 
An5 
I have energy 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities 
0 
1 
2 
3 
4 
An8 
I need to sleep during the day 
0 
1 
2 
3 
4 
An12 
I am too tired to eat 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I 
want to do 
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am 
tired
0 
1 
2 
3 
4 
 
 
 


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         82
FACIT-Fatigue Subscale Scoring Guidelines (Version 4) – Page 1
Instructions: *
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the  
    number of items answered.  This produces the subscale score.
4. The higher the score, the better the QOL.
Subscale
         Item Code       Reverse item?            Item response        
Item Score
FATIGUE
HI7
     
4
-
________
=________
SUBSCALE
HI12
4
-
________
=________
   
An1
4
-
________
=________
An2
4
-
________
=________
An3
4
-
________
=________
An4
4
-
________
=________
An5
0
+
________
=________
An7
0
+
________
=________
An8
4
-
________
=________
An12
4
-
________
=________
An14
4
-
________
=________
An15
4
-
________
=________
An16
4
-
________
=________
              Sum individual item scores: ________  
                   Multiply by 13: ________
Divide by number of items answered: ________=Fatigue Subscale score
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring Guidelines 
in the manual or on-line at www.facit.org.
Score range: 0-52


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         83 
APPENDIX G. COGNITIVE FUNCTIONING (FACT-COG) PATIENT QUESTIONNAIRE 
 
Below is a list of statements that other people with your condition have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
 
 
 
 
PERCEIVED COGNITIVE IMPAIRMENTS 
Never 
About 
once a 
week 
Two to 
three 
times a 
week 
Nearly 
every 
day 
Several 
times  
a day 
CogA1 
I have had trouble forming thoughts 
 
 
0 
1 
2 
3 
4 
CogA3 
My thinking has been slow                  
 
0 
1 
2 
3 
4 
CogC7 
I have had trouble concentrating 
 
0 
1 
2 
3 
4 
CogM9 
I have had trouble finding my way to a familiar 
place 
 
0 
1 
2 
3 
4 
CogM10 I have had trouble remembering where I put 
things, like my keys or my wallet 
 
 
0 
 
1 
 
2 
 
3 
 
4 
CogM12 
I have had trouble remembering new information, 
like phone numbers or simple instructions 
 
 
    0 
1 
2 
3 
4 
CogV13 
I have had trouble recalling the name of an object 
while talking to someone  
 
    0 
1 
2 
3 
4 
CogV15 
I have had trouble finding the right word(s) to 
express myself 
 
0 
1 
2 
3 
4 
CogV16 
I have used the wrong word when I referred to an 
object 
 
 
0 
1 
2 
3 
4 
CogV17b 
I have had trouble saying what I mean in 
conversations with others 
 
0 
1 
2 
3 
4 
CogF19 
I have walked into a room and forgotten what I 
meant to get or do there 
 
0 
1 
2 
3 
4 
CogF23 I have had to work really hard to pay attention or I 
would make a mistake 
 
0 
1 
2 
3 
4 
CogF24 I have forgotten names of people soon after 
being introduced 
 
0 
1 
2 
3 
4 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         84 
Please circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 
 
 
 
Never 
About 
once a 
week 
Two to 
three 
times a 
week 
Nearly 
every 
day 
 
Several 
times a 
day 
CogF25 
My reactions in everyday situations have been 
slow 
 
0 
1 
2 
3 
4 
CogC31 
I have had to work harder than usual to keep 
track of what I was doing 
 
0 
1 
2 
3 
4 
CogC32 
My thinking has been slower than usual  
 
0 
1 
2 
3 
4 
CogC33a 
I have had to work harder than usual to express 
myself clearly 
 
0 
1 
2 
3 
4 
CogC33c 
I have had to use written lists more often than 
usual so I would not forget things 
 
 
0 
1 
2 
3 
4 
CogMT1 
I have trouble keeping track of what I am doing if 
I am interrupted 
 
0 
1 
2 
3 
4 
CogMT2 
I have trouble shifting back and forth between 
different activities that require thinking 
 
 
0 
1 
2 
3 
4 
 
 
Please circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 
 
 
 
 
 
COMMENTS FROM OTHERS 
Never 
About 
once a 
week 
Two to 
three 
times a 
week 
Nearly 
every 
day 
 
Several 
times a 
day 
CogO1 
Other people have told me I seemed to have trouble 
remembering information 
 
0 
1 
2 
3 
4 
CogO2 
Other people have told me I seemed to have trouble 
speaking clearly  
 
0 
1 
2 
3 
4 
CogO3 
Other people have told me I seemed to have trouble 
thinking clearly 
 
     0 
1 
2 
3 
4 
CogO4 
Other people have told me I seemed confused
 
 
     0 
1 
2 
3 
4 


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         85 
  
Please circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 
 
 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
IMPACT ON QUALITY OF LIFE 
Not  
at all 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
CogQ35 
I have been upset about these problems 
 
 
0 
1 
2 
3 
4 
CogQ37 
These problems have interfered with my ability to work 
 
0 
1 
2 
3 
4 
CogQ38 
These problems have interfered with my ability to do 
things I enjoy 
 
0 
1 
2 
3 
4 
CogQ41 
These problems have interfered with the quality of my 
life
0 
1 
2 
3 
4 
 
 
 
 
PERCEIVED COGNITIVE ABILITIES 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
Cog
PC1 
I have been able to concentrate 
0 
1 
2 
3 
4 
Cog
PV1 
I have been able to bring to mind words that I wanted 
to use while talking to someone 
 
0 
 
1 
 
2 
 
3 
 
4 
Cog
PM1 I have been able to remember things, like where I left 
my keys or wallet 
 
0 
 
1 
 
2 
 
3 
 
4 
Cog
PM2 I have been able to remember to do things, like take 
medicine or buy something I needed 
 
0 
 
1 
 
2 
 
3 
 
4 
Cog
PF1 
I am able to pay attention and keep track of what I 
am doing without extra effort 
 
0 
 
1 
 
2 
 
3 
 
4 
Cog
PC
H1 
My mind is as sharp as it has always been 
0 
1 
2 
3 
4 
Cog
PC
H2 
My memory is as good as it has always 
0 
1 
2 
3 
4 
Cog
PM
T1 
I am able to shift back and forth between two 
activities that require 
 
0 
 
1 
 
2 
 
3 
 
4 
Cog
PM
T2 
I am able to keep track of what I am doing, even if I 
am 
 
0 
 
1 
 
2 
 
3 
 
4 


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FACT-Cog Scoring Guidelines (Version 3) – Page 1
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the  
    number of items answered.  This produces the subscale score.
4. Add subscale scores to derive total scores (Not applicable to the FACT-Cog*). 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PERCEIVED
CogA1 4
-
________
=________
COGNITIVE
CogA3 4
-
________
=________
IMPAIRMENTS
CogC7 4
-
________
=________
      (CogPCI)
CogM9 4
-
________
=________
      
CogM104
-
________
=________
      
CogM124
-
________
=________
      
CogV13 4
-
________
=________
CogV15 4
-
________
=________
      
CogV16 4
-
________
=________
CogV17b
4
-
________
=________
      
CogF19 4
-
________
=________
CogF23 4
-
________
=________
      
CogF24 4
-
________
=________
CogF25 4
-
________
=________
      
CogC31 4
-
________
=________
CogC32 4
-
________
=________
      
CogC33a
4
-
________
=________
CogC33c
4
-
________
=________
       CogMT1
NOT CURRENTLY SCORED
       CogMT2
NOT CURRENTLY SCORED
              Sum individual item scores: ________  
                      Multiply by 18: ________
Divide by number of items answered: ________=CogPCI subscale score
IMPACT OF PERCEIVED
COGNITIVE
CogQ35 4
-
________
=________
IMPAIRMENTS ON
CogQ37 4
-
________
=________
QUALITY OF LIFE
CogQ38 4
-
________
=________
      (CogQOL)
CogQ41 4
-
________
=________
           Sum individual item scores: ________  
    
                    Multiply by 4: ________
Divide by number of items answered: ________=CogQOL subscale score
(
g
)
Score range: 0-72
Score range: 0-16


MCC Protocol #: MCC-21-NEURO-11
Version Date: 8 February 2022
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Subscale
  Item Code    Reverse item?       Item response        
Item Score
COMMENTS FROM
CogO1 4
-
________
=________
OTHERS
CogO2 4
-
________
=________
    (CogOth)
CogO3 4
-
________
=________
      
CogO4 4
-
________
=________
     
             Sum individual item scores: ________  
                     Multiply by 4: ________
Divide by number of items answered: ________=CogOth subscale score
PERCEIVED  
CogPC1 0
+
________
=________
COGNITIVE ABILITIES 
CogPV1 0
+
________
=________
     (CogPCA)
CogPM1
0
+
________
=________
      
CogPM2
0
+
________
=________
      
CogPF1 0
+
________
=________
      
CogPCh1
0
+
________
=________
      
CogPCh2
0
+
________
=________
       
       CogPMT1
NOT CURRENTLY SCORED
       CogPMT2
NOT CURRENTLY SCORED
             Sum individual item scores: ________  
                     Multiply by 7: ________
Divide by number of items answered: ________=CogPCA subscale score
*FACIT recommends that either cognitive impairments or cognitive abilities be selected as a ‘primary’ score (we 
currently recommend cognitive impairments be used).
There are two options regarding the scoring of items CogMT1, MT2, PMT1 and PMT2: (1) include the 4 items in 
scoring and conduct some additional analyses to confirm the items fit with the scale (range 0-80, 0-36); or (2) score the 
scale without the additional 4 items (range 0-72, 0-28).
While CogMT1, MT2, PMT1 and PMT2 are not currently scored, they may be included in the total score if a measure of 
internal consistency (e.g., Cronbach’s alpha) and individual item-total score correlation coefficients indicate that the 
items fit with the scale. These extra steps would be needed because the items were added later and not included in the 
initial validation analyses.
Score range: 0-16
Score range: 0-28


 
MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         88 
 
 
APPENDIX H. MONTREAL COGNITIVE ASSESSMENT (MOCA) – STAFF-ADMINISTERED 
 
 
 
See next page.  
 
 


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MCC Protocol #: MCC-21-NEURO-11 
Version Date:  8 February 2022 
CNS Active Pembro+Chemo in Asymptomatic Brain Mets from NSCLC                                         90 
 
Montreal Cognitive Assessment (MoCA) Administration and Scoring Instructions 
 
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild cognitive 
dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, 
language, visuoconstructional skills, conceptual thinking, calculations, and orientation.  
Time to administer the MoCA is approximately 10 minutes.  
The total possible score is 30 points; a score of 26 or above is considered normal. 
 
Alternating Trail Making: 
Administration: The examiner instructs the subject: "Please draw a line, going from a number to a letter in 
ascending order. Begin here [point to (1)] and draw a line from 1 then to A then to 2 and so on. End here [point 
to (E)]." 
Scoring: Allocate one point if the subject successfully draws the following pattern: 
1 A- 2- B- 3- C- 4- D- 5- E, without drawing any lines that cross. Any error that is not immediately self-corrected 
earns a score of 0. 
 
Visuoconstructional Skills (Cube): 
Administration: The examiner gives the following instructions, pointing to the cube: “Copy this drawing as 
accurately as you can, in the space below”. 
Scoring: One point is allocated for a correctly executed drawing. 
Drawing must be three-dimensional 
All lines are drawn 
No line is added 
Lines are relatively parallel and their length is similar (rectangular prisms are accepted) 
A point is not assigned if any of the above-criteria are not met. 
 
Visuoconstructional Skills (Clock): 
Administration: Indicate the right third of the space and give the following instructions: 
“Draw a clock. Put in all the numbers and set the time to 10 after 11”. 
Scoring: One point is allocated for each of the following three criteria: 
Contour (1 pt.): the clock face must be a circle with only minor distortion acceptable (e.g., slight imperfection on 
closing the circle); 
Numbers (1 pt.): all clock numbers must be present with no additional numbers; numbers must be in the correct 
order and placed in the approximate quadrants on the clock face; Roman numerals are acceptable; numbers can 
be placed outside the circle contour; 
Hands (1 pt.): there must be two hands jointly indicating the correct time; the hour hand must be clearly shorter 
than the minute hand; hands must be centred within the clock face with their junction close to the clock centre. 
A point is not assigned for a given element if any of the above-criteria are not met. 


 
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Naming:       
 
Administration: Beginning on the left, point to each figure and say: “Tell me the name of this animal”. 
 
Scoring: One point each is given for the following responses: (1) camel or dromedary, (2) lion, (3) rhinoceros or 
rhino. 
 
 
Memory: 
 
Administration: The examiner reads a list of 5 words at a rate of one per second, giving the following instructions: 
“This is a memory test. I am going to read a list of words that you will have to remember now and later on. Listen 
carefully. When I am through, tell me as many words as you can remember. It doesn’t matter in what order you 
say them”. Mark a check in the allocated space for each word the subject produces on this first trial. When the 
subject indicates that (s)he has finished (has recalled all words), or can recall no more words, read the list a 
second time with the following instructions: “I am going to read the same list for a second time. Try to 
remember and tell me as many words as you can, including words you said the first time.” Put a check in the 
allocated space for each word the subject recalls after the second trial. 
At the end of the second trial, inform the subject that (s)he will be asked to recall these words again by saying, “I 
will ask you to recall those words again at the end of the test.” 
 
Scoring: No points are given for Trials One and Two. 
 
 
Attention: 
Forward Digit Span: Administration: Give the following instruction: “I am going to say some numbers and when 
I am through, repeat them to me exactly as I said them”. Read the five number sequence at a rate of one digit 
per second. 
Backward Digit Span: Administration: Give the following instruction: “Now I am going to say some more 
numbers, but when I am through you must repeat them to me in the backwards order.” Read the three number 
sequence at a rate of one digit per second. 
 
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct response for the backwards 
trial is 2-4-7). 
 
Vigilance: Administration: The examiner reads the list of letters at a rate of one per second, after giving the 
following instruction: “I am going to read a sequence of letters. Every time I say the letter A, tap your hand once. 
If I say a different letter, do not tap your hand”. 
 
Scoring: Give one point if there is zero to one errors (an error is a tap on a wrong letter or a failure to tap on letter 
A). 


 
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Version Date:  8 February 2022 
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Serial 7s: Administration: The examiner gives the following instruction: “Now, I will ask you to count by 
subtracting seven from 100, and then, keep subtracting seven from your answer until I tell you to stop.” Give this 
instruction twice if necessary. 
Scoring: This item is scored out of 3 points. Give no (0) points for no correct subtractions, 1 point for one 
correction subtraction, 2 points for two-to-three correct subtractions, and 3 points if the participant successfully 
makes four or five correct subtractions. Count each correct subtraction of 7 beginning at 100. Each subtraction 
is evaluated independently; that is, if the participant responds with an incorrect number but continues to 
correctly subtract 7 from it, give a point for each correct subtraction. For example, a participant may respond 
“92 – 85 – 78 – 71 – 64” where the “92” is incorrect, but all subsequent numbers are subtracted correctly. This 
is one error and the item would be given a score of 3. 
 
Sentence repetition: 
Administration: The examiner gives the following instructions: “I am going to read you a sentence. Repeat it 
after me, exactly as I say it [pause]: I only know that John is the one to help today.” Following the response, 
say: “Now I am going to read you another sentence. Repeat it after me, exactly as I say it [pause]: The cat always 
hid under the couch when dogs were in the room.” 
Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be exact. Be alert for errors that 
are omissions (e.g., omitting "only", "always") and substitutions/additions (e.g., "John is the one who helped 
today;" substituting "hides" for "hid", altering plurals, etc.). 
 
Verbal fluency: 
Administration: The examiner gives the following instruction: “Tell me as many words as you can think of that 
begin with a certain letter of the alphabet that I will tell you in a moment. You can say any kind of word you want, 
except for proper nouns (like Bob or Boston), numbers, or words that begin with the same sound but have a 
different suffix, for example, love, lover, loving. I will tell you to stop after one minute. Are you ready? [Pause] 
Now, tell me as many words as you can think of that begin with the letter F. [time for 60 sec]. Stop.” 
Scoring: Allocate one point if the subject generates 11 words or more in 60 sec. Record the subject’s response 
in the bottom or side margins. 
 
 
Abstraction: 
Administration: The examiner asks the subject to explain what each pair of words has in common, starting with 
the example: “Tell me how an orange and a banana are alike”. If the subject answers in a concrete manner, then 
say only one additional time: “Tell me another way in which those items are alike”. If the subject does not give 
the appropriate response (fruit), say, “Yes, and they are also both fruit.” Do not give any additional instructions 
or clarification. 
After the practice trial, say: “Now, tell me how a train and a bicycle are alike”. Following the response, 
administer the second trial, saying: “Now tell me how a ruler and a watch are alike”. Do not give any additional 
instructions or prompts. 
Scoring: Only the last two item pairs are scored. Give 1 point to each item pair correctly answered. The 
following responses are acceptable: 
Train-bicycle = means of transportation, means of travelling, you take trips in both; Ruler-watch = measuring 
instruments, used to measure. 
The following responses are not acceptable: Train-bicycle = they have wheels; Ruler-watch = they have 
numbers. 


 
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Version Date:  8 February 2022 
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Delayed recall: 
Administration: The examiner gives the following instruction: “I read some words to you earlier, which I 
asked you to remember. Tell me as many of those words as you can remember. Make a check mark (ض) for 
each of the words correctly recalled spontaneously without any cues, in the allocated space. 
Scoring: Allocate 1 point for each word recalled freely without any cues. 
 
 
 
Orientation: 
Administration: The examiner gives the following instructions: “Tell me the date today”. If the subject does not 
give a complete answer, then prompt accordingly by saying: “Tell me the [year, month, exact date, and day of 
the week].” Then say: “Now, tell me the name of this place, and which city it is in.” 
Scoring: Give one point for each item correctly answered. The subject must tell the exact date and the exact 
place (name of hospital, clinic, office). No points are allocated if subject makes an error of one day for the day 
and date. 
 
 
TOTAL SCORE, MoCA:  
Sum all subscores listed on the right-hand side. Add one point for an individual who has 12 years or fewer of 
formal education, for a possible maximum of 30 points. A final total score of 26 and above is considered 
normal. 
 
 
 
Optional: 
Following the delayed free recall trial, prompt the subject with the semantic category cue provided below for any 
word not recalled. Make a check mark (ض) in the allocated space if the subject remembered the word with the help 
of a category or multiple-choice cue. Prompt all non-recalled 
words in this manner. If the subject does not recall the word after the category cue, give him/her a multiple choice trial, using 
the following example instruction, “Which of the following words do you think it was, NOSE, FACE, or HAND?” 
Use the following category and/or multiple-choice cues for each word, when appropriate:  
FACE: 
category cue: part of the body 
multiple choice: nose, face, hand VELVET:
 
category cue: type of fabric 
multiple choice: denim, cotton, velvet CHURCH:
 
category cue: type of building 
multiple choice: church, school, hospital DAISY:
 
category cue: type of flower 
multiple choice: rose, daisy, tulip 
RED: 
category cue: a color 
multiple choice: red, blue, green 
Scoring: No points are allocated for words recalled with a cue. A cue is used for clinical information purposes 
only and can give the test interpreter additional information about the type of memory disorder. For memory deficits 
due to retrieval failures, performance can be improved with a cue. For memory deficits due to encoding failures, 
performance does not improve with a cue.