Pilot Study of Pembrolizumab and Stereotactic Radio-Surgery (SRS) for Patients With Melanoma or Non-Small Cell Lung Cancer (NSCLC) Brain Metastases (BM)
Phase: PHASE1
Conditions: Metastatic Malignant Neoplasm in the Brain, Metastatic Melanoma, Mucosal Melanoma, Ocular Melanoma, Stage IV Non-Small Cell Lung Cancer, Stage IV Skin Melanoma, Melanoma of Unknown Primary
Sponsor: Emory University

Product:  Pembrolizumab (MK-3475, IND 130757) 
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Rad3179-16 
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TITLE: Rad3179-16 (MK-3475-423) Pilot Study of Pembrolizumab and Stereotactic 
Radio-Surgery (SRS) for Patients with Melanoma or Non-Small Cell Lung Cancer 
(NSCLC) Brain Metastases (BM) 
 
INVESTIGATORS:  
 
 
Principal Investigator 
Radiation Oncology: Mohammad K. Khan, MD PhD;  
 
Sub-Investigators 
Radiation Oncology:   
 
 
 
Hui Kuo-Shu, MD Ph.D 
 
 
            Bree Eaton, MD 
 
 
 
Kristin Higgins, MD 
 
 
 
Shannon Kahn, MD 
 
 
 
Tony Eng, MD 
 
 
 
Jay Shelton, MD 
 
 
 
 
 
 
Medical Oncology: David H. Lawson, MD.     
  
 
       Ragini Kudchadkar, MD  
 
 
       Suresh Ramalingam, MD 
                               Taofeek Owonikoko, MD 
   
                   Rathi N. Pillai, MD 
 
 
       Melinda Yushak, MD 
 
 
       Dong M. Shin, MD 
 
 
       Conor Steuer, MD 
 
Neurosurgeon:       J. Jeffrey Olson, MD 
 
Translational Medicine: Rafi Ahmed, PhD. 
 
Biostatistics: Jeffery Switchenko, PhD. 
 
Pathology: Douglas Parker, MD. 
 
SPONSOR: Mohammad K. Khan, MD PhD 
 
SUPPORTER: Merck Sharp & Dohme Corp. 
 
IND NUMBER: 130757 
 
EudraCT NUMBER (Studies in Europe only): N/A 
 
 

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TABLE OF CONTENTS 
 
 
 
 
 
 
         PAGES 
1.0  
PROTOCOL SUMMARY 
 
 
 
 
 
 
3 
 
 
2.0  
TRIAL DESIGN/SCHEMA 
 
 
 
 
 
 
4 
 
3.0 
STUDY OBJECTIVES, ENDPOINTS, & HYPOTHESES 
 
 
7 
 
4.0 
BACKGROUND & RATIONALE 
 
 
 
 
 
9 
 
5.0 
ENROLLMENT CRITERIA    
 
 
 
 
 
19 
 
 
6.0 
ADMINSTRATION OF STUDY PHARMACEUTICAL 
 
 
22  
 
7.0  
DOSE MODIFICATION/DISCONTINUATION  
 
 
 
25 
 
8.0 
DOSE LIMITING TOXICITIES 
 
 
 
 
 
27 
 
9.0  
SUPPORTIVE CARE  
 
 
 
 
 
 
29 
 
10.0      DIET/ACTIVITY/CONTRACEPTION/OTHER CONSIDERATIONS 
 
33 
 
11.0      DELIVERY OF RADIATION THERAPY TREAMENT 
  
 
37 
 
 
12.0 
TRIAL FLOW CHART  
 
 
 
 
 
 
43 
 
13.0 
TRIAL PROCEDURES  
 
 
 
 
 
 
45 
 
 
  
14.0 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
60 
 
15.0 
LABELING, PACKAGING, STORAGE, AND RETURN OF  
CLINICAL SUPPLIES  
 
 
 
 
 
 
63 
 
 
 
 
 
 
 
 
 
 
16.0     DATA SAFETY MONITORING BOARD  
 
 
 
 
64 
 
17.0 
APPENDICES:  
 
 
 
 
 
 
              
 
APPENDIX I:    CTCAE COMMON TOXICITY CRITERIA STUDY               66            
APPENDIX II:   RECIST CRITERIA 
 
 
 
 
             67 
APPENDIX III:  IMMUNE RELATED RECIST CRITERIA 
 
             68 
   
 
APPENDIX IV:  KARNOFSKY PERFORMANCE STATUS & ECOG              71 
             
 
APPENDIX V:   RTOG RPA CLASSIFICATION SYSTEM 
 
             72 
 
APPENDIX VI:  RTOG GPA CLASSIFICATION SYSTEM 
 
             73 
 
APPENDIX VII:  ELIGIBILTY CHECKLIST  
 
 
             74 
 
 

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18.0  
BIBLIOGRAPHY 
 
 
 
 
 
 
 
76 

Product:  Pembrolizumab (MK-3475, IND 130757) 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
SRS and Pembrolizumab for Melanoma and Non-Small Cell Lung 
Cancer (NSCLC) brain metastases (BM). 
Trial Phase 
Pilot Study 
Clinical Indication 
Melanoma and NSCLC Brain Metastases 
Trial Type 
Pilot study with three different radiation dose cohorts. 
Type of control 
None 
Route of administration 
Pembrolizumab delivered 200 mg IV every 3 weeks +/- 7 days for 
at least 2 years, or until progression. 
Trial Blinding 
N/A 
Treatment Groups  
All receive pembrolizumab 200 mg IV every 3 weeks +/- 7 days 
until progression or at least 2 years, with 3 altered radiation dose 
fractionation groups delivered during first cycle of pembrolizumab. 
Number of trial subjects 
30 patients. 
Estimated enrollment period 2 years 
Description of enrollment 
In 2013, we delivered SRS to 20 metastatic melanoma brain 
metastases patients and 27 NSCLC BM patients. In 2014, we 
delivered SRS to 14 and 26 patients, respectively. Assuming similar 
numbers over the next two years, and accruing 45% of patients, we 
anticipate around 30 patients to enroll. 
   
These projected accrual numbers do not reflect the possibility of 
increased patient referrals from our satellite facilities, and/or 
increased regional/national referrals, once the trial is opened. We 
are also not aware of other potentially competing radiation SRS for 
melanoma and NSCLC brain metastases trials at our institution at 
this time. 
Duration of Intervention 
At least 12 months of Pembrolizumab, or until progression. 
Duration of Evaluation 
3 year ( 2 yrs during accrual, and at least 1 year follow-up for last 
patient accrued on the study) 
Estimated duration of trial 
3 years (2 years to accrue + 1 years to follow all patients) 
Duration of Participation 
3 years 
Study Center 
Emory University. Atlanta, Georgia. 
 
 
 
 
 
 
 
 

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2.0 TRIAL DESIGN/SCHEMA 
2.1 
Trial Overview 
Pembrolizumab (i.e. anit-PD-1) and stereotactic radiosurgery (SRS) will be delivered 
concurrently.  The safety and efficacy of this combination is not known. Preclinical data shows 
promise of this combination, but, has yet to be tested in humans with brain metastases. 
Pembrolizumab (200 mg IV every 3 weeks +/- 7 days for at least 2 years, or until 
progression) will be delivered on day 1 of cycle 1 and continued until at least 2 years or until 
disease progression per RECIST 1.1 (see Appendix II for RECIST Criteria). SRS will be 
delivered on day 2 or day 3 of cycle 1 (i.e. within 24-48 hours after anti-PD-1, with some 
flexibility allowed for SRS timing during cycle 1).  
Three different radiation doses (Table 1) will be delivered during cycle 1, in combination with 
Pembrolizumab.   All three radiation doses have different biological effectiveness doses (BED) 
for acute and late side effects, with Arm C being the most commonly used accepted arm; The 
primary objective will be to assess for dose limiting toxicity (i.e, ≥ grade 3 CNS toxicity at 
3 months)  when different radiation doses (Table 1) are delivered; Several secondary 
objectives will also be evaluated (section 3.0);  The primary point of the trial (dose limiting 
toxicity) is ≥ radiation therapy oncology (RTOG) CNS grade 3 toxicity, as defined in the 
original RTOG 90-05 trial, used to arrive at the currently used safest single radiation dose 
fraction (Arm C, Table 1) schemes for radiosurgery (Shaw E, et al. Int. J. Rad. Onc. & Biol. 
2000(47) 291-8);  Grade 3 CNS toxicity is defined as irreversible severe neurological 
symptoms as outpatient or inpatient requiring medication usage; It is also possible that 
while changing the radiation dose levels, we may also find a radiation dose level that is also 
more immunogenic when combined with PD1 inhibitor; This optimal radiation dose may or 
may not be the same as that per RTOG 90-05;  Preclinical data suggest that dose fraction sizes 
of 8-10 Gy may be more immunogenic compared with other dose fractionation regimens; This 
needs to be further evaluated in clinical trials;  
All patients will have a baseline PET scan as well as a diagnostic CT chest, abdomen, and 
pelvis. All pre-treatment and post treatment imaging will be per standard of care for staging 
and surveillance purposes. They will also have a baseline brain MRI. Post SRS treatment, they 
will continue to have diagnostic brain MRI (at 6 weeks, and then every 3 months) as well as 
CT chest/abdomen/pelvis (every 3 months) per standard of care, to evaluate response and to 
monitor for any unexpected toxicity. Routine standard of care blood work (CBC, BMP, LDH, 
etc) will also be ordered at baseline and with all subsequent visits. 
 
 

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Table 1 – Radiation Dose Arms 
Group 
Dose per 
fraction        
(Gy) 
Number of 
Fractions 
Acute BED 
Chronic BED 
A 
6 
5 
48 
90 
B 
9 
3 
51.3 
108 
C.    tumor volume  < 4cm3 
       tumor volume 4-14.15 
cm3 
           21 
           18 
1 
1 
65.1 
50.4 
168 
128 
BED = biological equivalent dose. Acute BED is the biological equivalent dose for acute radiation responding tissue, which 
includes malignant cells. Chronic BED biological is the biologic equivalent dose for late radiation responding tissue, which 
includes normal brain tissue. Increasing chronic BED doses predicts higher risk of sub-acute and chronic toxicities.  
2.2 
Altered Radiation Dose Arms (See Figure 1, in Section 2.4); 
This is a pilot study to look at the safety of concurrent PD-1 inhibitor and SRS for melanoma 
brain metastases using three different radiation arms currently used to treat brain metastases. 
An initial cohort of 6 patients will be enrolled on radiation arm A (6 Gy x 5) that has a lower 
biological effective doses (BED) for acute and chronic side effects (Table 1), radiation arm B 
(9 Gy x 3) which has the second lowest BED, and radiation arm C (21 Gy x 1 or 18 Gy x 1 
based on tumor volume) which has the highest acute and chronic BED; Arm C is also the most 
commonly accepted standard of care regimens, and based on RTOG 90-05 radiation dose 
escalation trial.  
The first 18 patients (6 per dose level) will be enrolled in sequence as follows:  
Arm A: patient #1-6,    Arm B: patient #7-12, Arm C: patient # 13-18; 
There will be a 3 month interim waiting period after 6 patients are enrolled on a given radiation 
arm and analyzed for any undue early dose limiting toxicity (DLT); The DLT toxicity 
definition is similar to that defined in the RTOG 90-05 (i.e, CNS grade 3 or more acute 
toxicity, which is considered irreversible severe neurological symptoms at 3 months 
requiring medications); The time point of 3 months is typical of when all post SRS acute side 
effects are expected to resolve. Thus, having acute side effects requiring medication usage for 
irreversible severe symptoms at 3 months would be unusual.  
The second 18 patients (6 per dose level) will be enrolled in a similar sequence as 
follows: 
 
 
Arm A: Closed, Arm B: patient #25-30, Arm C: patient #31-36; 
 
2.3 Acute Toxicity, Expansion Cohorts, and Late Toxicity Assessment: 
 
Once 6 patients are enrolled on any given dose level, there will be a waiting period of 3 months 
(i.e, at time of second post SRS MRI assessment after pembrolizumab dose (i.e, 3 months after 
Day 1, cycle 1); This time point of 3 months and the dose limiting toxicity (i.e. grade 3 RTOG 
CNS toxicity) is based on similar timeline used on earlier trial to determine the safest radiation 
dose.  Late toxicity (radionecrosis noted on MRI images will also be analyzed at 6 months and 
at 1 year, but will not be used to stop enrollment on any given dose arm.); 
During this 3 month waiting period, the MRI images and the patients will be assessed for any 

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signs or symptoms of RTOG CNS toxicity as well as early manifestations of radionecrosis.  ≥ 
Grade 3 CNS toxicity is the only DLT toxicity of principal concern. Patient can still be accrued 
on other dose arms during this waiting period, while data is being analyzed for safety concerns 
on a given radiation arm. 
• If ≤ 2/6 patients develop a DLT on a given radiation arm, accrual on the 
particular dose arm will continue for another 6 patients for a total of 12 patients 
per dose arm.  RTOG 90-05 used a 20% cutoff at 3 months as the DLT endpoint.  
We accept 2/6 (33%) based on a biological rationale that if there is slight 
increase in radiation toxicity, this may be offset by increased systemic 
responses through immune modulation of radiation when radiation is combined 
with anti PD-1 (see section 4.0 for biological rationale); 
• If ≥3/6 patients develop a DLT on a given radiation dose arm, this arm will stop 
accrual and considered unsafe;  
Late toxicity (i.e, toxicity starting after 3 months) will also be analyzed (a secondary 
endpoint of trial). The principal late toxicity of interest is symptomatic radiation necrosis. 
This is defined as radiographic (typically on MRI) changes consistent with radiation induced 
necrosis, and the patient also presenting with increased neurological symptoms.   
Symptomatic radiation necrosis will be recorded at 6 months and at 12 months;   
 
• The radiation dose arm which meets the lowest DLT (i.e. ≥ Grade 3 CNS 
Toxicity at 3 months) and late toxicity (any radiation necrosis) endpoints, but 
also potentially provides higher overall systemic response rate and OS, will be 
considered the best radiation dose level that can be combined with 
pembrolizumab.   
• Our published series of melanoma patients undergoing SRS alone had an 
average survival of 38% at 1 yr (Patel KR et al, American J. Clinic. Oncology. 
2015, May 16. Epub);  Our recent multi-institutional review in collaboration 
with Duke University suggested 1 yr overall survival of 78% for patients 
undergoing SRS and PD1 in combination (not published, accepted for annual 
presentation at American Society of Radiation Oncology Meeting, 2016).  
Thus, we suspect an improvement of 40% in OS compared with SRS alone. 
12 patients on the most immunogenic arm (9Gy x 3), would be expected to 
have lowest acute and late toxicity, as well as potentially the highest OS 
benefit. We suspect that this may be the arm for a future trial. However, this 
has not been tested in any currently prospective manner. 
 
Thus, the total enrollment will be 30 patients, and not less than 18. 
 
 

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2.4 
Trial Schema 
Figure 1: Trial Overview 
 
3.0 OBJECTIVES, ENDPOINTS & HYPOTHESES 
3.1 
Primary Objective, Endpoint, & Hypothesis 
3.1.1 Primary Objective   
a. To determine the safety of three different stereotactic radiosurgery (SRS) radiation 
arms in combination with pembrolizumab for melanoma and non-small cell lung 
cancer (NSCLC) brain metastasis (BM) patients. 
3.1.2 Primary Endpoint 
a. RTOG grade 3 CNS toxicity at 3 months (the Dose Limiting Toxicity); 
  
3.1.3 Primary Endpoint Definitions 
a. RTOG grade 3 CNS toxicity is defined as irreversible severe neurological 
symptoms requiring medications at 3 months; 
 
3.1.4 Primary Hypothesis   
a. The primary hypothesis of this pilot study is that the use of concomitant SRS using 

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three different SRS radiation doses with pembrolizumab in melanoma and NSCLC 
BM patients will be a safe, well-tolerated regimen.  
 
3.2 
Secondary Objective(s), Endpoint(s) & Hypothesis(es) 
3.2.1 Secondary Objectives  
b. To evaluate intracranial outcomes – control of the treated lesion in the brain with 
SRS+ pembrolizumab (i.e. local control), development of additional sites of disease 
in the brain that were not initially treated with SRS (i.e. anywhere intra-cranial 
failure), intra-cranial progression free survival (local control of the area that 
received SRS and anywhere intra-cranial failure), extra-cranial disease response 
(overall progression free survival), rate of leptomeningeal dissemination, and 
overall survival. 
c. To determine the overall response rate and overall survival of combination SRS 
and pembrolizumab compared to: 
i. SRS alone (historical control) 
ii. Pembrolizumab alone (historical control) 
 
d. To evaluate treatment response at un-irradiated and extra-cranial sites (i.e. the 
abscopal effect) with all three arms; 
e. To compare differences in potential immune biomarkers, pretreatment, during 
treatment, and post treatment; 
3.2.2 Secondary Endpoints 
a. Time to intracranial outcomes, including local recurrence, anywhere intra-cranial 
failure, leptomeningeal dissemination. 
b. Overall survival time. 
c. Overall response (intra-cranial and extra-cranial). 
d. Difference in pre and post treatment serum immune biomarkers between the three 
different radiation arms (see biomarkers section); 
e.  Symptomatic radiation necrosis rates at 6 months and at 12 months; 
 
3.2.3 Secondary Endpoint Definitions 
a. Time to recurrence for each of the intracranial events will be measured from the 
first treatment on cycle 1, day 1 to the earlier of the recurrence event and/or last 
follow up/death.  
b. Overall survival will be defined as time from first treatment on cycle 1, day 1 to 
the earlier of date of death and/or last follow up. 
c. Overall response will be defined using RECIST and immune RECIST Criteria. 
Response will be measured for all metastatic sites and at un-irradiated sites (i.e. 
the abscopal effect). 
d. Several serum biomarkers will be analyzed (See section 12) to note any 
differences between    the three arms. 

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e. Symptomatic radiation necrosis is defined as evidence of necrosis on MRI 
images (radiographic evidence or radionecrosis) and a patient having 
neurological symptoms attributed to the location where the radiosurgery was 
done (symptomatic); Secondary Hypotheses 
 
3.2.4 Secondary Hypotheses 
a. Using descriptive analyses, combination therapy will result in a higher median 
survival relative to a historical cohort treated with  pembrolizumab alone or SRS 
alone. 
b. Using descriptive analyses, combination therapy, relative to pembrolizumab alone 
cohort, will result in higher local control and intracranial control. 
c. Using descriptive analyses, combination therapy, relative to the cohort treated 
with pembrolizumab alone, will result in a higher improved RECIST and immune 
RECSIT response rate. 
d. We may see early difference in patients that develop enhanced abscopal 
response from those that do not, based on early biomarker analysis, and that this 
could potentially guide future therapy selection.  
e. Radiation necrosis rates may be same, or better with altered dose fractionation 
compared with single fraction, especially when combined with concurrent PD1; 
 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.0.1 Brain Metastasis  
 
In 2013, 10-30% of all adult cancer patients developed brain metastases, representing 
170,000 newly diagnosed secondary brain malignancies in the United States 1. While the 
highest number of BM arises from lung malignancies, stage IV melanoma has the highest 
relative proclivity – 50-75% – for developing brain metastases 2,3. Among non-small cell lung 
cancer (NSCLC) and melanoma patients with documented brain metastases, intracranial 
lesions contribute to death in up to 95% of cases4.  
Survival rates for brain metastases patients vary according to each cancer subtype, but 
overall have been dismal 5. Using 5 prospective RTOG studies with 1,960 brain metastases 
patients, Sperduto et al. developed a point scoring system to predict patient outcomes 6. 
Applying this graded partitioning analysis (GPA) to a multi-institution retrospective database 
with 4,259 brain metastases patients, they developed a prognostic criteria for each of the main 
pathologic primary sites of metastases7. For newly diagnosed melanoma brain metastases 
(MBM) patients, two factors predicted survival: Karnofsky performance status (KPS) and the 
number of intracranial metastases; for NSCLC, age and presence of extracranial metastases 
also predicts for survival prognosis. The median survival for melanoma and NSCLC brain 
metastases is 6.7 months and 7.0 months respectively; the best prognosis risk group has a 
survival of 13.2 months and 14.8 months, respectively, while the worse risk prognosis group 

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has a survival of 3.4 and 3.0 months only. Table 2 summarizes validated prognostic factors, 
risk groups, and outcomes for melanoma and NSCLC brain metastases patients. 
 
 
 
Table 2 – Median Survival of Brain Metastases patients stratified by histology and 
prognosis group 
 
Primary Tumor Site 
of Brain metastases 
Median 
survival 
(months) 
Median survival 
within poorest 
prognosis group 
Median survival 
with best prognosis 
group 
NSCLC 
7.0 
3.0 
14.8 
Melanoma 
6.7 
3.4 
13.2 
 
 
 
4.0.2  Stereotactic Radiation Surgery for Brain Metastasis 
 
Historically, most traditional cytotoxic chemotherapies have a limited role in brain 
metastasis, in part due to blood brain barrier (BBB) limiting penetration8. As a result, the 
standard of care for brain metastasis includes surgery and/or radiation therapy. Although very 
effective for symptomatic control, Kocher et al. demonstrated that surgical resection alone 
commonly results in high local failure of 59% at 2 years9. To improve local control (LC) and 
distant brain control (DBC), adjuvant whole brain radiation therapy (WBRT) has been utilized.   
With concern, for late neurocognitive toxicities from irradiating the whole brain10, 
more conformal radiation treatments have been developed. Stereotactic radiation therapy 
(SRS) is a technique that focuses high doses of radiation therapy to the tumor while minimizing 
radiation therapy to the rest of the brain. Although SRS has lower rates of distant intracranial 
control for non-targeted subclinical disease, a prospective study has illustrated that SRS alone 
has similar survival rates to WBRT alone11. Furthermore, the addition of WBRT to SRS for 
patients with 1—3 brain metastases did not improve OS9. Retrospective analyses in the post-
operative setting have also demonstrated SRS has similar LC and OS to WBRT after 
controlling for the number of brain metastases12. 
We at Emory have adopted this approach to treat brain metastasis, including melanoma 
and NSCLC, with SRS alone to delay WBRT and its related neurocognitive sequellae. Our 
contemporary analysis supports this regimen for brain metastasis patients: directly comparing 
post-operative SRS to WBRT, we found (Patel et al) both radiation treatments offer similar 
local control and median survival, but SRS in 80% of patients prevented the need for WBRT 
at 1 year12. In the intact brain metastases setting, we at Emory have illustrated (Prabhu et al) 
that 1 year local control rate with SRS was 82%13. The local control rate is comparable to other 
similar published series utilizing radiosurgery14. Our studies contribute to the body of evidence 
that SRS can help improve local intracranial control.  
 
4.0.3  Radiation Necrosis 
 

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While SRS may have a radiobiological advantage and help avoid neurocognitive 
decline from WBRT, it is not without toxicities. Radiation necrosis is a form of radiation 
induced damage to white matter tissue, causing demyelination, surrounding edema, and normal 
tissue necrosis and death15. Prospective clinical trials have demonstrated grade 3 toxicity rates 
of 10-15% with SRS16. Based on these studies, the radiation therapy oncology (RTOG) 
recommended doses for SRS were 24 Gy for tumors ≤20 mm, 18 Gy for tumors 21-30 mm, 
and 15 Gy for tumors 31-40 mm16 
Two of the largest studies have since analyzed predictive factors for the development 
of radiation necrosis after SRS for patients with intact brain metastasis. On multivariate 
analysis from both studies, the volume of disease receiving 10 and 12 Gy of radiation were 
predictive for developing both asymptomatic and symptomatic radiation necrosis14,15. To meet 
these criteria, while still providing adequate control, SRS has been offered over a 
hypofractionated (2-5 fractions) rather than a single fraction at a lower dose.   
Our series and others, comparing 30Gy in 5 fractions and 27Gy over 3 fractions to 
single fraction SRS, identified lower risk of radiation necrosis with hypofractionation, 
especially for larger lesions, and those next to critical organs. These altered fractionation have 
become our defacto standard for larger lesions, and in those which lesions are close to critical 
organs. Overall, these studies suggest that fractionated SRS is a safer way to treat brain 
metastases while still maintaining similar local control rates.  This is important for our trial, 
especially since we plan to deliver SRS with pembrolizumab at the same time, thus raising 
some concern for potential toxicity.  Thus, we have used altered SRS fractionation using SRS 
regimens that have been demonstrated to potentially reduce rates for radiation necrosis, even 
in larger lesions compared with larger, single fraction radiation doses.  Furthermore, these 
altered radiation doses using hypofractionation may also be more immunogenic compared 
with the single, large doses of radiation (i.e. 21 Gy in single fraction, or 18 Gy in single 
fraction). Thus, biologically and from safety point of view, the altered fractionated regimens 
(i.e. 2-5 fractions) may be more advantageous, than single, large dose radiation fractions. 
However, this has never been tested concurrently with PD-1, and basis for our trial. 
  
 
 

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4.1.1  The Immune System in Cancer 
 
In 2000, Hanahan and Weinberg published their seminal review describing the 6 
biological hallmarks acquired during the development from benign to malignant to metastatic 
tumors17. Eleven years later, they illustrated 2 further important processes that were since 
realized, including “evading the immune system”18. 
The immune system consists of two main components, innate and adaptive system. In 
brief, the innate system is a non-specific response to differences between innate and foreign 
pathogens, while the adaptive system is a more tailored response that induces memory. As part 
of this adaptive response, macrophages and dendritic cells present foreign antigens to the T 
cell’s receptors. Further T cell activation is regulated by multiple factors, including both 
positive (co-stimulatory) and negative (co-inhibitory) surface receptors. Tumors can subvert 
the related immune recognition in part through increase of co-inhibitory molecule expression; 
two of these regulatory molecules are cytotoxic T lymphocyte antigen-4 (CTLA-4) and 
programmed death 1 (PD-1) receptor. 
 
4.1.2 Anti-PD-1 in Pre-Clinical Models 
 
Programmed death 1 (PD-1) (or CD279) is part of the CD28 family of proteins, which 
includes CTLA-4 and ICOS, that regulate T cell activity21. PD-1 is a glycoprotein receptor that 
can be expressed on the surface of T cells, B cells and myeloid cells (monocytes and dendritic 
cells)21.  In T cells, PD-1 expression is primarily induced by T cell receptor (TCR) engagement 
and ligation with PD-L1 and PD-L2, expressed on antigen presenting cells, and induces an 
inhibitory signal that antagonizes TCR signaling and other important pathways necessary for 
optimal T cell activation  
Interestingly, melanoma, and to a lesser effect NSCLC, expresses abundant PD-1 
ligand (PD-L1), whereas T cells of advanced cancer patients notoriously express increased 
levels of PD-1. The combined effect is that these cancer cells are spared from T-cell-mediated 
cytotoxicity, and tumor infiltrating lymphocytes are maintained in a dysfunctional state, 
described as T cell exhaustion. Indeed, PD-1 expression on T cells of patients has been 
associated with progression to metastatic disease.  
Targeting the PD-1 pathway in pre-clinical models has demonstrated promising 
activity. Utilizing murine cancer cells, anti-PD1 antibody decreased tumor growth and 
decreased metastatic potential. Because B16 cells are PD-L1 expressing, the authors also used 
4T1, a PD-L1 negative murine cell line and demonstrated similar efficacy of PD-1 pathway 
blockade. Prior studies demonstrate that PD-L1 expression varies in response to the 
microenvironment, including increased expression in response to cell death. Consistent with 
this model of variable PD-L1 expression over time, several authors have since demonstrated 
the efficacy of anti-PD-1 antibodies in both PD-L1 positive and negative tumors. 
 
4.2.1 Efficacy of Anti-PD-1, Pembrolizumab, in Melanoma Patients 
 
Two clinical trials have recently investigated the safety and efficacy of anti-PD-1 
pembrolizumab therapy in melanoma. The first published trial by Hamid et al enrolled 135 
patients who had never received ipilimumab or had completed ipilimumab greater than 6 weeks 

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from enrollment19. Patients were treated with escalating doses of pembrolizumab, from 2mg/kg 
q3weeks to 10mg/kg q2weeks. After 4 cycles of induction therapy, patients were continued on 
pembrolizumab maintenance. The overall response rate was 38% of patients. Response rate 
was also dose related, with 2mg/kg cohort having a 25% response compared to the 10mg/kg 
cohort having a 52% response. With a median follow up of 11 months, 81% of patients 
continued to demonstrate a response and median survival had not been reached, suggesting 
majority of responses are durable and correlate with survival. 
The second reported by Robert et al was a phase I trial of pembrolizumab in metastatic 
melanoma patients. 173 patients refractory to ipilimumab were randomized in a 1:1 fashion to 
2mg/kg q3weeks or 10mg/kg q3weeks20. Overall response rate for both dose cohorts was 
similar: 26%. Of the 41 responding patients, 2 had a complete response (4.9%) while 39 had a 
partial response (95.1%). Another 24% had stable disease, for a disease control rate of 50%. 
Progression free survival was 22 weeks for the 2mg/kg arm and 14 weeks for the 10mg/kg 
arm, with no statistical difference between cohorts. 1 year overall survival was 58% for the 
2mg/kg cohort and 63% for the 10mg/kg cohort. 
Taken together (Table 3), these studies suggest pembrolizumab is an active agent in 
metastatic melanoma that is well tolerated. Based on these results, the FDA approved 
pembrolizumab for ipilimumab refractory patients, at a recommended dose of 2mg/kg every 3 
weeks +/- 7 days. 
 
Table 3 - Efficacy & Safety of Anti-PD-1 Antibody, Pembrolizumab in Melanoma 
 
 
 
 
 
 
4.2.2 Efficacy of Anti-PD-1, Pembrolizumab, in NSCLC Patients 
 
Building upon the success of pembrolizumab in melanoma, Garon et al. investigated 
the safety and efficacy of pembrolizumab alone in 495 stage IV non-small cell lung cancer 
patients21. Overall response rate for entire cohort was 19.4%. Current or prior smokers had a 
higher response rate than never smoker: 22.5% vs. 10.3%. PD-L1 expression on tumors 
correlated with higher response, as the 23% of patients with a proportion staining score of 50% 
or higher had a response of 50%. The role of pembrolizumab in combination with SRS for 
Trial 
First 
Author 
Number 
of 
Patients 
Drug Dose 
Overall 
Response 
Rate 
Overall  
Survival 
Grade  
3-4    Toxicity 
Hamid et 
al19 
135 
(i) 2mg/kg q3wks     
(ii) 10mg/kg q3wks 
(iii) 10mg/kg q2wks 
38% 
Median Survival 
not reached  
(median follow 
up: 11 months) 
13% 
Robert et 
al20 
173 
(i) 2mg/kg q3wks 
(ii) 10mg/kg q3wks  
26% 
1 year OS:        
58-63% 
12% 

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NSCLC brain metastases has not been evaluated, and is one of an additional area of 
investigation in our current trial. 
 
4.3.1 Rationale for Pembrolizumab Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety 
and clinical activity of single agent MK-3475 (pembrolizumab).  The dose escalation portion 
of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of MK-
3475 showed evidence of target engagement and objective evidence of tumor size reduction 
at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to 
date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule 
utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent 
data from other clinical studies within the MK-3475 program has shown that a lower dose of 
MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK model, 
clearance and volume parameters of MK-3475 were found to be dependent on body weight. 
The relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to have 
a wide therapeutic range based on the melanoma indication.  The differences in exposure for 
a 200 mg fixed dose regimen relative to a 200 mg200 mg Q3W body weight based regimen 
are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-
3475 in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 200 
mg200 mg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. 
The rationale for further exploration of 200 mg200 mg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab 
when dosed at either 200 mg200 mg or 10 mg/kg Q3W in melanoma patients, 2) the flat 
exposure-response relationships of pembrolizumab for both efficacy and safety in the dose 
ranges of 200 mg200 mg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or 
indication on distribution behavior of pembrolizumab (as assessed by the population PK 
model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not 
vary meaningfully with tumor type. 

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The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab showing 
that the fixed dose of 200 mg every 3 weeks +/- 7 days will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks +/- 7 days, 2) 
will maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients exposure 
in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
 
4.3.2  Safety and toxicity of Pembrolizumab 
Pembrolizumab has been administered to a total of 308 melanoma patients, from 2 
prospective clinical trials65-66. The first trial administered pembrolizumab at 3 different doses 
(2mg/kg q3weeks, 10mg/kg q3weeks, and 10mg/kg q2weeks) for 4 total cycles, followed by 
continued maintenance therapy until progression. Overall, 79% of patients develop any grade 
of toxicity. The most common toxicities were fatigue (30%), rash (21%), pruritus (21%), and 
diarrhea (20%). However, most of these symptoms were low grade, as only 13% developed 
grade 3- 4 toxicities. Furthermore, grade 3-4 adverse events were dose related: the 10mg/kg, 
q2week cohort was 23%, while the q3week cohorts was 4-9%. The grade 3 clinical toxicities 
documented included rash (2%), pruritus (1%), hypothyroidism (1%), diarrhea (1%), 
abdominal pain (1%), decreased appetite (1%), elevated AST (1%), and renal failure (1%). In 
the 2 cases of renal failure, both cases improved with discontinuation of pembrolizumab and 
initiation of glucocorticoid therapy 
In the trial of pembrolizumab in advanced melanoma patients, the toxicity profile was 
similar to that reported by Hamid et al: 82% developed any grade of toxicity, while 12% 
developed grade 3-4 toxicities. Most common toxicities were fatigue, pruritus, and rash. 
Reported grade 3-4 toxicities included fatigue (3%), elevated amylase (<1%), anemia (<1%), 
autoimmune hepatitis (<1%), confusion (<1%), diarrhea (<1%), dyspnea (<1%), 
encephalopathy (<1%), hypophysitis (<1%), hypoxia (<1%), muscular weakness (<1%), 
musculoskeletal pain (<1%), pancreatitis (<1%), peripheral motor neuropathy (<1%), 
pneumonitis (<1%), rash (<1%), rash maculopapular (<1%). Overall 6 patients (7%) developed 
adverse events leading to discontinuation of the drug. 3 of these cases (3%) were immune 
mediated. No drug related grade 5 toxicities were reported.  
In the phase 1 study with 495 NSCLC patients, no grade 3 or higher CNS toxicities 
were noted. Furthermore, the toxicity profile was similar to that identified in the two melanoma 
studies. Most common grade > 3 adverse events were fatigue (0.8%), decreased appetite 
(1.0%), nausea (0.8%), asthenia (1.0%), dyspnea (3.8%) and pneumonitis (1.8%). 1 patient 
who developed pneumonitis did die; overall, these findings demonstrate pembrolizumab is 
well tolerated and has similar toxicity profiles among the two histologies.  
 
4.4.1 Safety and Efficacy of Pembrolizumab Alone for Melanoma Brain Metastases 

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For both published pembrolizumab trials (Hamid et al & Robert et al), patients with 
melanoma brain metastases were excluded. With melanoma having a high incidence of 
developing brain metastases, the efficacy in this population is extremely important. To 
investigate this further, Kluger et al (Yale group) conducted a phase I study of pembrolizumab 
alone for melanoma brain metastases22. Only patients with asymptomatic lesions and ECOG 
PS 0-1 were included. 
Patients were treated with 10mg/kg q2weeks for 4 total cycles, followed by 
maintenance therapy. All patients were asymptomatic and not requiring steroids (less than or 
equal to 10 mg prednisone equivalent is ok)s at the time of start of treatment. 18 patients were 
enrolled; however 4 (22%) were deemed not evaluable due to intralesional hemorrhage (n=1) 
and extracerebral progression (n=3). 4 patients (22%) developed a response, with 1 a complete 
response and 3 with partial responses. Another 3 patients developed stable disease. In the 
evaluable patients, 7 out of the 14 developed progressive disease (50%). Given the response 
rate (22%) is similar to the response rate seen in the extra-cranial metastases patients (Hamid 
et al.; Robert et al.), the authors concluded pembrolizumab does have similar intracranial 
efficacy.   
However in comparison to the standard of care regimens such SRS alone, where 1 year 
LC rates in prospective studies are 67-75%10,11, the LC rates with pembrolizumab appear 
significantly lower. With 11 out of the 18 patients (61%) either not completing treatment or 
developing progressive disease, these tolerability-efficacy rate is markedly lower for 
pembrolizumab for non-CNS metastases23,24. One possible conclusion is that delayed 
immunologic response characteristic of pembrolizumab may not be quick enough in the brain, 
where relatively smaller amounts of progression can quickly increase neurologic morbidity 
and mortality. Another reason may be that pembrolizumab may not penetrate the blood brain 
barrier to enough concentrations to make a meaningful clinical impact.  Thus, the combination 
approach of SRS for local control of disease within the brain and pembrolizumab for the 
control of extra-cranial systemic disease makes the most logical sense. The safety and efficacy 
of these two combination delivered concurrently is not well characterized.  
 
4.5.1 Combining Radiation and anti PD-1  
 
While pembrolizumab demonstrates significant increases in median survival in 
advanced melanoma, response rates are modest (26-38%)66. Preclinical studies and case reports 
suggesting that combining radiation with CTLA-4 blockade can improve response rates24,25. 
Building upon these findings, numerous groups have investigated the combination of 
pembrolizumab and radiation therapy preclinically. Sharabi et al.26 and Dovedi et al.27 together 
demonstrate that radiation therapy increases the T cell repertoire and antigen presentation to T 
cells; furthermore, adding radiation to PD-1 blockade in mice models demonstrate significant 
improvement in systemic response and local control28. This combination of PD-1 blockade 
with radiotherapy has not been investigated in the clinical setting, and is the basis of our current 
protocol design. 
 
4.6.1 Rationale for stereotactic radiation surgery and Anti PD-1 Therapy, 
pembrolizumab 
 

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Numerous preclinical findings suggest that radiation therapy augments the immune 
response against melanoma25,29. Adding pembrolizumab to radiation therapy may markedly 
enhance the immunologic response to tumor antigen release from necrotic tumor cells by 
radiotherapy26,27. This combination may allow for improved control at the irradiated site and 
un-irradiated site (abscopal effect)27; the net effect may be to significantly improve overall 
response rates in patients. With Kluger et al demonstrating that pembrolizumab alone results 
in low local control rates for intracranial metastases22, there is a need for further intracranial 
treatment. Therefore, to build on these concepts, we propose a study to determine the safety of 
SRS with pembrolizumab.  
Furthermore, our own preclinical work has also demonstrated that radiation can be an 
immunotherapy agent. Figure 2 demonstrated a phenomenon, known as the “abscopal” effect, 
meaning that when radiation is delivered to one tumor site on a implanted mouse, a distant site, 
more remote to the tumor that has not been radiated also disappears.  This is believed to be 
immunologically mediated.  Furthermore, when we comparing the 20 Gy per single fraction 
with the 10 Gy per single fraction, we find that the 10 Gy radiation dose per single fraction 
appears to be responsible for a greater abscopal effect, compared with the larger/more ablative 
20 Gy per single fraction radiation dose.  Thus, this is the basis for our “altered” radiation dose 
fractionation regimen, that we have picked in our current trial design. 
 
 
 
4.6.2 Rationale for sequencing for stereotactic radiation surgery and pembrolizumab 
 
 
To date, no studies have reported on the efficacy of SRS and anti-PD1 checkpoint 
inhibitor, pembrolizumab. Three published pre-clinical studies have investigated combining 
radiation therapy and anti-PD1 in mouse models26-28. While they show a synergistic 

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relationship between the two therapies, these studies did not investigate the ideal sequencing 
of the two proposed therapies (anti-PD1 and SRS). While evidence for sequencing is therefore 
missing, the Memorial Sloan Kettering group retrospectively reported on the safety and 
efficacy of 46 patients treated with SRS and CTLA-4 checkpoint inhibitor, ipilimumab30. 15 
patients received SRS during ipilimumab, 19 received SRS before IPI and 12 received SRS 
after IPI.  Grade 3 or higher toxicities was 20% in the entire cohort, consistent with rates of 
grade 3 toxicities with ipilimumab alone31. Grade 3 or higher CNS adverse effects included 
seizure (4.6%) and CNS bleeding (10.9%). Rate of toxicities did not correlate with sequence 
of therapies; these findings are also consistent with our own institutional series as well as 
others.32-35 
Overall survival was higher in the cohort that received SRS before or during IPI, than 
those treated with SRS after ipilimumab. However, an inherent selection bias may account for 
these findings, as patients in the SRS after IPI cohort may be selected for SRS due for salvage 
after ipilimumab alone. Interestingly, the authors did find that 50% of patients treated with 
SRS before or during IPI had an increase in size > 150%, compared to 15% with those treated 
with SRS after IPI. They hypothesized that this increase in size represents T cell infiltration of 
the tumor, thereby demonstrating potential activity. Because (1) sequence did not correlate 
with toxicity, (2) but did correlate with possible activity, and (3) preclinical research suggests 
concurrent radiation and anti-PD-1 therapy is synergistic26-28, we will plan to utilize the 
approach of concurrent SRS with the checkpoint inhibitor pembrolizumab. 
We suspect that the maximum T cell activation, proliferation, and entry into the blood 
stream occurs within 48 hours. To maximize the exposure of these cells to the increased antigen 
expression and MHC levels, we will plan to deliver radiation with 24 to 48 hours after 
pembrolizumab is delivered (and no later than 7 days after the first PD-1 inhibitor infusion). 
 
4.6.3  Rationale for Primary Endpoint 
 
For intact brain metastases treated with SRS alone, Aoyama demonstrated 
prospectively that 8 out of 67 patients (12%) developed an acute grade 3 CNS toxicity. RTOG 
90-05 accepted a 20% acute grade 3 CNS toxicity in their trial design. Similar rates were 
observed in the cohort treated with SRS alone on the Kocher prospective study. For large 
lesions, we and others have retrospectively demonstrated a grade 2 toxicity rate of 10% for 
hypofractionation. For pembrolizumab alone, acute grade 3 nervous system toxicity was seen 
in 2 out of 18 patients (11%). Therefore, assuming toxicity is additive, we will accept a DLT 
toxicity rate of 25%, with a 5% room for error. Thus, our acceptable DLT is 33%.  This rate is 
justified given that (1) each therapy alone (SRS and anti PD-1 alone) have limitations as 
detailed above and (2) the combination may result in significantly higher response and perhaps 
improved outcomes in combination. 
 
 

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5.0 ENROLLMENT CRITERIA 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on the day of signing informed consent. 
3. ECOG PS of 0-1 (See Appendix IV for ECOG definition); Karnofsky Performance 
Status ≥ 70%; 
4. Patients must have histological diagnosis of melanoma or non-small cell lung cancer 
(biopsy will be done per standard of care, if needed to prove metastatic melanoma 
and/or NSCL as well as for clinically relevant mutation analysis); Additional biopsy 
will be per standard of care. 
5. Patients can be treated either in first line or in the refractory setting; PD-L1 positivity 
is not required for enrollment;  
6. All melanoma patients may be tested for BRAF as part of routine standard of care, but 
is not a requirement for the trial; All NSCLC patients may be tested for with EGFR and 
ALK as part of standard of care, but is not a requirement of the trial.  
7. Having gotten prior PD1 therapy is allowed for, especially if they have previously 
progressed on it. Progression may include extra-cranial as well as intra-cranial 
progression. After progressing on PD1 therapy, intervening chemotherapy and/or 
targeted therapy (BRAFi, etc) is allowed.  If they are on intervening chemotherapy 
and/or targeted therapy (BRAFi, etc), they have to have progression intra-cranially 
and/or extra-cranially and must be off intervening therapy for at least 2 weeks. 
8. Patient must be asymptomatic at time of getting SRS (day 0) on trial.  Prednisone 
<10mg/day for at least 7 days prior to treatment is allowed.  
9. Patients with ocular, mucosal and unknown primary melanoma will also be eligible 
10. Patients with 1-10 untreated brain metastases at time of initial brain metastases 
diagnosis (surgery to one of the brain lesions and/or biopsy of a lesion for diagnostic 
purposes and/or for standard of care purposes is acceptable). 
11. Largest brain metastases volume measures less than 14.15cc3 
12. Prior radiation to the primary and/or regional radiotherapy for melanoma and/or 
NSCLC is acceptable. 
13. Baseline labs as within standard of care (CBC, CMP, LDH, ESR, etc) are required 
within 14 days of enrollment 
14. Have measurable disease based on RECIST 1.1.   
15. Patients must have at least 14 days to recover from all prior treatment, including 
surgery, chemotherapy, immunotherapies, prior to enrollment on this protocol. 
16. Demonstrate adequate organ function as defined in Table 4, all screening labs should 
be performed within 14 days of treatment initiation.   
Table 4 - Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 

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Absolute 
neutrophil 
count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
17. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 2 weeks prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
a. Female subjects of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 120 days after the last dose of study medication 
(Reference Section 10.1.2).  Subjects of childbearing potential are those who 
have not been surgically sterilized or have not been free from menses for > 1 
year.  
b. Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy. 
c. Abstinence is acceptable, if this is the usual life style and preferred 
contraception for the patient. 

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5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has a diagnosis of immunodeficiency or is receiving systemic steroids (less than or 
equal to 10 mg prednisone equivalent at time of start of treatment is ok) therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment 
2. If they have brain metastases located in the brain stem (including midbrain, pons, or 
medulla); 
3. Inability to undergo MRI evaluation for treatment planning and follow-up 
4. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment.Has a diagnosis of immunodeficiency or 
is receiving systemic steroids (less than or equal to 10 mg prednisone equivalent at time 
of start of treatment is ok) therapy or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment. 
 
5. Has a known history of active TB   (Bacillus Tuberculosis) 
6. Hypersensitivity to pembrolizumab or any of its recipients. 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment. 
10. Has known history of (non-infectious) pneumonitis that required steroids (less than or 
equal to 10 mg prednisone equivalent at time of start of treatment is ok) or current 
pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   

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13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
6.0 ADMINSTRATION OF STUDY PHARMACEUTICAL  
In 2015, FDA approved Pembrolizumab (Keytruda) for the treatment of advanced melanoma 
and NSCLC patients; Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor. 
Programmed death 1 (PD-1) (or CD279) is part of the CD28 family of proteins, which includes 
CTLA-4 and ICOS, that regulate T cell activity21. PD-1 is a glycoprotein receptor that can be 
expressed on the surface of T cells, B cells and myeloid cells (monocytes and dendritic cells)21.  
In T cells, PD-1 expression is primarily induced by T cell receptor (TCR) engagement and 
ligation with PD-L1 and PD-L2, expressed on antigen presenting cells, and induces an 
inhibitory signal that antagonizes TCR signaling and other important pathways necessary for 
optimal T cell activation.  Clinical trials with Pembrolizumab in advanced melanoma and 
NSCLC patients lead to approval by the FDA. The recommended dose of Keytruda is 2mg/kg 
administered as IV infusion over 30 minutes every 3 weeks +/- 7 days until disease progression, 
or unacceptable toxicity. Alternative dosing regimens are also available. 
The IV treatment to be used in this trial is outlined below in Table 5. Radiation treatment 
outline/table is listed in 10.0 
Table 5  Pembrolizumab Treatment 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 
mg  
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
6.1.1 Dose Selection 
6.1.1.1 Dose Selection 
Patients will receive pembrolizumab 200 mg. Pembrolizumab will be delivered over a 30-
minute period every 3 weeks +/- 7 days until at least 2 year, progression of disease, and/or 
unacceptable toxicity at the discretion of the treating physician. Infusions should be given over 
30 minutes (not bolus or IV push). 
 

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The rationale for selection of the dose (200 mg) to be used in this trial is provided in Section 
4.0 – Background and Rationale.   
6.1.1.2 Pembrolizumab Dose Calculation 
Calculate Total Dose as follows: 200 mg; 
Calculate Total Infusion Volume as follows: 
Total dose in mg ÷ 10 mg/mL = infusion volume in mL 
 
Calculate Rate of Infusion as follows: 
Infusion volume in mL ÷ 30 minutes = rate of infusion in mL/min. 
 
For example, a patient weighing 75 kg (165 lb.) would be administered 200 mg of 
pembrolizumab  with an infusion volume of 20 mL (2000 mg ÷ 10 mg/mL = 20 mL) at a rate 
of approximately 0.66 mL/min in 30 minutes (20 mL ÷ 30 minutes). 
6.1.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks +/- 7 
days.  Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
6.1.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
6.2 
Randomization Allocation 
Not applicable 
6.3 
Stratification 
Not applicable 

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6.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The sponsor-investigator should discuss any questions regarding 
this with the Merck Clinical team. The final decision on any supportive therapy or vaccination 
rests with the sponsor-investigator and/or the subject's primary physician.  
6.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and within 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered 30 days after the last dose of trial treatment should be recorded for 
SAEs and ECIs as defined in Section 13.2.3.2. 
6.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids (less than or equal to 10 mg of prednisone equivalent at time 
of start of treatment is ok). Anything more than this may be approved after consultation 
with the Sponsor. 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 

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The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.5 
Administration of Pembrolizumab Beyond Progression  
If the initial week 12 scan shows disease progression per RECIST 1.1, patients are allowed to 
continue treatment until progression is confirmed again at a subsequent 4-6 week later, to 
account for atypical response patterns. If the repeat imaging shows evidence of disease 
stabilization or objective response (relative to the previous scan that showed PD) as per 
RECIST I.1, pembrolizumab may be continued per treatment calendar.  However, if the repeat 
assessment shows disease progression relative to the previous scan that showed PD, then 
pembrolizumab should be discontinued;   The minimum criteria to continue must include 
absence of symptoms/signs of disease progression, no decline in performance status, and  
absence of rapid progression of disease at critical anatomic sites (i.e cord compression) 
requiring urgent alternative medical intervention.  
7.0 DOSE MODIFICATION  
7.0.1 Dose Modification, General 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose, or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 6 and Table 7 below. 
See Section 8.0 and 9.0 as well as Events of Clinical Interest Guidance Document for 
supportive care guidelines, including use of corticosteroids (less than or equal to 10 mg 
prednisone equivalent at time of start of treatment is ok). 
 
7.0.1 Dose Modification, Non CNS toxicities 
Table 6 Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose; Refer to Table – 
Infusion Treament Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug 
for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks +/- 7 days 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
7.0.2 Dose Modification, CNS toxicities 
 
Toxicity 
Hold 
Treatm
ent For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Central 
Nervous 
2-3 
 
Toxicity resolves to Grade 0-
1. 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 

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Toxicity 
Hold 
Treatm
ent For 
Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
System 
Necrosis 
(see exception below)1 
1 mg or less of dexamethasone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Seizure 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose. 
4 
Permanently discontinue 
Permanently discontinue 
Cognitive 
Impairment 
or Cognitive 
Disturbance 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
1 mg or less of dexamethasone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Stroke  
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose 
3-4 
Permanently discontinue 
Permanently discontinue 
 
1 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at 
physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 12 weeks of the last dose.   
8.0 DOSE LIMITING TOXICITIES 
Dose limiting toxicity definition 
Dose limiting toxicity is defined as symptomatic (i.e, presenting with neurological symptoms) 
radiation necrosis rate that exceeds 30% at 6 months as outlined in section 2;  Imaging evidence 
post SRS (MRI and/or PET) must confirm the presence of radionecrosis along with associated 
clinical symptoms.  The symptoms can be described as “Nervous system disorders” with a 
CTCAE 4.0 grade 3 or 4 or higher. 
 
Please see APPENDIX 1 for list of all CNS Nervous system disorders and appropriate grading. 
Below is a table of the most common CNS Nervous System Disorders;  
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Central Nervous 
System Necrosis 
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate 
symptoms; 
corticosteroids 
indicated 
Severe symptoms; 
medical 
intervention 
indicated 
Life-
threatening 
consequenc
es; urgent 
intervention 
indicated 
Death 

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Seizure (Definition: 
A disorder 
characterized by a 
sudden, involuntary 
skeletal muscular 
contractions of 
cerebral or brain 
stem origin.) 
Brief partial 
seizure; no loss of 
consciousness 
Brief generalized 
seizure 
Multiple seizures 
despite medical 
intervention 
Life-
threatening; 
prolonged 
repetitive 
seizures 
repetitive 
seizures 
Death 
Cognitive 
Impairment 
Mild inattention 
or decreased level 
of concentration 
Moderate 
impairment in 
attention or 
decreased level of 
concentration; 
limiting 
instrumental ADL 
Severe 
impairment in 
attention or 
decreased level of 
concentration; 
limiting self care 
ADL 
 
 
Cognitive 
Disturbance 
Mild cognitive 
disability; not 
interfering with 
work/school/life 
performance; 
specialized 
educational  
services/devices 
not indicated 
Moderate cognitive 
disability; 
interfering with 
work/school/life 
performance but 
capable of 
independent living; 
specialized 
resources on part 
time basis indicated 
Severe cognitive 
disability; 
significant 
impairment of 
work/school/life 
performance 
 
 
Stroke 
Asymptomatic or 
mild neurologic 
deficit; 
radiographic 
findings only 
Moderate 
neurologic deficit 
Severe neurologic 
deficit 
Life-
threatening 
consequenc
es; urgent 
intervention 
indicated 
Death 
Intracranial 
Hemorrhage (A 
disorder 
characterized by 
bleeding from the 
cranium.) 
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate 
symptoms; medical 
intervention 
indicated 
Ventriculostomy, 
ICP, monitoring, 
intraventricular 
thrombolysis, or 
operative 
intervention 
indicated 
Life-
threatening 
consequenc
es; urgent 
intervention 
indicated 
Death 
Headache 
(definition: A 
disorder 
characterized by a 
sensation of marked 
discomfort in various 
parts of the head, not 
confined to the area 
of distribution of any 
nerve.) 
Mild Pain 
Moderate pain, 
limiting 
instrumental ADL 
Severe pain, 
limiting self care 
ADL 
 
 
 

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9.0 SUPPORTIVE CARE 
9.1.1 Supportive Care, General 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous 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.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 7.0 for dose 
modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
9.1.2 Supportive Care, Guidelines for Non-CNS toxicities 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience 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.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  

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o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 

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• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Table 7 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 7 Infusion Reaction 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 subject is deemed medically 
stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will 
be held until symptoms resolve 
and the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration. 
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 
sequellae (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: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
 

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9.1.3 Supportive Care, Guidelines for CNS toxicities 
• Central Nervous System Necrosis:  
o For Grade 2 events, treat with systemic steroids, pentoxyfilline and vitamin E. 
Consider starting with doses less than dexamethasone 6mg PO daily (2 mg 
TID), if clinically acceptable and indicated.  
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, such as hyperbaric oxygen 
and/or surgical intervention. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
immediately, continued over no less than 4 weeks. 
o It may be that a patient may need low doses of steroids long term, in that case, 
the goal is to achieve the lowest tolerated steroid levels to manage the 
radiation necrosis. 
• Seizure: 
o For Grade 1-2 events, treat with oral anti-seizure medications. If clinically safe 
and acceptable, consider starting with levetiaceram 1000mg BID, or alternative. 
o For Grade 3-4 events, treat with oral and/or IV anti corticosteroids with 
consideration for surgery, if clinically feasible. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Cognitive Impairment or Cognitive Disturbance 
o For Grade 2 events, treat with systemic steroids. Consider starting with doses 
less than 6 mg PO dexamethasone (2 mg TID), if clinically acceptable and 
indicated. Memantine or other Alzheimer related medication can also be 
considered. 
o For Grade 3-4 events, immediately treat with intravenous steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
10.0 DIET/ACTIVITY/OTHER CONSIDERATIONS 
10.1.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
10.1.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  For this trial, male 
subjects will be considered to be of non-reproductive potential if they have azoospermia 
(whether due to having had a vasectomy or due to an underlying medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  

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(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡:  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 

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• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.   
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study. 
10.1.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 13.2.2. 
10.1.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 

Product:  Pembrolizumab (MK-3475, IND 130757) 
38 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
10.2 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the sponsor-investigator if enrollment into the trial is inappropriate, the trial plan 
is violated, or for administrative and/or other safety reasons 
. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed extra-cranial radiographic disease progression 
• Unacceptable adverse experiences as described in section 7, 8, and 9. 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed at least 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, or whichever occurs last; 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment at the discretion of their treating physician, especially if 
their disease is clinically stable; 
• Administrative reasons 
• Confirmed radiographic disease progression per RECIST criteria. 
a. Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 6.5 
The End of Treatment and Follow-up visit procedures are listed in Section 12 (Protocol Flow 
Chart) and Section 13. After the end of treatment, each subject will be followed for 30 days 
for adverse event monitoring (serious adverse events will be collected for 90 days after the end 
of treatment as described in Section 13.2.3.1).  Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up.  After documented disease progression each subject will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
10.2.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 

Product:  Pembrolizumab (MK-3475, IND 130757) 
39 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.   
10.3 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
11.0 DELIVERY OF RADIATION THERAPY TREATMENT 
Definitive SRS will be administered for up to 1-10 lesions using stereotactic radiosurgery 
techniques starting on day 2-3. Treatment will be timed such that the first fraction of radiation 
will be delivered 24-48 hours after the first infusion of pembrolizumab. SRS will consist of 1-
5 treatments, depending on dose level. For multiple fraction regimens, each treatment will be 
delivered > 40 hours apart, and should be completed by week 2, day 14.  
 
11.1.2  Radiation Simulation and Diagnostic Procedures 
1. All simulation and treatment procedures represent current institutional practice and will be 
the same for all study participants in each dose level 
 
CT Simulation: A CT simulation will be performed for radiation therapy treatment planning 
purposes several days to the initiation of radiation therapy. This procedure consists of a CT 
scan performed in the treatment position. It is not for diagnostic purposes and is not itself 
therapeutic, but the CT image is required for radiation planning and delivery. This procedure 
is standard of care prior to therapeutic radiation. The CT simulation will occur with the patient 
supine position in a framed and/or frameless thermoplastic head mask at discretion of treating 
physician. 
-CT simulation scan slice thickness may not exceed 1.25 mm 
 
2. Pre-treatment MRI of the brain:  A high resolution MRI with and without gadolinium 
contrast for treatment planning will be acquired within 2 weeks before treatment delivery. This 
planning MRI is standard of care for patients with intracranial metastases planned for SRS. 
-Treatment planning MRI slice thickness may not exceed 3 mm. 

Product:  Pembrolizumab (MK-3475, IND 130757) 
40 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
 
11.1.3 SRS Based Radiation Therapy Options Criteria 
1. Treatment shall be delivered with one of two approaches: 
a. Linear accelerated (LINAC) based stereotactic radiosurgery 
b. Gamma knife based stereotactic radiosurgery 
 
11.1.4 LINAC, SRS Based Radiation Therapy, Required Criteria 
1. Treatment shall be delivered with megavoltage machines of a minimum energy of 4 MV 
photons. Selection of the appropriate photon energy should be based on optimizing the 
radiation dose distribution within the target volume and minimizing dose to non-target normal 
tissue. 
 
2. LINAC treatment should also include isocentric conical collimators, mini-multi-leaf (5 mm 
or less) technology or linear accelerators mounted on robotic arms. 
 
3. Either a framed or frameless stereotactic, relocatable immobilization system will be used for 
treatment simulation and delivery. These systems may include modified stereotactic frames, 
camera-based localization systems, etc. The immobilization/ relocalization system should be 
capable of reproducing the patient setup to within 3 mm. 
 
4. Single fraction radiosurgery treatment may be delivered with intensity modulated radiation 
surgery (IMRS) or dynamic conformal arcs (DCA).  Multiple fraction radiation treatment can 
be delivered by intensity modulated radiation therapy (IMRT) or volume modulated arc 
therapy (VMAT).  
 
5. Patients must be positioned for each treatment using 3-dimensional imaging i.e. 
Cone Beam CT. Cone beam CT scans with each radiation fraction on the treatment 
machine will be performed daily prior to SRS with the patient in the treatment position 
to assure accurate repositioning of  the PTVs.  
 
6. Radiation therapy will consist of 1-5 fractions. All radiation treatment fractions should be 
completed by end of week 2 of treatment 
 
7. Multiple vertex and coplanar/noncoplanar beams should be used and arranged with the goal 
of excluding as much normal brain tissue as possible outside of the PTV at high and 
intermediate dose levels. 
 
11.1.5 Gamma Knife, SRS Based Radiation Therapy, Required Criteria 
1. Treatment shall be delivered with megavoltage machines of a minimum energy of 4 MV 
photons. Selection of the appropriate photon energy should be based on optimizing the 
radiation dose distribution within the target volume and minimizing dose to non-target normal 
tissue. 
 
2. Single fraction radiosurgery treatment may be delivered with intensity modulated radiation 
surgery (IMRS) or dynamic conformal arcs (DCA).  Multiple fraction radiation treatment can 

Product:  Pembrolizumab (MK-3475, IND 130757) 
41 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
be delivered by intensity modulated radiation therapy (IMRT) or volume modulated arc 
therapy (VMAT).  
 
3. Patients must be positioned for each treatment using 3-dimensional imaging i.e. Cone 
Beam CT.  
Cone beam CT scans with each radiation fraction on the treatment machine will be 
performed daily prior to SRS with the patient in the treatment position to assure accurate 
repositioning of the PTVs.  
 
4. Radiation therapy will consist of 1-5 fractions. All radiation treatment fractions should be 
completed  
before end of week 2 of treatment. 
 
11.1.6  Target Volume Determination 
 
1. The gross tumor volume (GTV) will be defined by as the MRI defined T1 post 
contrast enhancing brain metastasis. Surrounding areas of edema will not be 
considered part of the target volume     
 
 
2. The clinical target volume (CTV) will be the GTV without margin in all directions 
 
 
 
-for resected brain metastases, an 1mm expansion should be utilized: 
CTVresection-cavity = GTVresection-cavity + 1mm expansion. 
 
 
3. The planning target volume (PTV) will be the CTV + 1.5 mm margins.  
 
11.1.7  Total dose determination 
All three arms will initially enroll patients, followed by a 3 month toxicity assessment 
for dose limiting toxicity (i.e. radionecrosis);  If clinically significant necrosis (as 
defined in section  
2.0) is noted, this arm will be stopped. However, enrollment on the other arms will 
continue. 
 
11.1.8  Dose prescription and dosimetry requirements 
1.  Dose will be prescribed to the isodose line that encompasses the entirety of the PTV.  
Treatment planning and dose acceptance will be per institutional standard of care.   
A. If intensity modulated radiosurgery (IMRS) is utilized, standard prescription 
isodose is to 98% (range 95-100%, acceptable) 
B.  If dynamic conformal arcs (DCA) are utilized, standard prescription isodose 
is to 80% (range 70-90%, acceptable).  
C. If gamma knife is used, standard prescription isodose is to 50% (range 40-
60% acceptable) 
2.  Doses are specified such that at least 95% of the PTV shall receive 100% of the 
prescribed dose. 
3.  The marginal dose and the 100% dose (isocenter dose) may be recorded for each 
patient. 

Product:  Pembrolizumab (MK-3475, IND 130757) 
42 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
4.  For quality control, representative isodose lines (e.g. 20%, 40%, 60%, 80%, 90%) 
may be generated for each patient. 
 
Quality of PTV coverage will be categorized according to selected isodose line: 
 
 
A. Total – selected isodose line completely encompasses the PTV 
B. Marginal – selected isodose line incompletely encompasses the PTV, but not 
by more than 10% of the PTV volume. 
C. Subtotal - selected isodose line incompletely encompasses the PTV, but by 
more than 10% of the PTV volume. This will not be accepted.  
5.  Conformality index requirements (ratio of prescription isodose volume to the target 
volume (PI/TV)) 
1.  Per protocol if between 1.0 and 2.0, acceptable 
 
 
 
2.  Acceptable variation if ≥ 0.9 but < 1.0 or >2.0 but ≤ 3.5. 
 
 
 
3.  Unacceptable deviation if > 3.5. 
 
11.1.9  Dose Limitation to Critical Structures  
1. In addition to the above defined GTVs, CTVs and PTVs, both eyes, the lenses of 
both eyes, the optic nerves, the optic chiasm, cochlea, the brainstem, and the spinal 
must be evaluated per standard of care approaches. Dose-volume histograms will be 
generated and whole organ dose and maximum point dose will be recorded for each 
critical structure. Dose limitations to normal structures are defined in Table 9. 
2. If the patient has received no prior cranial irradiation, the maximal point doses 
permissible to the structures from the current radiation therapy plan are listed 
below. 
3. Patient cannot have received whole brain radiation or SRS prior to being enrolled on 
this trial.  However, once on the trial, patient can have received multiple SRS and or 
whole brain radiation as part of the standard of care treatments for progressive disease;  
If the patient has received previous brain radiation therapy (while on the trial), the 
previous dose received to critical structures should be obtained or a representative dose 
distribution file should be simulated. This dose should then be converted to BED 
(assuming an alpha-beta ratio of 3 for late effects) and added to the BED to the critical 
structures from the current treatment plan. This sum BED must meet the cumulative 
dose constraint below¶. No adjustments for time between previous radiation treatment 
will be made for the purpose of this protocol.  
 
Table 9 – Normal Tissue Constraints Based on the number of radiation fractions 
 
Normal Tissue Constraints, 5 Radiation Fractions 
Cumulative 
BED3 
 
Volume 
No Previous 
RT* 
Previous RT¶ 
Endpoint  
( > Grade 3 
AE) 
Maximum Dose 
(Gy) 
Maximum 
Cumulative 
BED3 
 
Brainstem 
Max, 
 
0.03cc 
26 
90 
Cranial 
Neuropathies 

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43 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
Spinal Cord 
Max, 
 
0.03cc 
22.5 
75 
Myelitis 
Eye 
(Globe), 
each 
Max, 
 
0.03cc 
20 
66 
Vision Loss 
Lens, each 
Max, 
 
0.03cc 
5 
12 
N/A* 
Optic 
Nerve, 
each 
Max, 
 
0.03cc 
25 
90 
Vision Loss 
Optic Chiasm 
Max, 
 
0.03cc 
25 
90 
Vision Loss 
Cochlea 
Max, 
 
0.03cc 
27.5 
90 
Hearing Loss 
 
Normal Tissue Constraints, 3 Radiation Fractions 
Cumulative 
BED3 
 
Volume 
No Previous 
RT* 
Previous RT¶ 
Endpoint  
( > Grade 3 
AE) 
Maximum Dose 
(Gy) 
Maximum 
Cumulative 
BED3 
 
Brainstem 
Max, 
 
0.03cc 
18 
90 
Cranial 
Neuropathies 
Spinal Cord 
Max, 
 
0.03cc 
18 
 
75 
Myelitis 
Eye 
(Globe), 
each 
Max, 
 
0.03cc 
18 
66 
Vision Loss 
Lens, each 
Max, 
 
0.03cc 
4 
12 
N/A* 
Optic 
Nerve, 
each 
Max, 
 
0.03cc 
15 
90 
Vision Loss 
Optic Chiasm 
Max, 
 
0.03cc 
15 
90 
Vision Loss 
Cochlea 
Max, 
 
0.03cc 
20 
90 
Hearing Loss 
 
Normal Tissue Constraints, 1 Radiation Fraction 
Cumulative 
BED3 
 
Volume 
No Previous 
RT* 
Previous RT¶ 
Endpoint  
( > Grade 3 
AE) 
Maximum Dose 
(Gy) 
Maximum 
Cumulative 
BED3 
 

Product:  Pembrolizumab (MK-3475, IND 130757) 
44 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
Brainstem 
Max, 
 
0.03cc 
10 
90 
Cranial 
Neuropathies 
Spinal Cord 
Max, 
 
0.03cc 
18 
 
75 
Myelitis 
Eye 
(Globe), 
each 
Max, 
 
0.03cc 
16 
66 
Vision Loss 
Lens, each 
Max, 
 
0.03cc 
2.5 
12 
N/A* 
Optic 
Nerve, 
each 
Max, 
 
0.03cc 
8 
90 
Vision Loss 
Optic Chiasm 
Max, 
 
0.03cc 
8 
90 
Vision Loss 
Cochlea 
Max, 
 
0.03cc 
12 
 
90 
Hearing Loss 
*Lens toxicity is cataract formation, which for the purposes of this trial is not a dose limiting 
toxicity.  
 
11.1.10    Radiation Toxicity Evaluation 
Patients should undergo evaluation for development of acute and chronic radiotherapy toxicity 
at the time of protocol visits. This should be at done 1 month after completing SRS (between 
weeks 4-6 post SRS, per standard of care) and then during follow-up visits and maintenance 
therapy every 3 months, or as otherwise indicated.  Suspected radiosurgery-related toxicity 
should be graded using the CTCAE 4.0 adverse events grading system. If there is a suspicion 
of a novel or unexpected toxicity of grade 3 or higher severity that is suspected to be related to 
the combination of pembrolizumab and radiosurgery, the study coordinator should be 
immediately notified. If possible, a determination should be made whether the toxicity is likely 
to be the result of immune therapy, radiosurgery or was exacerbated by the combination. The 
AE or SAE should be attributed as definite, probable, possible, or unlikely for each. 
 
11.1.11  Progression of CNS disease 
If a patient has new CNS lesions on the 6 weeks follow-up MRI, patient can undergo repeat 
SRS to the new lesions and/or whole brain radiation treatments (and/or CSI-if leptomeningeal 
disease), at the discretion of the treating physician, and per routine standard of care.  However, 
if there is any doubt, please contact the PI.  The goal is to continue to manage the patient per 
routine standard of care to salvage the intra-cranial disease by either repeated SRS treatments 
to the new lesions and/or whole brain radiation treatments (Cranio-spinal XRT can be used if 
significant leptomeningeal disease is suspected). The patient would still continue with anti-
PD-1 treatments until progression of extra-cranial disease, undue toxicity, and/or at least 2 
year, at the discretion of the treating physician.  Radiation treatments should be timed with the 
administration of the next cycle of PD-1 treatments, or as close as possible (whenever clinically 
possible/applicable); 
 
 

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45 
Protocol/Amendment 
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Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
12.0 TRIAL FLOW CHART 
12.1 Study Flow Chart (see next page) 
 
Screening Phase                                                                Treatment Phase                                               
Post-Treatment          
 Procedure
Pre- Treatment  
(w ithin 28 days of 
starting)
Cycle 1, Day 
1 w eek 1
Cycle 1, Day 2-3
Cycle 1, Day 4-
-6
Cycle 1, Day 6-15
Cycle 2, Day 
22
Days 24-40 
(Post SRS 
check)
Cycle 3, Day 
43
Cycle 4, Day 
64
q3WK cycles x 2yr, or 
until progression**
Follow  Up (q12 w ks for 1 
years)
Pre-screening for eligible patients
X
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical Histor
X
Prior and Concomitant Medication
X
Full Physical Examination
X
X
X
X
X
X
X
Review of Systems
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Karnofsky Performance Status 
(KPS) and ECOG
X
X
X
X
X
X
X
X
HBcAb, HepC Ab
X
Brain MRI
X
X (SOC-4-6 
w k check)
X
Diagnostic Imaging                         
(CTN/ C/A/P and/or PET scan)
X
X (Cycle 4-5)
X
Adverse effects Assessment
X
X
X
X
X
X
X
Labs
     CBC with differential
X
X
X
X
X
X
X
     CMP, LDH, ESR
X
X
X
X
X
X
X
     T3, FT4, TSH
X
X
X
     Pregnancy Test - urine or seru
X
     Urinanalysis
X
uric acid, mg, phos, Coags (PTT,a
X
Correlative Biomarkers
Blood/Serum markers
X
X (pre-PD1)
X (Post PD1 or Pre-SRS)
x (post-SRS)
X (post SRS)
x (pre- PD-1)
X (Pre-PD-1)
X (Pre-PD1)
X *
X at 3, 6,& 12 mo 
Skin Biopsy site (if needed)
X
Treatment
Pembrolizumab 200 mg IV
X
X
X
X
x
Stereotactic Radiosurgery, first 
fraction
X
Stereotactic Radiosurgery, 
fractions 2-5 (if applicable)
X
x
Survival Analysis
Grade 3 CNS
X
X (every 3 mo)
X (3,6,12 mo)
 
** Pembrolizumab 200 mg IV q3wk should be given for at least 2 yr and/or until progression. 
* Only collect additional samples beyond section 12.2, at the discretion of Dr. Khan

Product:  Pembrolizumab (MK-3475, IND 130757) 
46 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
 
12.2 Blood and Srum Biomarker Correlates  
We plan to monitor the immune responses of the patients enrolled in this clinical trial, by 
collecting peripheral blood before treatment and during treatment, as outlined above under 
“serum biomarkers”.  
When possible, blood collection will be synchronized to pembrolizumab infusion cycles (C). 
Blood will be collected at 14 days prior to enrollment (baseline sample), C1D1 (2nd baseline 
sample, pre PD-1 infusion), C1D2-3 (post PD1 or pre first fraction of SRS), C1D4-6 (Post 
second fraction of SRS), C1D6-15(Post SRS completion), C2D1 (Pre-PD1), C3D1 (Pre- PD1), 
C4D1 (Pre-PD1) and at restaging at 3 and 6 months after SRS;  
A final peripheral blood collection  will be obtained at 12 months follow up, which will be one 
year after patient completed their two year treatment plan or discontinued treatment due to 
disease progression.  
Samples will be drawn into three 8 ml CPT tubes for PBMC and plasma isolation, and one 4.5 
ml K3EDTA tube, for whole blood analysis. Only one 8 ml CPT tube of blood will be collected 
at C1D2-3 (Post PD1 or pre first fraction of SRS). Tubes will be labeled and logged at Emory's 
Winship Cancer Institute by a skilled clinical research nurse or phlebotomist.  They will be 
maintained at room temperature until transport to Dr. Ahmed's laboratory. Samples distributed 
to the Ahmed laboratory will only be identifiable by an assigned donor number, study identifier 
and a draw date. Samples will be transported in sealed biohazard containers between sites per 
standard protocol. Whole blood and/or PBMC will be used fresh or will be frozen and banked 
for future batch analyses. Plasma will be frozen at -80C. Frozen PBMC samples will be stored 
in liquid nitrogen at the Emory Vaccine center.  All assays will be performed as per Ahmed 
lab standard of practice.   Briefly, frequency and absolute cell counts will be determined for 
the major lymphocyte populations (CD3, CD4, CD8, CD19) and monocytes (CD14) through 
the use of BD TruCount tubes.  Detailed phenotypic analysis will be performed through whole 
blood staining with the following markers; CD3, CD4, CD8, Foxp3, CD45RA, CCR7, CD28, 
CD27, CD127, PD-1, Ki-67, Bcl-2, HLA-DR, CD38, ICOS, CD137, Tbet, eomes, Granzyme 
B, Perforin, CTLA-4, Tim-3, CD14, CD16, CD11c, CD123, PD-L1, CD86. HLA-A2 positive 
patients will be monitored for the presence and activation of MART-1 and NY-ESO-1-specific 
CD8 T cells. Additional phenotypic, genomic and/or proteomic analysis may be performed on 
banked PBMC samples. Besides flow cytometry phenotypic analysis, sample collected at early 
time points after irradiation, will be used for transcriptional profiling36. Frozen plasma will be 
used for monitoring cytokine expression and/or possibly other translational analysis (i.e., 
isolation of exosomes for proteomics and genomics analysis). 
When possible, fresh tumor tissue will be collected from biopsy or surgical procedure. 
Depending on material availability samples will be analyzed by flow cytometry or florescence 
microscopy with some of the markers listed above. 
 
 

Product:  Pembrolizumab (MK-3475, IND 130757) 
47 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
13.0 TRIAL PROCEDURES 
13.1 Trial Procedures 
The Trial Flow Chart – Section 12.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points, if deemed clinically necessary by the investigator, 
and within standard of care. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
13.1.1 Administrative Procedures 
13.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
13.1.1.2 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 

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Protocol/Amendment 
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Rad3179-16 
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13.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
13.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
13.1.1.5 Prior and Concomitant Medications Review 
13.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 14 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
13.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 13.2. 
13.1.1.6 Disease Details and Treatments 
13.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. This includes RTOG RPA class and GPA class, as outlined in APPENDIX II and III. 
13.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
13.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  

Product:  Pembrolizumab (MK-3475, IND 130757) 
49 
Protocol/Amendment 
No.: 
 
Rad3179-16 
(MK-3475-423), 
v.12/03/2019 
 
 
 
 
 
13.1.1.7 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see APPENDIX I).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab, all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs).  
Please refer to section 13.2 for detailed information regarding the assessment and recording of 
AEs.   
13.1.1.8 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
13.1.1.9 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
13.1.1.10 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 12.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
13.1.1.11 Karnofsky Performance Status Scale and ECOG Performance Scale 
The investigator or qualified designee will assess ECOG and KPS status at screening. ECOG 
status will be assessed prior to the administration of each dose of trial treatment and 
discontinuation of trial treatment as specified in the Trial Flow Chart.  After the intial 
assessment, ECOG alone during subsequent follow-up will be the minimum that is required on 
the trial. 

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13.1.1.12 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory tests for hematology, chemistry, urinalysis, and others are 
specified in Table 5.  Peripheral blood for serum biomarker analysis will also be obtained, as 
defined in section 12.0 at the appropriate time intervals.   

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Table 5:  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
• 
see biomarkers section 12.1 
• 
The additional blood that is 
collected will be sent to Dr 
Rafi Ahmed’s lab for this 
analysis 
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.   
‡ If considered standard of care in your region. 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
13.1.1.13Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 8.0 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete at least 24 months of treatment 
with pembrolizumab may stop taking the drug and discontinue the trial, at the discretion of the 
treating physician. After discontinuing treatment following assessment of CR, these subjects 
should return to the site for a Safety Follow-up Visit and then proceed to the Follow-Up Period 
of the study. 
13.1.1.14Blinding/Unblinding 
Not Applicable, as this is an open pilot study. 
13.1.2 Visit Requirements 
Visit requirements are outlined in Section 12.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 13.0 - Trial Procedures. 
13.1.2.1 Screening 
13.1.2.1.1 Screening Period 
The screening period will be 28 days from enrollment. During this period, inclusion and 
exclusion criteria, and other information listed in section 12.0 and 13.0 should be conducted. 
A planning MRI, as detailed in the radiation section 11.0, should also be obtained during the 
screening period, as part of our institutional standard of care. 
 
13.1.2.2 Enrollment and Treatment Period 
Enrollment period to accrue all 30 patients will be over two years, with the goal to enroll at 
least 18 patients, as outlined in section 2.0. 
Treatment period will last from cycle 1, day 1 until disease progression and/or at least 12 
months of pembrolizumab being delivered q3wks. Pembrolizumab 200 mg IV q3 weeks +/- 7 
days will be given for at least 2 years as described above or until disease progression. Safety 
evaluations should be conducted during the first day of each cycle, as detailed in the flow sheet 
12.0. All AEs that occurred leading up to these treatment visits should be recorded. Post-

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Protocol/Amendment 
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v.12/03/2019 
 
 
 
 
 
Treatment Visits and all subsequent imaging and tumor assessments will be per standard of 
care. All required blood and imaging will be per standard of care, except for the biomarker 
analysis, as outlined in section 12.0. 
13.1.3.2.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 6.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
13.1.2.3 Follow-up Visits 
Subjects who complete treatment after 2 years or discontinue trial treatment for a reason other 
than disease progression should be assessed every 12 weeks (84 ± 14 days) or at physicians 
discretions by radiologic imaging to monitor disease. Subjects who show disease progression 
after the initial week 12 scan must have another assessment 4-6 weeks later by radiologic 
imaging to confirm evidence of disease progression. If disease progression is evident, 
treatment should be discontinued and subject should be assessed every 12 weeks (84 ± 14 days) 
by radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the subject begins retreatment with pembrolizumab 
as detailed in Section 6.5.  Information regarding post-study anti-neoplastic treatment will be 
collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 6.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 13.1.3.4 for Retreatment.   
13.1.2.4 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 

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▪ Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
▪ Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 12.0 – Trial Flow Chart. 

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13.1.2.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
 
13.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject associated with the use of a test article and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product or SRS, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product or SRS in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported to Merck and the PI by the investigator if they 
cause the subject to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be documented by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 

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v.12/03/2019 
 
 
 
 
 
13.1.3.2 and 13.2.3.1. The investigator will make every attempt to follow all subjects with 
non-serious adverse events for outcome. 
 
13.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose, for a 100 kg patient).  No specific information is 
available on the treatment of overdose of pembrolizumab. Appropriate supportive treatment 
should be provided if clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity.   
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
13.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Merck product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 

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13.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
13.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of a drug 
product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is an other important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study  that occurs 
to any subject must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study, whether or not related to the Merck product, must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 

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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
13.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 13.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  

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13.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 13.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 
13.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
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Protocol/Amendment No.:  Rad3179-16 (MK-3475-423), v.5/18/17 
 
 
 
 
Table 6  Evaluating Adverse Events 
Known  acute side effects for SRS include: Alopecia within the portal sites, fatigue, headache, nausea, vomiting, worsening baseline 
neurological deficits due to increased edema or radionecrosis, seizure, skin irritation or redness; Late side effects include radiation 
necrosis, secondary cancer, seizure, worsening neurological deficit due to edema, death, hair loss within the portal fields.   
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of investigational product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 

 
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Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 
 

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Protocol/Amendment No.:  Rad3179-16 (MK-3475-423), v.6/23/17 
 
 
  
 
 
 
13.2.5 Sponsor Responsibility for Reporting Adverse Events 
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its occurrence. 
If the event is fatal or is deemed to be life threatening, the report will be made within 7 calendar 
days.  The IND sponsor will also make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be provided 
to the Emory University IRB, which, in turn will make a final determination.  If the Emory 
IRB determines an event is a UP it will notify the appropriate regulatory agencies and 
institutional officials. 
14.0 STATISTICAL ANALYSIS PLAN 
14.1 Statistical Analysis Plan Summary 
14.1.1 Study Design  
The study is a pilot study to look at the safety of concurrent PD-1 inhibitor and SRS for 
melanoma brain metastases. An initial cohort of 6 patients will be enrolled on each radiation 
dose levels starting with radiation Arm A (6 Gy x 5), radiation Arm B (9 Gy x 3), and then 
radiation Arm C (21 Gy x 1 or 18 Gy x 1 based on tumor volume); Once 6 patients are enrolled 
on any given dose level, the dose limiting toxicity (DLT) interval is defined as RTOG grade 3 
CNS toxicity at 3 months after first pembrolizumab dose (i.e. Day 1, cycle 1). This interval is 
based upon inclusion of the known median times to onset of (1) common adverse effects 
attributed to pembrolizumab, and of (2) unusual radiation related adverse effects beginning as 
early as 3 months post SRS, and (3) typical timeline used in other similar trials.  
The first 18 patients (6 per dose level) will be enrolled in sequence as follows:  
Arm A: patient #1-6,    Arm B: patient #7-12, Arm C: patient # 13-18; 
 
If ≤ 2/6 patients develop a DLT on a given radiation arm during, accrual on the particular dose 
arm will continue for another 6 patients on a given dose arm for a total of 12 patients per dose 
arm.  RTOG 90-05 used a 20% cutoff at 3 months as the DLT endpoint.  We accept 2/6 (33%) 
based on a biological rationale that if there is slight increase in radiation toxicity, this may be 
offset by increased systemic responses through immune modulation of radiation when 
radiation is combined with PD-1 (see section 4.0 for biological rationale); 
If ≥3/6 patients develop a DLT on a given radiation dose arm, this arm will stop accrual and 
considered unsafe; 
There will be a 3 month interim waiting period after 6 patients are enrolled on a given radiation 
arm and analyzed for any undue early dose limiting toxicity (DLT); The DLT toxicity 
definition is similar to that defined in the RTOG 90-05 (i.e, CNS grade 3 or more acute toxicity, 
which is considered irreversible severe neurological symptoms at 3 months requiring 
medications); The time point of 3 months is typical of when all post SRS acute side effects are 
expected to resolve. Thus, having acute side effects at 3 months would be unusual.  
 

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The second 18 patients (6 per dose level) will be enrolled in a similar sequence as follows, 
with arms containing 3 or more DLTs within the first 6 patients omitted from expansion: 
 
Arm A: Closed, Arm B: patient #25-30, Arm C: patient #31-36; 
 
14.1.2 Acute Toxicity, Expansion Cohorts, and Late Toxicity Assessment: 
 
Once 6 patients are enrolled on any given dose level, there will be a waiting period of 3 months 
(i.e, at time of second post SRS MRI assessment after pembrolizumab dose (i.e, 3 months after 
Day 1, cycle 1); This time point of 3 months and the dose limiting toxicity (i.e. grade 3 RTOG 
CNS toxicity) is based on similar timeline used on earlier trial to determine the safest radiation 
dose.  Late toxicity (radionecrosis noted on MRI images will also be analyzed at 6 months and 
at 1 year, but will not be used to stop enrollment on any given dose arm); 
During this 3 month waiting period, the MRI images and the patients will be assessed for any 
signs or symptoms of RTOG CNS toxicity as well as early manifestations of radionecrosis. 
≥Grade 3 CNS toxicity is the only DLT toxicity of principal concern, since the currently used 
radiation doses are based on this primary endpoint. Patient can still be accrued on other dose 
arms during this waiting period, while data is being analyzed for safety concerns on a given 
radiation arm. 
Late toxicity (i.e, toxicity starting after 3 months) will also be analyzed. The principal 
late toxicity of interest is symptomatic radiation necrosis. This is defined as radiographic 
(typically on MRI) changes consistent with radiation induced necrosis, and the patient 
also presenting with increased neurological symptoms.   Symptomatic radiation necrosis 
will be recorded at 6 months at at 12 months follow-up;   
 
The radiation dose arm which meets the lowest acute and late toxicity endpoints, but also 
potentially provided a higher overall systemic response rate, will be considered the best 
radiation dose level that can be combined with pembrolizumab.  Our published series of 
melanoma patients undergoing SRS alone had an average survival of 38.5% at 1 yr (Patel KR 
et al, American J. Clinic. Oncology. 2015, May 16. Epub);  Our recent multi-institutional 
review in collaboration with Duke University suggested 1 yr overall survival of 78% for 
patients undergoing SRS and PD1 in combination (not published, accepted for annual 
presentation at American Society of Radiation Oncology Meeting, 2016).  Thus, we suspect 
an improvement of 40% in OS compared with SRS alone. With 12 patients on the most 
immunogenic arm (9Gy x 3), we would be expected to have lowest acute and late toxicity as 
well as potentially the highest OS benefit and would likely be the arm for a future trial. 
 
With 12 patients per group, a 2-year accrual time with an additional 1 year of follow-up (3 
total years), we have 72% power to detect a difference in survival of 40% (78% vs. 38%) at 1 
year.   
 
14.2 Study Design for Expansion Cohort Phase 
After the initial pilot phase with 6 patients per radiation dose arm, patients will then be enrolled 
into the expansion cohort (6 more patients) and treated assuming toxicity is acceptable during 
the initial enrollment period of the first 6 patients on each arm.  This would bring the total 

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patients up to 12 per radiation dose arm: (Arm A: 6 patients total, Arm B: 12 patients, Arm C: 
12 patients), for a total of 30 patients for all 3 different radiation dose arms. 
The total number of patients enrolled in the entire trial will thus depend on the RTOG grade 3 
CNS acute toxicity seen on each of the dose arms. If no DLT are identified, then the minimum 
number of patients in the expansion cohort will be 30; if each cohort has a DLT, then the 
maximum number of patients enrolled in the dose escalation phase is 12 (6 patients X 2 
different radiation dose arms). Therefore, the range of patients to be enrolled in this study is 
expected to be 18-30. The expansion of arm A is stopped.  Arm B and C will continue to enroll, 
as is currently designed.  
14.3 Statistical Analyses  
14.3.1 Safety 
Proportion of acute and late toxicity for each arm out of 12 (or 6 if no expansion) will 
be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson 
method.  
14.3.2 Response 
Both overall response and response at un-irradiated sites will be determined at week 
12, 3 months after completing the first cycle of pembrolizumab and SRS (i.e C1D2-3). 
Responses will be determined by the RECIST and immune RECIST criteria, as 
described in APPENDIX II and III. Response will also be assessed at 1 year from 
C1D2-3.  Response rates will be reported along with 95% confidence intervals will be 
estimated using the Clopper-Pearson method. 
 
14.3.3 Overall Survival 
For overall survival, death from any cause will be defined as the event. Patients will be 
censored at time of last follow-up. OS will be estimated using the Kaplan-Meier product-limit 
method. 
 
14.3.4 Intracranial Outcomes  
Local control (LC), anywhere intra-cranial failure (also called distant brain failure, DBR), 
leptomeningeal disease (LMD), radionecrosis (RN) and symptomatic (SRN) – will be 
estimated using cumulative incidence methodology, with death considered a competing risk. 
Rates for these outcomes will be censored at the time of salvage whole brain radiation and/or 
last follow-up.   

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14.3.5 Biological variables 
Descriptive statistics for the frequency and absolute cell counts for the major 
lymphocyte populations (CD3, CD4, CD8, CD19) T cells and monocytes (CD14) 
along with other markers listed above will be estimated.   
 
15.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
15.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
15.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
15.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
15.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 

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15.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
16.0 DATA AND SAFETY MONITORING PLAN  
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research 
being conducted by Winship Cancer Institute Investigators produces high-quality scientific 
data in a manner consistent with good clinical practice (GCP) and appropriate regulations 
that govern clinical research.    Depending on the risk level of the protocol, the DSMC 
review may occur every 6 months or annually.  For studies deemed High Risk, initial study 
monitoring will occur within 6 months from the date of the first subject accrued, with 2 of the 
first 5 subjects being reviewed.  For studies deemed Moderate Risk, initial study monitoring 
will occur within 1 year from the date of the first subject accrued, with 2 of the first 5 
subjects being reviewed.  Subsequent monitoring will occur in routine intervals per the 
Winship Data and Safety Monitoring Plan (DSMP).  
The DSMC will review pertinent aspects of the study to assess subject safety, compliance 
with the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer 
Institute Internal Monitors assigned to the DSMC may verify informed consent, eligibility, 
data entry, accuracy and availability of source documents, AEs/SAEs, and essential 
regulatory documents.  Following the monitoring review, monitors will provide a preliminary 
report of monitoring findings to the PI and other pertinent individuals involved in the conduct 
of the study.  The PI is required to address and respond to all the deficiencies noted in the 
preliminary report.  Prior to the completion of the final summary report, monitors will 
discuss the preliminary report responses with the PI and other team members (when 
appropriate).  A final monitoring summary report will then be prepared by the monitor.  Final 
DSMC review will include the final monitoring summary report with corresponding PI 
response, submitted CAPA (when applicable), PI Summary statement, and available 
aggregate toxicity and safety data.   
The DSMC will render a recommendation and rating based on the overall trial conduct.  The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB.  Continuing Review submissions will include the DSMC recommendation letter.  
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes.  The 
Committee reserves the right to conduct additional audits if necessary.  

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16.1. Data Collection:  
        Data that will be captured in OnCore for the following procedures 
-       Inclusion/Exclusion Criteria 
-       Demographics and Medical History 
-       Vital Signs 
-       Weight 
-       Karnofsky Performance Status (KPS) & ECOG 
-       HBcAb, HepC Ab 
-       Brain MRI [RECIST] 
-       Diagnostic Imaging [RECIST] 
-       Adverse Events Assessment 
-       CBC with differential 
-       CMP, LDH, ESR 
-       T3, FT4, TSH 
-       Pregnancy Test – urine or serum b-HCG 
-       Urinalysis 
-       Uric Acid, MG, Phos, Coags (PTT, PT, INR) - [seconds] 
-       Serum Biomarkers 
-       Skin Biopsy (if needed) 
-       Stereotactic Radiosurgery 
-       Survival Analysis 
-       Grade 3 CNS 
  

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17.0 APPENDICES 
APPENDIX I 
 
CTCAE (Common Terminology Criteria for Adverse Events), version 4.03 
The exact full criteria for toxicity assessment can be obtained at the NCI CTEP website at the 
following link:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX II 
 
Tumor assessment via RECIST Criteria, Guideline Version 1.1 
Eisenhauer, E.A., Therasse, P., Bogaerts, J., et al. New Response Evaluation Criteria in Solid 
Tumours: Revised RECIST Guideline (version 1.1). Europ J Cancer. 2009. 45; 228-247. 
http://imaging.cancer.gov/clinicaltrials/imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX III 
Tumor Assessment per Immune-Related Response Criteria 
Immune-related Response Criteria (irRC) are derived from modified World Health 
Organization (mWHO) conventions. Assessments of lymph nodes are derived from 
current RECIST guidelines. 
 
a.) Definitions of Measurable/non-Measurable Lesions 
All measurable and non-measurable lesions should be assessed at the initial 
Screening/enrollment, at the defined tumor assessment time points (see Time and Events 
Schedule), and during regular maintenance.  Additional assessments may be performed, as 
clinically indicated for suspicion of progression. The Investigator will base response to 
treatment using the irRC. 
 
i.) Measurable Disease 
Measurable non-lymph node disease is defined as lesions that can be accurately 
measured in 2 perpendicular Diameters. Size criteria is defined based on the properties 
of the CT scan 
-Spiral CT, 0.5cm thickness slice: both diameters must be at least > 1.0cm 
-For > 0.5cm thickness slices: larger diameter >2.0cm; the other > 1.0cm 
 
Lymph nodes are measurable only if CT slice thickness is <0.5cm. Size criteria are that 
the lymph node be at least 15 mm in short axis. 
 
ii.) Non-Measurable Lesions 
Non-measurable (evaluable) lesions are all other lesions, including one-dimensional 
measurable disease and small lesions (not meeting the above criteria), and any of the 
following:  
-lesions occurring in a previously irradiated, extracranial area (unless they are 
documented as new lesions since the completion of radiation therapy),  

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bone lesions,  
-leptomeningeal disease,  
-ascites, 
 
-effusion (pleural or pericardial) 
 
-cystic lesions 
 
-abdominal masses not histological confirmed 
 
Lymph nodes with a short axis < 10 mm are considered not pathological, and are not 
measurable. 
 
b.) Definitions of Index/non-Index Lesions 
 
i.) Index Lesions 
Measurable lesions, up to a maximum of 5 lesions per organ and ten lesions in total, 
must be identified as index lesions to be measured at Screening. The index lesions 
should be representative of all involved organs. In addition, index lesions must be 
selected based on their size (e.g., lesions with the longest diameters), their suitability 
for accurate repeat assessment by imaging techniques, and how representative they are 
of the subject’s tumor burden. At Screening, a Sum of the Product Diameters (SPD) for 
all index lesions will be calculated and considered the baseline SPD. The baseline sum 
will be used as the reference point to determine the objective tumor response of the 
index lesions at tumor 
assessment. 
 
ii.) Non Index Lesions 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, 
will be identified as non-index lesions. Non-index lesions will be evaluated at the same 
assessment time points as the index lesions. After the initial assessment, changes in 
non-index lesions will contribute only in the assessment of complete response. 
 
c.) Calculation of Sum of Product of Diameters (SPD) 

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Sum of Product of Diameters is an estimate of tumor burden. The 2 greatest 
perpendicular diameters are used to estimate the size of each tumor lesion. The SPD is 
calculated as the sum of the product of the diameters for index tumor lesions. Several 
variations of the SPD are identified for the purpose of classification of tumor responses. 
 
i.) SPD at Baseline  
The sum of the product of the diameters for all index lesions identified at baseline prior 
to treatment on Day 1. 
 
ii.) SPD at tumor assessment 
 For every on-study tumor assessment collected per protocol or as clinically indicated, 
the SPD at tumor assessment will be calculated using tumor imaging scans. All index 
lesions and all new measurable lesions that have emerged after baseline will contribute 
to the SPD at tumor assessment (irSPD). 
 
iii.) SPD at NADIR 
For tumors that are assessed more than 1 time after baseline, the lowest value of the 
SPD (SPD Baseline or SPD at tumor assessment) is used to classify subsequent tumor 
assessments for each subject. The SPD at tumor assessment using the irRC for 
progressive disease incorporates the contribution of new measurable lesions. Each net 
percentage change in tumor burden per assessment using irRC accounts for the size and 
growth kinetics of both old and new lesions as they appear. In this study the irRC as 
defined by the Investigator will serve as the basis of key endpoints for efficacy analyses 
and guide clinical care. 
 
 
 
 
 
 

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APPENDIX IV 
 
KARNOFSKY PERFORMANCE SCALE 
 
100 Normal; no complaints; no evidence of disease 
90 Able to carry on normal activity; minor signs or symptoms of disease 
80 Normal activity with effort; some sign or symptoms of disease 
70 Cares for self; unable to carry on normal activity or do active work 
60 Requires occasional assistance, but is able to care for most personal needs 
50 Requires considerable assistance and frequent medical care 
40 Disabled; requires special care and assistance 
30 Severely disabled; hospitalization is indicated, although death not imminent 
20 Very sick; hospitalization necessary; active support treatment is necessary 
10 Moribund; fatal processes progressing rapidly 
       0 Dead 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 

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APPENDIX V 
RTOG RPA Classification System for Brain Metastasis 
RPA Class I 
All of the following criteria: 
 
KPS ≥ 70%  
 
Age < 65 years  
 
Absence of extracranial metastases  
 
Controlled primary cancer  
RPA Class II 
KPS ≥ 70% and  
 
One or more of the following criteria:  
 
Age > 65 years  
 
Presence of extracranial metastases  
 
Uncontrolled primary cancer  
RPA Class III 
KPS < 70%  
 
 

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APPENDIX VI 
 
Graded Prognostic Assessment (GPA) for Brain Metastasis 
 
  
0 points 
0.5 points 
1 point 
2 points 
NSCLC 
  
  Age 
>60 
50-59 
<50 
-  
  KPS 
<70 
70-80 
90-100 
         - 
  Number of Cranial Mets > 3 
2-3 
1 
         - 
  Extra-Cranial Mets 
Present 
-  
Absent 
 - 
Melanoma 
  
  KPS 
<70 
-  
70-80 
90-100 
  Number of Cranial Mets > 3 
-  
2-3 
1 
 
Median Survival Based on GPA 
 
 
 
 
     Median Overall Survival (Months) 
GPA 
score 
NSCLC 
Melanoma 
0-1 
3 
3.4 
1.5-2.5 
6.5 
4.7 
3 
11.3 
8.8 
3.5-4.0 
14.8 
13.2 
Overall 
7 
6.7 
 

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APPENDIX VII 
Eligibility Checklist 
1. ______  
Willing and able to provide consent; 
2. ______ 
≥ 18 yrs old on day of consent; 
3. ______ 
Pathological proven diagnosis of one of the following: 
                                    non-small cell lung cancer or melanoma. (biopsy per SOC, if needed) 
 
 
 
Ocular melanoma, mucosal melanoma, and unknown melanoma are  
eligible; 
4. ______      Patients can be treated either in first line or in the refractory  
setting, as long as they can get PD-1 as standard of care; PD-L1
 
positivity is not required for enrollment;  
 
5. ______ 
1-10 intact brain metastasis (having had surgery to one lesion is not an  
exclusion criteria).     
 
6. ______      Largest lesion < 14.15cm3 
 
7. ______      Prior whole brain radiation therapy or SRS is allowed 
 
 
*Previous history of radiation to the primary tumor site is eligible; 
 
8. _______    Having gotten prior PD1 therapy is allowed for, especially if they have 
previously progressed on it. Progression may include extra-cranial as well as intra-
cranial progression. After progressing on PD1 therapy, intervening chemotherapy 
and/or targeted therapy (BRAFi, etc) is allowed.  If they are on intervening 
chemotherapy and/or targeted therapy (BRAFi, etc), they have to have progression 
intra-cranially and/or extra-cranially and must be off intervening therapy for at least 
2 weeks. 
 
9. ______      Patient asymptomatic at time of SRS (day 0).  Use of 10 mg 
prednisone equivalent at time of start of treatment  is permitted as long at the 
dose has been less than or equal to 10mg for at least 7 days prior to treatment 
start.    
 
10. _______     MRI of brain within 28 +/- 2 weeks days of enrollment showing 
evidence of BM     
 
11. ______    Baseline pre-enrollment CT chest/abdomen/pelvis and/or PET/CT. 
 
 
* Baseline MRI images of chest/abdomen/pelvis can substitute 
 
       * Baseline bone scan can also be substituted;  
 
 
(all imaging must be completed within 28 +/- 2 weeks days of 
enrollment) 
     
12. ______     Photographs of any skin metastases are encouraged, but not required. 
 

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13. ______ 
Baseline labs (CBC, CMP, LDH, ESR, etc); collected within 14 days of 
enrollment  
 
14. ______ 
Measurable disease based on RECIST 1.1; 
 
15. ______ 
ECOG performance status 0-1 and Karnofsky Performance Status ≥ 
70% on initial visit;  Subsequent visits need to only document ECOG 
PS; 
 
16. ______     No concurrent chemotherapy (no chemotherapy starting 14 days before 
start of radiation to 14 days after completion of radiation).   
 
17. ______ 
Adequate organ function as defined in Table 4; 
 
18. ______     Negative serum pregnancy test within 2 weeks of enrollment  
 
19. ______     No active or chronic infection with TB, HIV, Hepatitis B or C 
 
20. ______     No history of or active history of autoimmune disease. 
 
21. ______    Can-not have a diagnosis of immunodeficiency or is receiving systemic 
steroid therapy or any other form of immunosuppressive therapy within 7 days prior 
to the first dose of trial treatment 
 
22. ______     No history of active clinical diverticulitis 
 
23. ______     No Brain metastases within the brain stem; 
 
24. ______   All melanoma patients may be tested for BRAF as part of routine standard 
of care, but not required on the trial; All NSCLC patients may be tested 
for with EGFR and ALK as part of standard of care, but not required on 
the trial.  
 
 
25. _______ No known history of (non-infectious) pneumonitis that required steroids 
(less than or equal to 10 mg prednisone equivalent at time of start is 
ok) or current pneumonitis. 
 
 
 
 

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18.0  BIBLIOGRAPHY 
 
1. 
Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Current oncology 
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2. 
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence 
proportions of brain metastases in patients diagnosed (1973 to 2001) in the 
Metropolitan Detroit Cancer Surveillance System. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2004;22(14):2865-2872. 
3. 
Amer MH, Al-Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central 
nervous system metastases: incidence, diagnosis, treatment and survival. Cancer. 
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4. 
Sampson JH, Carter JH, Jr., Friedman AH, Seigler HF. Demographics, prognosis, and 
therapy in 702 patients with brain metastases from malignant melanoma. Journal of 
neurosurgery. 1998;88(1):11-20. 
5. 
Coia LR. The role of radiation therapy in the treatment of brain metastases. 
International journal of radiation oncology, biology, physics. 1992;23(1):229-238. 
6. 
Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and 
comparison to three other indices for patients with brain metastases: an analysis of 
1,960 patients in the RTOG database. International journal of radiation oncology, 
biology, physics. 2008;70(2):510-514. 
7. 
Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, 
indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a 
multi-institutional analysis of 4,259 patients. International journal of radiation 
oncology, biology, physics. 2010;77(3):655-661. 
8. 
Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic 
targets. Nature reviews. Cancer. 2011;11(5):352-363. 
9. 
Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus 
observation after radiosurgery or surgical resection of one to three cerebral metastases: 
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Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases 
treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised 
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Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain 
radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: 
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12. 
Patel KR, Prabhu RS, Kandula S, et al. Intracranial control and radiographic changes 
with adjuvant radiation therapy for resected brain metastases: whole brain radiotherapy 
versus stereotactic radiosurgery alone. Journal of neuro-oncology. 2014. 

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13. 
Prabhu RS, Dhabaan A, Hall WA, et al. Clinical outcomes for a novel 6 degrees of 
freedom image guided localization method for frameless radiosurgery for intracranial 
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Product:   Pembrolizumab (MK-3475) 
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