Clinical trial NCT02681549
Conditions: Melanoma Non-small Cell Lung Cancer Brain Metastasis
Sponsor: Yale University
Start date: 2016-05-01; Completion date: 2025-03-31
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this phase 2 trial is to study the activity of pembrolizumab in combination with bevacizumab in patients with untreated brain metastases from melanoma or NSCLC to determine activity and safety of the drug combination. Furthermore, in patients who undergo resection of biopsy of a brain metastasis, we will evaluate biomarkers predictive of treatment benefit, and will also conduct correlative biomarker studies on extra-cerebral specimens in all patients in whom a systemic biopsy is feasible or in archival tumor tissue when available.

A total of 53 eligible patients will be enrolled on this trial (40 with melanoma and 13 with NSCLC). Individual cohorts of the study can be stopped if insufficient activity is observed in the first stage of that cohort. The study will accrue for approximately 84 months, and will be open for approximately 12 additional months as patients on study are being followed.

Detailed description:

Arms: arm 1: pembrolizumab plus bevacizumab arm 2: pembrolizumab plus bevacizumab
Interventions: intervention 1: Pembrolizumab plus Bevacizumab
Intervention descriptions: intervention 1: Pembrolizumab will be administered on day 1 of every cycle until disease progression or withdrawal from study. Bevacizumab will be administered in addition to pembrolizumab on day 1 of cycles 1, 2, 3, and 4 (or alternative cycles if bevacizumab is held during these cycles). Three weeks constitutes one cycle.

Protocol documents:
Prot_SAP_000.pdf: 
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SPONSOR: Yale University 
 
TITLE: A phase 2 trial of pembrolizumab plus bevacizumab in patients with metastatic 
melanoma or non‐small cell lung cancer with untreated brain metastases. 
 
IND NUMBER: 129774 
 
Coordinating Center: 
Yale Cancer Center 
 
Principal Investigator: 
Harriet Kluger, M.D. 
Section of Medical Oncology 
Yale Cancer Center 
333 Cedar Street, WWW‐213 
New Haven, CT 06520 
Tel: (203) 737‐2572 
Fax: (203) 785‐3788 
Harriet.Kluger@yale.edu 
 
Co‐Principal Investigators: 
Sarah Goldberg, M.D., M.P.H. 
Section of Medical Oncology 
Yale Cancer Center 
333 Cedar St., FMP130 
New Haven, CT 06520 
Tel: (203) 785‐7564 
Fax: (203) 785‐3788 
Sarah.Goldberg@yale.edu 
 
Veronica Chiang, M.D. 
Department of Neurosurgery 
333 Cedar Street, TMP4 
New Haven, CT 06520 
Tel: (203) 785‐2808 
Fax: (203) 785‐2098 
Veronica.Chiang@yale.edu
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CONTENTS 
Contents 
1.0 TRIAL SUMMARY ............................................................................................................ 6 
2.0 TRIAL SYNOPSIS ............................................................................................................. 6 
3.0 TRIAL DESIGN ................................................................................................................ 11 
3.1Trial Design and duration ............................................................................................. 11 
3.2 Trial Diagram ................................................................................................................ 13 
3.3 OBJECTIVE(S) & HYPOTHESIS(ES) .......................................................................... 16 
3.3.1  Primary Objective(s) & Hypothesis(es) ...................................................................... 16 
3.3.2 
Secondary Objective(s) & Hypothesis(es) ............................................................. 16 
3.3.3 
Exploratory Objective ............................................................................................ 17 
4.0 BACKGROUND & RATIONALE .................................................................................. 17 
4.1.1 
Pharmaceutical and Therapeutic Background .................................................... 17 
4.1.2 
Preclinical and Clinical Trial Data for pembrolizumab ...................................... 18 
4.2 Rationale ............................................................................................................................ 19 
4.2.1 Rationale for combining pembrolizumab and bevacizumab .............................. 19 
4.2.2. Rationale for Trial and Selected Subject Population ............................................ 21 
4.2.3 Rationale for Dose Selection/Regimen/Modification .............................................. 22 
4.2.4. Rationale for Endpoints ........................................................................................... 23 
5.0 METHODOLOGY ........................................................................................................... 24 
5.1 Entry Criteria ................................................................................................................ 24 
5.1.1. Diagnosis/Condition for Entry into the Trial ..................................................... 24 
5.1.2 Subject Inclusion Criteria ..................................................................................... 24 
5.1.3 Subject Exclusion Criteria .................................................................................... 26 
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5.2 Trial Treatments ........................................................................................................... 28 
5.2.1 Dose Selection/Modification .................................................................................. 28 
5.2.2 Timing of Dose Administration ............................................................................ 38 
5.2.3 Duration of Therapy .............................................................................................. 38 
5.2.4 Treatment Beyond Progression ............................................................................ 39 
5.2.5 Duration of Follow-up ........................................................................................... 39 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) ............................. 39 
5.3.1 Acceptable Concomitant Medications .................................................................. 39 
5.3.2 Prohibited Concomitant Medications .................................................................. 40 
5.4 Local Therapy ............................................................................................................... 40 
5.5 Rescue Medications & Supportive Care ..................................................................... 41 
5.5.1 Supportive Care Guidelines ..................................................................................... 41 
5.5.2 Supportive Care Guidelines for Events of Clinical Interest (ECIs) and Immune- 
related Adverse Events (irAEs)............................................................................. 43 
5.5.3. Supportive Care Guidelines for Pneumonitis.......................................................... 44 
5.6 Diet/Activity/Other Considerations ............................................................................. 44 
5.6.1 Diet ....................................................................................................................... 44 
5.6.2 Contraception ......................................................................................................... 45 
5.6.3 Use in Pregnancy .................................................................................................... 45 
5.6.4 Use in Nursing Women .......................................................................................... 46 
5.7 Subject Withdrawal/Discontinuation Criteria ........................................................... 46 
5.7.1 Discontinuation of Study Therapy after CR ....................................................... 47 
6.0 TRIAL FLOW CHART ................................................................................................... 48 
6.1  
Study Flow Chart .................................................................................................... 48 
7.0 TRIAL PROCEDURES ................................................................................................... 51 
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7.1 Administrative Procedures .......................................................................................... 51 
7.1.1  Informed Consent ................................................................................................... 51 
7.1.1.2 General Informed Consent ................................................................................. 51 
7.1.2 Inclusion/Exclusion Criteria ..................................................................................... 51 
7.1.3 Medical History .......................................................................................................... 51 
7.1.4 Prior and Concomitant Medications Review .......................................................... 52 
7.1.5  Disease Details and Treatments ............................................................................. 52 
7.2 Clinical Procedures/Assessments ................................................................................. 52 
7.2.1 Adverse Event (AE) Monitoring ........................................................................... 52 
7.2.2 Full Physical Exam ................................................................................................ 53 
7.2.3 Directed Physical Exam ......................................................................................... 53 
7.2.4 Vital Signs ............................................................................................................... 53 
7.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ................ 53 
7.2.6 Tumor Imaging and Assessment of Disease ........................................................ 53 
7.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling .................. 53 
7.3 Laboratory Procedures/Assessments .......................................................................... 54 
7.4 Other Procedures .......................................................................................................... 56 
7.4.1 Withdrawal/Discontinuation ................................................................................. 56 
7.5 Visit Requirements ....................................................................................................... 56 
7.5.1 Safety Follow-Up Visit ........................................................................................... 56 
7.5.2 Follow-up Visits ...................................................................................................... 56 
7.6 Assessing and Recording Adverse Events .................................................................. 57 
7.6.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ........................................................................................ 58 
7.6.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck .............. 58 
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7.6.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck ........... 59 
7.6.4 Reporting to the Food and Drug Administration ............................................... 60 
7.6.5 Reporting to the Yale Human Investigation Committee .................................... 60 
7.6.6 Evaluating Adverse Events ................................................................................... 61 
7.6.7 Sponsor Responsibility for Reporting Adverse Events ...................................... 64 
7.6.8 Events of Clinical Interest ..................................................................................... 64 
8.0 STATISTICAL ANALYSIS PLAN................................................................................. 64 
8.1 Statistical Design ........................................................................................................... 64 
8.2 Analytic Plan for Primary Objectives: ....................................................................... 67 
8.3 Analytic Plan for Secondary Objectives: .................................................................... 67 
8.4 Exploratory Objective .................................................................................................. 68 
9.0  
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ......................................................................................................................... 69 
9.1 Investigational Product ................................................................................................ 69 
9.2 Packaging and Labeling Information ......................................................................... 69 
9.3 Clinical Supplies Disclosure ......................................................................................... 69 
9.4 Storage and Handling Requirements .......................................................................... 69 
9.5 Returns and Reconciliation .......................................................................................... 69 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS ............................................. 70 
10.1 Compliance with Trial Registration and Results Posting Requirements ............... 70 
10.2 Quality Management System ..................................................................................... 70 
10.2.1 Monitoring ............................................................................................................ 70 
10.2.2 Audit and inspection ............................................................................................ 71 
10.2.3 Data Safety Monitoring Committee (DSMC) .................................................... 71 
11.0 BIOMARKER STUDIES ............................................................................................... 72 
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11.1 Tissue-based correlative studies: ............................................................................... 72 
11.2 Blood-based studies: ................................................................................................... 73 
11.3 Collection and Handling of Specimens ..................................................................... 74 
12.0  
MEASUREMENT OF RESPONSE ...................................................................... 74 
12.1 Brain Metastasis Response Assessment ..................................................................... 74 
12.2 Brain Metastasis Measurable disease ......................................................................... 74 
12.3 Brain Metastasis Nonmeasurable disease .................................................................. 75 
12.4 Modified Response Criteria for Brain Metastases .................................................... 75 
12.5 Systemic Disease Response Assessment ..................................................................... 75 
12.6 Evaluation of Best Overall Response .......................................................................... 76 
13.0 APPENDICES ................................................................................................................. 78 
13.1 ECOG Performance Status ........................................................................................ 78 
13.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ..................... 78 
14.0 REFERENCES ................................................................................................................ 79 
 
 
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1.0 TRIAL SUMMARY 
 
Abbreviated Title 
Pembrolizumab and bevacizumab in untreated brain metastases 
Trial Phase 
II 
Clinical Indication 
Untreated brain metastases from melanoma or non-small cell lung cancer 
Trial Type 
Open label 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
NA 
Treatment Groups 
Two cohort phase II trial, one for melanoma patients and one for non-small 
cell lung cancer patients 
Number of trial subjects 
53 
Estimated enrollment period 
January 1, 2016 – December 31, 2022 
Estimated duration of trial 
96 months 
Duration of Participation 
36 months 
 
2.0 TRIAL SYNOPSIS 
 
Concept and Rationale: Important progress has recently been made in treating metastatic 
melanoma and non-small cell lung cancer (NSCLC) using pembrolizumab, an inhibitor of 
PD-1, a negative immune check-point regulator found on cytotoxic T-cells_ENREF_1. 
Approximately 34% of patients with melanoma and 25% with NSCLC have partial or complete 
responses to this drug at optimal doses, and additional patients have prolonged stable 
disease. An ongoing study of pembrolizumab in patients with brain metastases from 
melanoma or NSCLC has shown that while the drug has substantial activity in brain 
metastases, peri-lesional edema can result in significant morbidity. Bevacizumab, an 
antibody to VEGF has been shown in a number of prior clinical studies to reduce peri- 
lesional edema in the CNS. Moreover, in preclinical models the addition of VEGF inhibitors 
to PD-1 inhibitors has been shown to enhance anti-tumor immunity, providing further 
rationale for combining pembrolizumab and bevacizumab in this patient population. 
 
Every year there are almost 50,000 patients from these diseases who will develop brain 
metastases. Melanoma in particular tends to metastasize to the brain frequently, and the 
incidence on autopsy is up to 70%. Brain metastases are present in 10% of patients with 
NSCLC at diagnosis, and another 30% develop CNS disease over the course of their disease. 
Multifocal disease is common in both of these diseases, with about half of patients with CNS 
disease presenting with more than one brain lesion. 
 
Many effective drugs currently in development have not been well studied for CNS 
penetration, and patients with brain metastases are excluded from most clinical trials. With 
recent advances in delivery of local therapies, particularly stereotactic radiosurgery (SRS), 
local control of brain metastases has improved. However, SRS still has limitations and 
complications such as radiation necrosis, cerebral edema, and delayed tumor hemorrhage. 
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Beyond these local therapies, effective systemic therapies that are active in the CNS may be of 
significant benefit to patients. 
The purpose of this trial is to study the activity of pembrolizumab in combination with 
bevacizumab in patients with untreated brain metastases from melanoma or NSCLC to 
determine activity and safety of the drug combination. Furthermore, in patients who undergo 
resection of biopsy of a brain metastasis, we will evaluate biomarkers predictive of treatment 
benefit, and will also conduct correlative biomarker studies on extra-cerebral specimens in all 
patients in whom a systemic biopsy is feasible or in archival tumor tissue when available. 
Confirmed, objective CNS responses were seen in 11 of the first 20 melanoma patients, for a 
brain metastasis response rate of 55%. The primary endpoint of the study for the melanoma 
cohort has been met. We will validate the findings in the melanoma cohort in the next 20 
melanoma patients. The NSCLC component is a pilot study  
Primary Objectives/Endpoints: 
(1) To determine the brain metastasis response rate in patients with melanoma or NSCLC 
with untreated brain metastases, treated systemically with pembrolizumab plus bevacizumab. 
Secondary Objectives/Endpoints: 
1) To determine the incidence of steroid use for control of cerebral edema during 
treatment with pembrolizumab plus bevacizumab in patients with metastatic 
melanoma or NSCLC to the brain compared to previous study of patients treated with 
pembrolizumab alone. 
2) To determine the best overall response rate (ORR) in patients with brain metastases 
from melanoma or NSCLC treated with combination pembrolizumab plus 
bevacizumab. 
3) To evaluate median progression free survival (PFS) and overall survival (OS) in 
patients with melanoma or NSCLC metastatic to the brain, treated with 
pembrolizumab plus bevacizumab. 
4) To determine the safety of pembrolizumab in combination with bevacizumab in 
patients with untreated brain metastases from melanoma or NSCLC 
Exploratory objective: 
To study PD-L1 expression and other potential predictive biomarkers in CNS, tumors 
and blood, and correlate results with response to pembrolizumab plus bevacizumab. 
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Study Design: This is a phase II study with the 2 tumor types treated in separate cohorts. Key 
eligibility criteria include advanced melanoma or non-squamous NSCLC with at least 1 brain 
metastasis that is at least 5mm but smaller than 2cm in size, and no requirement for systemic 
steroids to control peri-lesional CNS edema. Patients who have had prior resection of a CNS 
lesion will be required to provide a tumor block for correlative studies and all patients   will   be  
required to provide an extra-cerebral specimen when feasible 
Pembrolizumab will be administered on day 1 of every cycle until disease progression or 
withdrawal from study. Bevacizumab will be administered in addition to pembrolizumab on 
day 1 of cycles 1, 2, 3, and 4 (or alternative cycles if bevacizumab is held during these 
cycles).  Three weeks constitutes one cycle. 
Efficacy evaluation will be performed every 6 weeks for the first 3 months of treatment, and 
every 9 weeks thereafter, including MRI of the brain and CT or PET scans of systemic 
disease. Patients will continue on study until they have disease progression, toxicities that 
preclude continuing the study drug, withdrawal from study, development of other severe 
illness, neurologic or systemic complications following local therapy to any lesion, 
termination of study, or death. Dose reductions for severe immune-related toxicities will not 
be allowed, however, discontinuation of one of the drugs will be allowed for toxicity if the 
investigator determines that the other drug is providing clinical benefit. Patients may remain 
on study after disease progression if they are deemed by the investigator to be deriving 
clinical benefit from treatment. 
Number of Patients: 
A total of 40 melanoma patients and 13 NSCLC patients will be enrolled for a total of 
53 patients. The study will accrue for approximately 24 additional months and will be open 
for approximately 12 additional months after the last patient is accrued as patients on study 
are being followed. 
 
 
 
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Statistical Methods 
 
The primary goal of this study is to determine the efficacy and safety of pembrolizumab plus 
bevacizumab in patients with untreated brain metastases from melanoma or NSCLC. The 
primary endpoint is the brain metastasis response rate (BMRR). A drug with minimal activity 
would be expected to have a BMRR of 10%. The study was initially designed so that this 
combination would be considered worthy of further study in patients with untreated brain 
metastases if its true BMRR is similar to the systemic response rate with pembrolizumab 
(Melanoma - 34%, NSCLC with PD-L1 positive tumors - 25%).As of February 2019, 20 
patients had been accrued to the melanoma cohort of the trial and brain metastasis responses 
were observed in 55%, 95% CI: 0.32-0.77) Therefore, the statistical plan was amended to 
include an additional 20 patients to the melanoma cohort to validate the findings in the initial 
cohort. The initial pre-defined criterion that the combination of pembrolizumab and 
bevacizumab would not be worthy of further study if the BMRR was <10% was modified to 
30%, which is the lower bound of the 95% confidence interval from the first 20 melanoma 
patients. To account for the uncertainty of the historical response rate, we will now follow the 
approach proposed by Thall and Simon (1994),63 and after enrolling and evaluating the 
outcomes of the 20 patients in the confirmatory cohort, we will conclude the combination 
worthy of further study if there are at least 8 responses in these 20 patients.  
 
A pilot study of 13 NSCLC will be conducted. See statistical analyses section for more details. 
 
 
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: A phase 2 trial of pembrolizumab plus bevacizumab in patients with 
metastatic melanoma or non-small cell lung cancer with untreated brain metastases 
 
Protocol Version: 12 
 
By signing this agreement, I, the Site Investigator named above, acknowledge receipt of this 
protocol version. I have read this protocol in its entirety and agree to conduct this study 
according to this protocol, Good Clinical Practices and all applicable codes of federal 
regulations (CFRs) and guidelines. 
 
 
Site Investigator’s Printed Name:  _______________________ 
 
 
 
Signature:  ______________________________ 
 
 
 
Date:  ________________________________ 
 
 
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3.0 
TRIAL DESIGN 
 
3.1 
Trial Design and duration 
 
This is a phase II study for melanoma and a pilot study for NSCLC. Patients will be treated 
in separate cohorts. After establishing eligibility criteria, target lesions in the CNS will be 
chosen and will be followed by modified RECIST (mRECIST) criteria to determine best 
brain metastasis response. When feasible, after obtaining informed consent, patients may 
undergo local therapy (resection or laser interstitial thermocoagulation therapy - LITT) to the 
brain. Biopsy of tumor tissues from extra-cerebral sites will be studied for PD-L1 and other 
biomarkers (see section 11.0 below) as potential predictors of sensitivity to pembrolizumab 
and bevacizumab, although it should be noted that the presence of a biomarker is not necessary 
for melanoma patients to go on trial. Expression of PD-L1 determined by Central and/or 
local testing of PD-L1 IHC by any FDA-approved assay or an assay performed in a CLIA 
laboratorywill be required for eligibility for NSCLC patients. This will be followed by 
treatment with pembrolizumab 200mg IV every 3 weeks. Bevacizumab 7.5 mg/kg will be 
administered on Day 1 of cycles 1, 2, 3, and 4 (or alternative cycles if bevacizumab is held 
during these cycles). Day 1 of the study will be defined as the first day a patient receives 
pembrolizumab. Each cycle is 3 weeks. 
 
Clinically Evaluable Lesion(s): A clinically evaluable lesion is at least one asymptomatic, 
untreated brain metastasis that measures at least 5 mm in minimum cross-sectional diameter 
and < 20 mm in maximum cross-sectional diameter as determined by brain MRI at baseline, 
and is determined by the investigator to be safe to follow clinically without local therapy. If 
MRI slice thickness is >2.5mm, the minimum cross-sectional diameter must be at least twice 
the MRI slice thickness. An untreated brain metastasis is defined as a lesion not present at 
the time of whole brain radiation therapy or included in a stereotactic radiotherapy field (or 
within 2mm of a treated lesion), or any lesion that is new or unequivocally progressing since 
prior radiation therapy. At time of enrollment, the clinically evaluable lesion(s) will be 
defined. 
 
Patients will proceed directly to therapy with bevacizumab and pembrolizumab. If, at any 
time while on study, the patient develops symptoms related to any cerebral metastases the 
patient may have brain imaging prior to the pre-defined imaging time points and proceed to 
local therapy of the lesion(s) if indicated. 
 
Efficacy evaluation will be performed every 6 weeks for the first 3 months and every 9 
weeks thereafter, including PET or CT scans of systemic disease. Brain metastasis response 
will be determined using modified RECIST (mRECIST) criteria. Patients will continue on 
study until they have overall disease progression in either their clinically evaluable CNS 
lesions (by mRECIST criteria) or in their systemic metastases (by RECIST 1.1 criteria), 
toxicities that preclude continuing the study drugs, withdrawal from study, development of 
other severe illness, neurologic or systemic complications following local therapy to any 
lesion, termination of study, or death. There will be no dose reduction for either 
pembrolizumab or bevacizumab but one drug may be held as outlined below. If a patient 
develops symptoms related to ANY lesion, local therapy may be administered to that lesion. 
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Patients with new symptoms from CNS lesions, or progressing lesions may be treated with local 
therapy to the brain metastases. These patients can continue therapy with both drugs or one of the drugs 
if the patient is otherwise deemed to be deriving clinical benefit. If patients develop clear intralesional 
or perilesional hemorrhage they can stay on study with cessation of bevacizumab. 
 
Treatment beyond progression: If the treating physician determines that a patient is deriving clinical 
benefit from therapy, treatment beyond progression (as defined by mRECIST for CNS lesions and 
RECIST 1.1 for extracerebral lesions) will be allowed. 
 
Discontinuation of bevacizumab OR pembrolizumab and continuation of monotherapy: Patients who 
develop toxicity clearly attributable to one drug who are felt to be benefitting from therapy will be 
allowed to remain on study. Examples include proteinuria, or thromboembolic events attributed to 
bevacizumab and severe autoimmune toxicity not controllable with steroids from pembrolizumab. 
 
The plan is to enroll an additional 40 melanoma patients and 13 NSCLC patients in a pilot study 
for 53 patients total.  
 
 
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3.2 Trial Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD‐L1 positive 
PD‐L1 
negative 
or 
unevaluable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CR, PR, SD 
PD 
 
 
 
 
 
 
Evaluate patients with untreated brain metastases and/or post‐treatment progressing brain 
metastases for eligibility and select clinically evaluable lesions 
Obtain archival or fresh 
tumor tissue if available 
Obtain archival or fresh tumor tissue for PD‐L1 
status*** 
Eligible 
Ineligible 
Initiate pembrolizumab 200mg q 3w + bevacizumab 7.5mg/kg on D1 of C1, C2, C3 and C4* 
Response evaluation for brain and body q6w for 3 months and then 
q9w thereafter 
Continue on treatment if 
stable or responding** 
Consider local therapy to isolated growing 
lesions 
Continue on treatment 
Remove from study** 
*Bevacizumab may be administered during later cycles if held during cycles 1‐4, with the goal of administering a total of 4 cycles of combination
pembrolizumab and bevacizumab 
** Subjects who experience PD may continue on study if they are determined to be deriving clinical benefit from the study drugs and they continue
to meet all other criteria for treatment 
*** Subjects with PD‐L1 test results from outside the study are not required to repeat testing for determination of eligibility as long as
no systemic 
therapy was administered after the test results were obtained. If patients do not undergo PD‐L1 testing for eligibility, fresh or archival
tissue is still 
required at study entry for correlative studies. 
 
Cohort A: 
Melanoma 
Cohort B: 
NSCLC 
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3.3 OBJECTIVE(S) & HYPOTHESIS(ES) 
 
3.3.1  Primary Objective(s) & Hypothesis(es) 
 
1) Primary Objective: To determine the brain metastasis response rate in patients with 
melanoma or NSCLC treated with pembrolizumab plus bevacizumab. 
 
Hypothesis: The combination of pembrolizumab and bevacizumab will result in 
enhanced anti-tumor activity. 
 
3.3.2 Secondary Objective(s) & Hypothesis(es) 
 
(1) Objective: To determine the incidence of steroid use for control of cerebral edema 
during treatment with pembrolizumab and bevacizumab in combination in patients 
with metastatic melanoma or NSCLC. 
 
Hypothesis: The combination of pembrolizumab and bevacizumab will result in 
reduced steroid use to control CNS edema compared to a historical cohort of patients 
treated with pembrolizumab alone. 
 
(2) Objective: To determine the best overall response rate (ORR) in patients with brain 
metastases from melanoma or NSCLC treated with combination pembrolizumab and 
bevacizumab. 
 
Hypothesis: The combination of pembrolizumab and bevacizumab will result in 
enhanced anti-tumor activity compared to a historical cohort of patients with 
pembrolizumab alone. 
 
(3) Objective: To evaluate median progression free survival (PFS) and overall survival 
(OS) in patients with melanoma or NSCLC metastatic to the brain, treated with 
pembrolizumab plus bevacizumab. 
 
Hypothesis: The combination of pembrolizumab and bevacizumab will result in 
longer PFS and OS compared to a historical cohort of patients with pembrolizumab 
alone. 
 
(4) Objective: To determine the safety and toxicity of pembrolizumab in combination 
with bevacizumab in patients with untreated brain metastases 
 
Hypothesis: The combination will result in an improved central nervous system 
toxicity profile and less perilesional edema than pembrolizumab monotherapy 
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3.3.3 Exploratory Objective 
 
(1)  Objective: To study PD-L1 expression and other potential predictive biomarkers in 
CNS, tumors and blood, and correlate results with response to pembrolizumab plus 
bevacizumab. 
 
 
Hypothesis: Patients with high PD-L1 tumor content AND high TIL content, 
particularly increased CD-8 TILs, will be more likely to respond to the combination 
of pembrolizumab and bevacizumab. 
 
4.0 
BACKGROUND & RATIONALE 
 
4.1 
Background 
 
Although immune-modulating antibodies are becoming the standard of care for treating 
melanoma and other malignancies, little is known regarding the effects of these agents on 
brain metastases. Ten to 40% of patients with metastatic melanoma develop brain metastases 
during their lifetime and > 75% have metastases at autopsy 1-5. Among patients with non- 
small cell lung cancer (NSCLC), 10% have brain metastases at presentation and another 30% 
develop them over the course of their disease. Survival after the development of brain 
metastases is as dismal in those with NSCLC as it is for melanoma. Multifocal disease is 
common in both of these malignancies, with about half of patients with CNS disease 
presenting with more than one brain lesion 6. Typical local management involves surgery or 
stereotactic radiosurgery (SRS), depending on the size and number of lesions, while whole 
brain radiation (WBRT) is used for patients with multiple lesions, or large lesions 7,8. However, 
SRS has limitations and can cause complications such as radiation necrosis, cerebral edema 
and delayed tumor hemorrhage 9. With the advent of active systemic therapies in these 
diseases, it is possible that brain metastases might be controlled with these newer drugs, 
similar to control of extra-cerebral metastases. The ability of systemic therapies to cross the 
leaky blood brain barrier found in tumors is the subject of ongoing investigations 3,10,11. To 
date, most systemic therapy trials exclude patients with active brain metastases because 
of poor prognosis and unknown CNS penetration, and their activity in CNS metastases is 
typically understudied 3,12. 
4.1.1 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T- 
cells  under  healthy  conditions,  is  to  down-modulate  unwanted  or  excessive  immune
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responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). 
The structure of murine PD-1 has been resolved. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine- 
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved 
in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells. Expression has also been shown during thymic development on CD4- CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands 
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety 
of cell types, including non-hematopoietic tissues as well as in various tumors. Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. 
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
 
 
4.1.2 Preclinical and Clinical Trial Data for pembrolizumab 
 
Please refer to the Investigator’s Brochure for additional preclinical and clinical data. 
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4.2 
Rationale 
 
4.2.1 Rationale for combining pembrolizumab and bevacizumab 
 
Pembrolizumab Rationale: 
Antibodies blocking either PD-1 or its ligand PD-L1 are the most active of the immune 
modulating antibodies studied in clinical trials to date. Initial trials of antibody-mediated 
blockade of PD-1 alone showed promising results with durable tumor regression or 
prolonged disease stabilization in patients with advanced solid tumors including melanoma13- 
15 and lung cancer 13. Results from a phase 1b study of pembrolizumab, a monoclonal 
antibody against PD-1, in metastatic melanoma showed an overall response rate of 34% and 
a median PFS of 36 months 15. Eighty percent of patients had a continued response to 
therapy. Based on this study, pembrolizumab, is now approved by the FDA for the treatment 
of metastatic melanoma 14. A randomized phase III trial comparing pembrolizumab to 
ipilimumab in the frontline setting demonstrated a response rate of 34% in patients receiving 
pembrolizumab 16. Recent data regarding activity of pembrolizumab in previously untreated 
NSCLC was presented at ASCO, 2014 and showed an overall response rate of 26% with 
100% of patients having an ongoing response 17. Additional studies have been conducted 
showing response rates that vary based on PD-L1 status and cut-points for positivity 18-21. A 
phase III trial is underway comparing pembrolizumab to standard chemotherapy in NSCLC. 
In almost all trials conducted to date, clinical response to PD-1/PD-L1 pathway antagonists 
has been strongly associated with pre-treatment tumor cell or tumor infiltrating lymphocyte 
(TIL) surface expression of PD-L1. Correlative data also suggest that in many patients, pre- 
treatment tumor PD-L1 expression is induced by adjacent cytokine-producing T-cells; 
however, a subset of tumors can express PD-L1 in the absence of T-cell infiltration, 
presumably as a result of aberrant cell signaling 22. Tumors expressing PD-L1 but lacking 
TIL, and conversely tumors containing non-cytokine producing TIL and absent PD-L1 
expression, are less likely to respond to PD-1/PD-L1 pathway antagonists. 
 
Even in the subgroup of patients most likely to respond to PD-1/PD-L1 pathway antagonists 
(i.e., tumors containing TIL and associated PD-L1 expression), combinations may be 
necessary to higher rates of durable responses. Particularly for patients with  metastatic disease 
to the brain, the addition of a second agent in combination with pembrolizumab may allow 
for improved responses with decreased deleterious inflammatory effects, such as peri- lesional 
edema. Optimal approaches to such combinations are influenced by both preclinical studies 
and results from post-treatment biopsies conducted on patients in our institution with brain 
metastases treated with pembrolizumab, in which there can be peri-lesional edema with tumor 
regression or so-called pseudoprogression (necrosis and associated inflammation). Data 
from a phase II trial of pembrolizumab in patients with metastatic melanoma or non- small 
cell lung cancer with untreated brain metastases in our institution showed an acceptable safety 
profile; responses have also been seen, however, in some patients, early cerebral edema 
has required discontinuation of therapy and/or treatment with steroids to control 
inflammation. In a survival analysis of 23 melanoma patients enrolled on this trial, 48% of 
patients were alive at 24 months, demonstrating durable responses and responses were 
concordant between the brain and extracerebral sites.   In the preliminary results from the 
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phase II portion of this trial combining pembrolizumab and bevacizumab, 11 out of 20 
patients with melanoma had a response in brain metastases as of February 2019. 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
 
Bevacizumab Rationale: 
Bevacizumab, a recombinant humanized monoclonal antibody blocking angiogenesis by 
vascular endothelial growth factor A (VEGF-A) inhibition, is a compelling combination 
partner for PD-1 pathway antagonists in patients with metastatic disease to the brain. VEGF 
decreases dendritic cell function and subsequently antigen presentation and T cell activation 
while promoting the development of myeloid-derived suppressor cells.23,24 VEGF is 
commonly found in the tumor microenvironment where it functions in immune evasion by 
altering the tumor vasculature to reduce lymphocyte adhesion to vessel walls within the 
microenvironment, thus contributing to decreased trafficking across endothelium into tumor 
deposits.25-27 Restoration of dendritic cell and T cell function may improve T cell response 
and result in overall improved clinical activity. 
 
In a murine melanoma model, the combination of VEGF blockade and adoptive 
immunotherapy was synergistic, resulting in improved antitumor activity, prolonged survival 
and increased trafficking of T cells into tumors.28 Other murine models have tested combined 
inhibition of PD-L1 and VEGF pathway in the syngeneic colorectal cancer model MC-38, 
showing synergism between the drugs. In addition, in the melanoma Cloudman model, 
bevacizumab was synergistic with PD-1 pathway blockade.29,30 
 
Synergistic effects of immunotherapy and VEGF blockade have been observed clinically in 
patients with melanoma receiving anti-CTLA-4 and bevacizumab.31 In a cohort of 10 patients 
with metastatic renal cell carcinoma treated with bevacizumab and  MPDL3280A, McDermott 
et al.32 reported partial response (PR) in 4 patients and an additional 5 patients achieved 
stable disease (SD). Treatment was well-tolerated with no unexpected toxicities. Responses 
were observed in a variety of other tumors.33 Specific to metastatic melanoma, Phase 1 
studies were recently initiated combining bevacizumab with MPDL3280A (anti-PD- L1) and 
a large randomized phase 2 trial is ongoing comparing MPDL3280A with bevacizumab 
versus MPDL3280A with sunitinib versus MPDL3280A alone in previously untreated 
patients with metastatic renal cell carcinoma. 
 
For NSCLC, bevacizumab is an approved drug for patients with non-squamous histology in 
first-line therapy when added to chemotherapy. Initial studies showed a median survival of 
12.3 months with the addition of bevacizumab to paclitaxel plus carboplatin compared to 
10.3 months with chemotherapy alone.34 As predicted, patients with brain metastases were 
excluded from this trial because of the risk of CNS hemorrhage. However, as early as 2009, 
bevacizumab was explored for the treatment of brain metastases in solid tumors. A phase 2 
trial, AVF3752g (PASSPORT), specifically addressed safety in patients with NSCLC and 
previously treated brain metastases who underwent systemic therapy with bevacizumab.35 
CNS hemorrhage was rare.   Subsequently, bevacizumab was retrospectively studied in a 
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small cohort of patients with NSCLC and active brain metastases who received bevacizumab 
alone and in combination with chemotherapy.36 One of 6 patients had an asymptomatic 
grade 1 intra-tumoral hemorrhage which occurred in the setting of concurrent 
anticoagulation. Notably, these patients required less corticosteroids when given 
bevacizumab. In another study, 18 patients with untreated brain metastases from various 
malignancies were treated with bevacizumab based therapy; 60% had PRs and overall the 
edema was reduced.37 
 
Bevacizumab has long been established as a safe and effective treatment of glioblastoma 
(GBM). Angiogenesis in brain tumors such as GBM leads to a highly permeable blood brain 
barrier which results in disruption of autoregulated cerebral blood flow.38 Angiogenesis in 
the brain promotes intravascular fluid extravasation into the extracellular spaces, otherwise 
known as vasogenic edema. If severe, this may lead to ischemia in the brain and ultimately, 
deterioration of neurologic function. Initial studies of bevacizumab for the treatment of GBM 
showed clinical activity, decreased tumor size, increased progression-free survival (PFS) and 
a decreased steroid requirement for edema.39,40 The risk of cerebral hemorrhage appears to be 
independent of bevacizumab therapy.41   Many studies have investigated the effects of 
bevacizumab in the treatment radiation necrosis in a variety of brain tumors, and it has been 
shown to be highly effective.42-45,46 . These studies, while small, suggested that bevacizumab 
may have some inflammatory antitumor effects in addition to restoration of vascular 
permeability of the blood brain barrier, which might improve drug delivery. 
 
4.2.2. Rationale for Trial and Selected Subject Population 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been established.47 Antagonists of PD-1 and PD-L1 have been shown to 
produce significant clinical activity in patients with metastatic melanoma and NSCLC. Current 
research efforts with these agents are directed towards identifying patients who are most 
likely to benefit from treatment and also to develop combinations that increase clinical 
activity in both the ‘responsive’ and non-responsive populations. In almost all trials 
conducted to date, clinical response to PD-1/PD-L1 pathway antagonists has been strongly 
associated with pre-treatment tumor cell or tumor infiltrating lymphocyte (TIL) surface 
expression of PD-L1.48,49 Correlative data also suggest that in many patients, pre-treatment 
tumor PD-L1 expression is induced by adjacent cytokine-producing T-cells; however, a 
subset of tumors can express PD-L1 in the absence of T-cell infiltration, presumably as a 
result of aberrant T-cell signaling22. Lack of PD-L1 expression suggests that TILs are either 
unable to produce cytokines or cannot recognize tumor antigens. Tumors expressing PD-L1 
but lacking TIL, and conversely tumors containing non-cytokine producing TIL and absent 
PD-L1 expression, are unlikely to respond to PD-1/PD-L1 pathway antagonists. 
 
Even in the subgroup of patients that are most likely to respond to PD-1/PD-L1 pathway 
antagonists (i.e., with tumors containing TIL and associated PD-L1 expression), combination 
therapies may be necessary to achieve very high rates of durable complete responses. We 
know that pembrolizumab has activity in untreated brain metastases in a subset of patients, 
however, in our institutional experience from an ongoing phase II trial of pembrolizumab in 
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patients with melanoma or NSCLC and untreated brain metastases, some patients develop 
peri-lesional edema. This might limit the ability to administer pembrolizumab and often 
requires steroids. A number of lines of evidence support the synergistic effects of the 
combination of bevacizumab and pembrolizumab. We propose a phase 2 trial of these two 
agents in patients with metastatic melanoma and a pilot study of NSCLC patients with 
untreated brain metastases. We postulate that bevacizumab would substantially decrease the 
cerebral inflammatory effects of pembrolizumab and vasogenic edema, and may have some 
antitumor efficacy, as well. It is expected that the results of this trial will produce sufficient 
data to determine if a subsequent randomized trial is justified for further development of this 
combination in melanoma and NSCLC as well as other metastatic malignancies. 
 
 
4.2.3 Rationale for Dose Selection/Regimen/Modification 
 
An open-label Phase I trial (Protocol 001) has been conducted to evaluate the safety and 
clinical activity of single agent 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 pembrolizumab 
showed evidence of target engagement and objective evidence of tumor size reduction at all 
dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date. 
 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, 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. Pembrolizumab 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 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab 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. 2 mg/kg 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 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 will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe. 
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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. 
 
Rationale for administering pembrolizumab at a flat dose of 200mg every 3 weeks and 
bevacizumab at 7.5 mg/kg on day 1 of cycles 1, 2, 3 and 4: 
 
A phase II trial of pembrolizumab in patients with melanoma or NSCLC and untreated brain 
metastases conducted at Yale is ongoing. Interim analysis shows good anti-tumor activity. 
However, a number of patients have had to hold doses or take steroids due to peri-lesional 
edema. Our ongoing trial is utilizing a dose of 10mg/kg every 2 weeks. Safety MRI of the 
brain, which has been an important component of the trial, is done at 4 weeks and complete 
staging studies are conducted every 8 weeks. Prior trials using bevacizumab every 2 weeks 
for treating perilesional CNS edema have determined the safety and efficacy of a regimen of 
7.5mg/kg of bevacizumab every 2 weeks 50. For simplicity and convenience, we will 
administer both drugs every 3 weeks for the first four doses (on Day 1 of cycles 1, 2, 3 and 
4), while continuing pembrolizumab every 3 weeks. 
 
4.2.4. Rationale for Endpoints 
 
Efficacy Endpoints 
 
The primary purpose of this trial is to determine the activity of pembrolizumab and 
bevacizumab in combination in patients with untreated brain metastases from melanoma or 
NSCLC. The primary endpoint is therefore brain metastasis response rate. In our previous 
experience there is a small number of patients that have discordant responses in the brain and 
the body, and extra-cerebral response as well as overall response are therefore secondary 
efficacy endpoints. PFS and OS is expected to be shorter in this patient population with very 
advanced disease than in stage IV patients with melanoma or NSCLC without brain 
metastases, and determination of OS and PFS are secondary endpoints. We note that patients 
might receive additional active antineoplastic agents after progression on these drugs, 
resulting in more prolonged OS than expected for an untreated population of patients with 
brain metastases. 
 
Safety Endpoints 
 
One of the secondary endpoints is to determine the safety of pembrolizumab in combination 
with bevacizumab. A previous trial with pembrolizumab monotherapy in this population 
showed that many of these patients develop peri-lesional edema, and we expect that the 
combination will be better tolerated and result in a decrease in steroid use. 
 
Biomarker Research 
 
Biomarker studies (Section 11) will be conducted retrospectively with the goal of improving 
patient selection for this regimen. If predictive biomarkers or a predictive biomarker panel is 
identified, it  will  be  further  studied  prospectively  in  future  trials.  These  studies  are 
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considered exploratory at this juncture, and we note that the panel of biomarkers studied 
might change over time as the scientific field evolves. 
 
5.0 
METHODOLOGY 
 
5.1 Entry Criteria 
 
5.1.1. Diagnosis/Condition for Entry into the Trial 
 
Metastatic melanoma or non-squamous NSCLC with untreated brain metastases and/or post- 
treatment progressing brain metastases. 
 
5.1.2 Subject Inclusion Criteria 
 
1. Biopsy proven metastatic melanoma or non-squamous NSCLC with at least one untreated 
cerebral metastasis that is at least 5 mm AND twice the MRI slice thickness, but less than 
20 mm, that is asymptomatic and does not require local therapy at the time of enrollment 
(“clinically evaluable lesion(s)”). An untreated brain metastasis is defined as a lesion not 
present at the time of whole brain radiation therapy or included in a stereotactic 
radiotherapy field (or within 2mm of a treated lesion), or any lesion that is new or 
unequivocally progressing since prior radiation therapy. All MRIs at screening will be 
reviewed centrally at Yale for sign off of eligibility. 
2. Age ≥18 
3. ECOG performance status < 2 
4. Any number of previous treatments with the exception of previous inhibitors of PD-1, 
PD-L1, or PD-L2. Other prior systemic therapies must have been administered at least 2 
weeks before administration of pembrolizumab; the exception to this  is  ipilimumab which 
must have been administered at least 4 weeks prior to the start of pembrolizumab. Patients 
are not required to have had prior systemic therapy. 
5. Life expectancy of at least 3 months 
6. A history of previously treated brain metastases is allowed, provided that at least 7 days 
have lapsed between radiation and initiation of pembrolizumab.   Any brain metastasis 
≥20mm or causing symptoms must be treated with local therapy (i.e. radiation or surgical 
resection, as clinically appropriate) prior to study enrollment. Any lesion present at the 
time of WBRT or included in the stereotactic radiotherapy field (or within 2mm of the 
treated lesion) will NOT be considered evaluable unless it is new or documented to have 
progressed since treatment. 
7. PD-L1 expression >1% in tumor tissue from any site is required for patients with NSCLC. 
Tumor tissue can be archival if no intercurrent systemic therapy was administered, 
however if no archival tissue is available or if intercurrent systemic therapy was 
administered, then a biopsy must be obtained for PD-L1 testing. PD-L1 expression must 
be obtained via central and/or local testing of PD-L1 IHC by any FDA-approved assay or 
an assay performed in a CLIA-certified laboratory. PD-L1 expression is not required for 
patients with melanoma. 
8. All patients are required to submit a tumor specimen for analysis (brain or extra- cerebral). 
A formalin-fixed paraffin-embedded (FFPE) tissue block, or a 4mm punch from an 
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FFPE block must be submitted.  If it is not possible to safely obtain a biopsy due 
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to anatomic location of tumors, and no prior tissue is available, this requirement may be 
waived upon discussion with the study PI or co-PI. 
 
9. Patients must have normal organ and marrow function as defined below: 
System 
Laboratory Value 
Hematological 
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 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
Prothrombin Time (PT) 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
Activated Partial Thromboplastin Time 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
(aPTT) or Partial Thromboplastin Time 
as long as PT or PTT is within therapeutic range of intended use 
(PTT) 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours 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. 
 
11. 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 5.6.2— 
Contraception). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
 
12. 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. 
 
5.1.3 Subject Exclusion Criteria 
 
1. Symptomatic brain metastases. Any neurologic symptoms present must have resolved 
with local therapy by the time of administration of study drug. 
2. Patients with brain metastases for whom complete surgical resection is clinically 
appropriate. 
3. Patients with lung cancer with squamous histology.
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4. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to 
start of treatment or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to a previously administered agent. Previous radiation to extracranial sites may be 
completed at any time prior to initiation of pembrolizumab. 
a. Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy. 
b. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the 
inclusion requirements for laboratory parameters. 
5. Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent. 
6. The use of corticosteroids to control cerebral edema or treat neurologic symptoms will 
not be allowed, and patients who previously required corticosteroids for symptom control 
must be off steroids for at least 1 week prior to treatment on day 1 of cycle 1. Low-dose 
steroid use (≤10 mg of prednisone or equivalent) as corticosteroid replacement therapy is 
allowed 
7. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
8. Presence of leptomeningeal disease 
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 (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
10. Pregnancy or breast feeding. Should a woman become pregnant or suspect  she  is pregnant 
while participating in this study, she should inform her treating physician immediately. 
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with pembrolizumab, breastfeeding must be 
discontinued if the mother is treated with pembrolizumab. 
11. Patients may not be receiving any other investigational agents and may not have 
participated in a study of an investigational agent or using an investigational device 
within 4 weeks of the first dose of treatment. 
12. Either a concurrent condition (including medical illness, such as active infection 
requiring treatment with intravenous antibiotics or the presence of laboratory 
abnormalities) or history of a prior condition that places the patient at unacceptable risk if 
he/she were treated with the study drug or a medical condition that confounds the ability 
to interpret data from the study. 
13. Concurrent, active malignancies in addition to those being studied (other than cutaneous 
squamous cell carcinoma or basal cell carcinoma) 
14. Patients with active hemoptysis. 
15. Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted 
medical devices).  An MRI safety questionnaire is required prior to MR imaging. 
16. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
17. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C 
(HCV) infection. 
18. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
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19. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg 
and/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achieve 
these parameters is allowable. 
20. History  of  myocardial  infarction  or  unstable  angina  within  3 months   prior   to Cycle 
1, Day 1 
21. History of stroke or transient ischemic attack within 3 months prior to Cycle 1, Day 1 
22. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1 
23. Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of 
therapeutic anticoagulation). Any history of significant bleeding or thrombosis should be 
discussed with the study PIs. 
24. Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of dipyramidole, 
ticlopidine, clopidogrel, or cilostazol 
25. Warfarin is not permitted. Prophylactic or therapeutic use of low molecular-weight 
heparin (e.g., enoxaparin), direct thrombin inhibitors or Factor Xa inhibitors (Direct or 
Indirect) are permitted. 
26. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 
6 months prior to Cycle 1, Day 1 
27. Serious, non-healing or dehiscing wound 
28. Proteinuria > 2.0 g of protein in a 24-hour urine collection. All patients with 2 protein on 
dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein. 
29. Has a history of (non-infectious) pneumonitis that required steroids, current pneumonitis 
or evidence of interstitial lung disease. 
 
 
5.2 Trial Treatments 
 
The treatments to be used in this trial are pembrolizumab 200mg every 3 weeks and 
bevacizumab 7.5mg/kg on day 1 of cycle 1, 2, 3, and 4 (or alternative cycles if bevacizumab 
is held during these cycles). Each cycle is 3 weeks. Our intent is to treat with the combination 
of pembrolizumab and bevacizumab for four cycles and pembrolizumab monotherapy for up 
to 2 years. 
 
5.2.1 Dose Selection/Modification 
 
 Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 4.0— 
Background and Rationale. 
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual. 
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Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab and combination therapy 
 
AEs associated with pembrolizumab exposure, including coadministration with additional compounds, 
may represent an immunologic aetiology. These immune-related AEs (irAEs) may occur shortly after the 
first dose or several months after the last dose of pembrolizumab/combination treatment and may affect 
more than one body system simultaneously. Therefore, early recognition and initiation of treatment is 
critical to reduce complications.  Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Dose modification and toxicity management guidelines 
for irAEs associated with pembrolizumab/combination treatment are provided in Table 1. 
 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to a single 
component is likely to be difficult.  Therefore, while the investigator may attribute a toxicity event to the 
combination, to bevacizumab alone or to pembrolizumab alone, for adverse events listed in Table 1, both 
interventions must be held according to the criteria in Table 1 Dose Modification and Toxicity 
Management Guidelines for Immune-Related Adverse Events Associated with Pembrolizumab. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-related, both 
interventions should be held according to recommended dose modifications. 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab in 
this study, as described in Table 1. 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must be 
discontinued from all study interventions. 
• If the toxicities do resolve and conditions are aligned with what is defined in Table 1, the combination 
of Bevacizumab and pembrolizumab may be restarted at the discretion of the investigator. In these cases 
where the toxicity is attributed to the combination or to Bevacizumab alone, re-initiation of 
pembrolizumab as a monotherapy may be considered at the principal investigator’s discretion. 
 
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 of the scheduled interruption, unless 
otherwise discussed with the PIs. The reason for interruption should be documented in the patient's study 
record. 
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Table 1: Dose Modification Guidelines for Drug-Related Adverse Events for Pembrolizumab monotherapy and IO 
Combinations 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 


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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 


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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or 
DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 


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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Grade 3 
Withhold or 
discontinue based 
on the event e  
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 


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Dose Selection/Modification of Bevacizumab 
 
No reductions in bevacizumab dose are allowed in this study.  Modification to 
bevacizumab administration should be done according to the label and per 
institutional guidelines. If adverse events occur that necessitate holding 
bevacizumab, the weight-based dose in mg/kg will remain unchanged after 
treatment resumes. 
 
Patients who discontinue bevacizumab transiently or permanently for adverse 
events may continue on single-agent pembrolizumab until disease progression. 
 
For non irAEs, temporary suspension of bevacizumab must occur if a patient 
experiences a serious adverse event or a Grade 3 or 4 non-serious adverse event 
assessed by the investigator as related to bevacizumab.  If the event resolves to 
Grade ≤ 1, bevacizumab may be restarted at the same dose level. 
 
The appropriate interval between the last dose of bevacizumab and major surgery 
is unknown.  Because bevacizumab has a half-life of approximately 21 days, 
elective surgery should be delayed whenever possible. Re-initiation of 
bevacizumab should occur after wounds have healed.  Re-initiation of 
bevacizumab after surgery requires approval of the principal investigators. 
 
Infusion of bevacizumab should be interrupted in patients who develop dyspnea or 
clinically significant hypotension. Patients who experience an NCI CTCAE Grade 3 or 
4 allergic reaction/hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab treatment.  
If possible, a sample for ATA assessment will be collected at the time of 
discontinuation. 
 
Bevacizumab infusion should be slowed to ≤ 50% or interrupted for patients who 
experience any infusion-associated symptoms not specified above.  If the 
infusion is interrupted, it may be resumed at ≤ 50% of the rate prior to the 
reaction after the patient’s symptoms have adequately resolved and increased in 
50% increments up to the full rate if well tolerated. Infusions may be restarted at 
the full rate during the next cycle. 
 
Patients who develop Grade 4 toxicities (not immune related) related to bevacizumab for 
> 21 days should permanently discontinue bevacizumab. 
 
If bevacizumab is held due to toxicity that resolves, it can be initiated during any subsequent 
cycle for a total number of four cycles of bevacizumab per patient. 
 
 
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Table 2: Dose Modification Guidelines for Non Immune related Drug‐Related Adverse 
Events for Bevacizumab 
 
 
Event 
Action to Be Taken 
Hypertension 
Grade 1 (asymptomatic, transient [< 24 hr] 
blood pressure increase by > 20 mmHg 
(diastolic) or to > 150/100 mmHg if previously 
within normal limits) 
No bevacizumab dose modifications. 
Grade 2 (recurrent or persistent [> 24 hr] or 
symptomatic increase by > 20 mmHg (diastolic) 
or to > 150/100 mmHg if previously within 
normal limits) 
Hold bevacizumab. Start antihypertensive 
therapy per institutional guidelines. After blood 
pressure is < 150/100 mmHg, patient may 
continue bevacizumab therapy. 
Grade 3 
Requires more than one antihypertensive drug 
or more intensive therapy than previously: If 
not controlled to 150/100 mmHg with 
medication, discontinue bevacizumab. 
Grade 4 (including hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
Grade 1 or 2 non-pulmonary or non-CNS 
events 
No bevacizumab modifications. 
Grade 3 non-pulmonary or non--brain or 
non-spinal cord hemorrhage 
Hold bevacizumab until all of the following 
criteria are met: 
• 
The bleeding has resolved and 
hemoglobin is stable. 
• 
There is no bleeding diathesis that would 
increase the risk of therapy. 
• 
There is no anatomic or pathologic 
condition that significantly increases the 
risk of hemorrhage recurrence. 
Patients who experience a repeat Grade 3 
hemorrhagic event will be discontinued from 
bevacizumab. 
Grade 4 non-pulmonary or non-brain or 
non-spinal cord hemorrhage 
Discontinue bevacizumab. 
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Event 
Action to Be Taken 
Grade 1 pulmonary or brain or spinal cord 
hemorrhage 
Hold bevacizumab until all of the following 
criteria are met: 
• 
The bleeding has resolved and hemoglobin 
is stable. 
• 
There is no bleeding diathesis that would 
increase the risk of therapy. 
• 
There is no anatomic or pathologic 
condition that significantly increases the 
risk of hemorrhage recurrence. 
Grade 2, 3, or 4 pulmonary hemorrhage 
Grade 2, 3 or 4 brain hemorrhage 
Discontinue bevacizumab. 
Discontinue bevacizumab until all hemorrhagic 
lesions have undergone local therapy and upon 
discussion with the study PIs 
Venous thromboembolic event 
Grade 1 or 2 
No bevacizumab modifications. 
Grade 3 or 
asymptomatic Grade 4 
If the planned duration of full-dose 
anticoagulation is < 2 weeks, bevacizumab 
should be held until the full-dose 
anticoagulation period is over. If the planned 
duration of full-dose anticoagulation is > 2 
weeks, bevacizumab may be resumed after 
2 weeks of full-dose anticoagulation if all of the 
following criteria are met: 
• 
The patient must have an in-range INR 
(usually between 2 and 3) if on warfarin; 
LMWH, warfarin, or other anticoagulant 
dosing must be stable prior to restarting 
study treatment. 
• 
The patient must not have had a Grade 3 
or 4 hemorrhagic event while on 
anticoagulation. 
Symptomatic Grade 4 
Discontinue bevacizumab. 
Arterial thromboembolic event 
(new onset, worsening, or unstable angina, 
myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial 
thromboembolic event) 
Any grade 
Discontinue bevacizumab. 
Congestive heart failure 
(left ventricular systolic dysfunction) 
Grade 1 or 2 
No bevacizumab modifications. 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 
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Event 
Action to Be Taken 
Proteinuria 
Grade 1 (urine dipstick 1 + or urine collection 
0.15 to 1.0 g/24 hr) 
No bevacizumab modifications. 
Grade 2 (urine dipstick 2 + to 3 + or urine 
collection > 1.0 to 3.5 g/ 
24 hr) 
For 2 + dipstick, may administer bevacizumab 
and obtain 24-hour urine prior to next dose. 
For 3 + dipstick, obtain 24-hour urine prior to 
administration of bevacizumab. 
Hold bevacizumab for proteinuria >2 g/24 hr and 
resume when proteinuria is ≤ 2 g/24 hr.a 
Grade 3 
(urine dipstick 4 + or urine collection > 3.5 g/24 
hr) 
Hold bevacizumab. Resume when proteinuria 
is ≤ 2 g/24 hr.a 
Grade 4 
(nephrotic syndrome) 
Discontinue bevacizumab. 
GI perforation 
Any grade 
Discontinue bevacizumab. 
Fistula 
Any grade tracheoesophageal fistula 
Discontinue bevacizumab. 
Grade 4 fistula (other than tracheoesophageal) 
Discontinue bevacizumab. 
Bowel obstruction 
Grade 1 
Continue patient on study for partial obstruction 
not requiring medical intervention. 
Grade ≥ 2 
Discontinue bevacizumab. 
Wound dehiscence 
Any grade 
(requiring medical or surgical therapy) 
Discontinue bevacizumab. 
Reversible posterior leukoencephalopathy 
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab. 
CNS = central nervous system; GI = gastrointestinal; LMWH = low molecular-weight heparin. 
a   All proteinuria values are from 24-hour urine collection. 
 
 
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5.2.2 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. 
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. 
 
5.2.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 
2 years or until one of the following criteria applies: 
 
1 
Disease progression and absence of clinical benefit 
2 
Symptomatic deterioration of health status without objective evidence of disease 
progression. Every effort should be made to document objective progression of 
disease in such cases. 
3 
Imminent risk in the case of progressing lesion or new/worsening edema seen on 
brain MRI 
4 
Unmanageable toxicity most probably attributed to pembrolizumab 
5 
Development of intercurrent illness limiting the ability to comply with study or the 
development of uncontrolled concurrent illness that prevents further administration 
of treatment or confound the ability to interpret data 
6 
General or specific  changes  in  the  patient’s  condition  rendering  the  patient 
unacceptable for further treatment in the judgment of the investigator 
7 
Patient request for discontinuation, patient withdrawal from study, or patient lost to 
follow up 
8 
Development of neurologic or systemic complications following local therapy to any 
lesion 
9 
Death 
10 
Study termination by sponsor 
 
 
 
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5.2.4 Treatment Beyond Progression 
 
If radiologic imaging shows PD, tumor assessment should be repeated <4 weeks later in 
order to confirm PD with the option of continuing treatment while awaiting radiologic 
confirmation of progression. If repeat imaging shows a reduction in tumor burden compared 
to the initial scan demonstrating PD, treatment may be continued as per treatment calendar. 
If repeat imaging confirms progressive disease, subject will be discontinued from study 
therapy unless the investigator believes that the patient is deriving benefit. Patients may 
continue treatment with pembrolizumab and/or bevacizumab beyond PD by RECIST 1.1 (in 
the body) or mRECIST in the brain, if they are determined by the investigator to be deriving 
clinical benefit from treatment and they continue to meet all other criteria for treatment. 
Patients who have rapid progression of disease or clinical deterioration will be removed from 
study. The decision to continue treatment beyond initial progression should be discussed 
with the study PIs. 
 
Additionally, in cases where the majority of the disease is stable or responding, and 
progressing lesions can be controlled with local therapy (i.e. resection or radiotherapy), the 
patient may be continued on trial following local therapy. 
 
5.2.5 Duration of Follow-up 
 
Patients who discontinue early or who complete the study treatment period in full will be 
followed for survival after removal from study until death. See Trial Flow Chart (Section 6.0) 
for more details. 
 
5.3 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 investigator should discuss any questions regarding this 
with the Principal Investigator. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. 
 
5.3.1 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 30  days  after  the  last  dose  of  trial  treatment  should  be  recorded.    Concomitant 
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medications administered after 30  days  after  the  last  dose  of  trial  treatment  should  be 
recorded for SAEs and ECIs as defined in Section 7.6.3.1. 
 
5.3.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial as listed below: 
 
• Antineoplastic systemic chemotherapy or biological therapy < 2 weeks prior to 
treatment Day 1 
• Immunotherapy not specified in this protocol < 2 weeks prior to treatment Day 1 
• Investigational agents other than pembrolizumab or bevacizumab < 2 weeks prior to 
treatment Day 1 
• Radiation therapy 
o Note: Radiation therapy to individual symptomatic solitary extra-cerebral 
lesions or to the brain may be allowed at the investigator’s discretion. This 
should be discussed with the study PIs. 
• 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 may be approved after consultation with the PI. 
• Anticoagulation other than low molecular weight heparin, direct thrombin inhibitors, 
or Factor Xa inhibitors (Direct or Indirect). 
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. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 Local Therapy 
 
Local therapy for brain metastases: 
 
Local surgical therapy in the form of craniotomy or LITT (laser interstitial thermacoagulation 
therapy) will be performed when clinically appropriate prior to initiating systemic therapy. 
Patients will be required to provide tissue for research when available. At any time point
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throughout the study, local therapy (surgery, radiotherapy or LITT) will be administered to a 
lesion that becomes clinically concerning if deemed necessary by the investigators. This can 
be followed by continuation on treatment, provided that the patient is otherwise benefiting 
from therapy. Approval from the study PI or co-PIs is required to continue treating the 
patient on pembrolizumab and bevacizumab. A brain metastasis that has been treated locally 
will not be considered evaluable for response and will not be included when calculating the 
sum of largest dimensions. If the treated lesion constitutes > 25% of the target lesions (for 
example, if one of three target lesions is treated locally), this will be considered progressive 
disease. If >75% of the baseline lesions are not treated with local therapy and evaluable by 
imaging, the patient will be considered evaluable, and response for the primary endpoint 
analysis will be assessed based on the remaining lesions. Additional response evaluation will 
be performed; those patients who require local therapy due to unequivocal growth while on 
study will be considered as having PD at the time of local therapy. Lesions requiring local 
therapy due to hemorrhage or edema will be considered unevaluable. 
 
Local therapy for extra-cerebral metastases: 
 
Local surgery or radiation therapy (if indicated for palliative measures only after discussion 
with the study PI or co-PIs) may be permitted and the patient can continue to receive 
pembrolizumab provided there is otherwise evidence of clinical benefit from treatment (i.e. 
stable disease or response in measurable lesions). The criteria applied for assessing brain 
metastasis response will be applied to extra-cerebral metastases as well. 
 
5.5 Rescue Medications & Supportive Care 
 
5.5.1 Supportive Care Guidelines 
 
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 along with the dose modification 
guidelines in Table 1. 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.). 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 3. 
 
Table 3: 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 therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications 
indicated for < =24 hrs 
Stop Infusion 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, 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. 
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). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
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. For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov 
 
 
 
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5.5.2 Supportive Care Guidelines for Events of Clinical Interest (ECIs) and Immune- 
related Adverse Events (irAEs) 
 
Events of clinical interest of a potential immunologic etiology (irAEs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the pembrolizumab, its 
mechanism of action, and reported experience with immunotherapies that have a similar 
mechanism of action. Special attention should be paid to AEs that may be suggestive of 
potential irAEs. An irAE can occur shortly after the first dose or several months after the last 
dose of treatment. 
 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAEs. Subjects 
who develop a Grade 2 or higher irAEs should be discussed immediately with the Merck 
Clinical Monitor. 
 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 4. 
 
Table 4 General Approach to Handling irAEs 
 
irAEs 
Withhold/Discontinue 
    pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic 
treatment 
Grade 2 
May withhold 
pembrolizumab 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment 
Grade 3  
and Grade 4 
 Withhold pembrolizumab 
   
Discontinue if unable to 
reduce corticosteroid dose to 
< 10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated 
in addition to appropriate 
symptomatic treatment. May utilize 1 
to 2 mg/kg prednisone or equivalent 
per day. 
Steroid taper should be considered 
once symptoms improve to Grade 1 
or less and tapered over at least 4 
weeks. 
 
 
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5.5.3. Supportive Care Guidelines for Pneumonitis 
 
Subjects with grade 2 pneumonitis (symptomatic pneumonitis requiring medical 
intervention) should immediately stop receiving pembrolizumab and have an evaluation. 
The evaluation may include bronchoscopy and pulmonary function tests to rule out other 
causes such as infection. If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in Table 5 and follow-up will be as 
routine for AEs associated with study drug including monitoring until full resolution of the 
AEs/pneumonitis. 
 
Table 5. Recommended Approach to Handling Pneumonitis 
 
Study drug 
associated 
pneumonitis 
Withhold/Discontinue 
pembrolizumab? 
Supportive 
Care 
Grade 1 
(asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold 
pembrolizumab, 
may return to 
treatment if 
improves to Grade 1 
or resolves within 
12 weeks 
Systemic corticosteroids are indicated. 
Taper as indicated. 
Grade 3 and Grade 4 Discontinue 
pembrolizumab 
Systemic corticosteroids are indicated. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
 
• First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis ≥ Grade 2 
 
5.6 Diet/Activity/Other Considerations 
 
5.6.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
 
 
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5.6.2 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. Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be 
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
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, they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.6.2—Reporting of 
Pregnancy and Lactation to the Sponsor and to Merck. If there is any question that a subject 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
 
5.6.3 Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with bevacizumab and/ or 
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 7.6.2—Reporting of Pregnancy and Lactation to the Sponsor 
and to Merck. 
 
 
 
 
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5.6.4 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. 
 
5.7 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 investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details 
regarding discontinuation or withdrawal are provided in Section 7.4—Other Procedures. 
 
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 radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 
5.2.3—Duration of Therapy 
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 5.2.4—Treatment Beyond Progression 
• Unacceptable 
adverse 
experiences 
as 
described 
in 
Section 
5.2.1—Dose 
Selection/Modification 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed  24  months  of  uninterrupted  treatment  with  pembrolizumab  or  35 
administrations of study medication, whichever is later. 
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 if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 5.7.1—Discontinuation of Study 
Therapy after CR 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.5 (Visit Requirements). 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 7.6.3.1). 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 
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end of the study, whichever occurs first. 
 
5.7.1 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 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab 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
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6.0 TRIAL FLOW CHART 
 
6.1  Study Flow Chart 
 
Screening evaluations are to be conducted within 28 days prior to start of systemic therapy. 
Scans must be done within 28 days prior to the start of systemic therapy and after other 
therapy not specified in this protocol is stopped. Screening labs must be done within 10 days 
of Cycle 1 Day 1. In the event that the participant’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
All assessments must be performed prior to administration of any study medication. All study 
assessments and medications should be administered within ± 3 days of the protocol- 
specified date, unless otherwise noted. 
 
 
Screening 
Visit 
On‐Study Visits 
Follow‐up 
Visit 
Long Term 
Follow‐up 
Day ‐28 
to ‐1 
Day 1 of 
each 
Cycle 
Day 1 of 
Cycles 1, 
2, 3, and 
4 
Day 1 
Cycles 3 
and 5 
Day 1 
Cycle 8, 
and every 
9 weeks 
thereafter 
Day 28 +/‐ 
7 days 
from last 
study 
treatmenti 
Every 3 
months +/‐ 
14 days 
after the 
follow‐up 
visit 
Informed Consent 
X 
History/Full Physical 
Exam 
X 
X 
X 
Height/Weight/Vital 
SignsA 
X 
X 
X 
Performance Status 
X 
X 
X 
CBC, serum 
chemistry, liver 
function tests, LDHB 
X 
X 
X 
INR or PT & aPTT or 
PTT 
X 
Urinalysis 
X 
X 
X 
TSH, free T3, free T4 
X 
X 
NSCLC patients: 
Determination of 
PD‐L1 expression in 
tumorN 
X 
 
 
 
 
 
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Screening 
Visit 
On‐Study Visits 
Follow‐up 
Visit 
Long Term 
Follow‐up 
Day ‐28 
to ‐1 
Day 1 of 
each 
Cycle 
Day 1 of 
Cycles 1, 
2, 3, and 
4 
Day 1 
Cycles 3 
and 5 
Day 1 
Cycle 8, 
and every 
9 weeks 
thereafter 
Day 28 +/‐ 
7 days 
from last 
study 
treatmenti 
Every 3 
months +/‐ 
14 days 
after the 
follow‐up 
visit 
Plasma and PBMCs 
for correlative 
studies 
XH 
X 
XO 
Obtain tumor 
specimen for 
correlative studies 
(Refer to Section 
11.1)J,M 
X 
Pregnancy TestC 
X 
X 
CT chest/abdomen 
(plus pelvis if 
disease is present) 
X 
XD 
XD 
X E 
Brain MRI 
X F 
XG 
XG 
X E 
Selection of 
“clinically evaluable 
lesion(s)” 
X 
Review concomitant 
medicationsL 
X 
X 
X 
Smoking Status 
X 
Adverse events 
assessment 
X 
X 
Administration of 
pembrolizumab 
X 
Administration of 
bevacizumabK 
X 
Survival Follow‐up 
X 
AIncludes blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. Height at 
screening only. 
BIncludes CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, glucose, calcium), 
magnesium, phosphate, liver function tests (albumin, total protein, alkaline phosphatase, total bilirubin, 
ALT, AST), LDH 
CPregnancy test (serum or urine) is required for women of childbearing potential only on Day 1 of each cycle 
prior to treatment administration. 
DCT scan of the chest/abdomen/pelvis can be performed +/‐ 5 days. Response evaluation is performed using 
RECIST 1.1 
ECT scan of the chest/abdomen/pelvis and brain MRI should continue every 9 weeks (+/‐ 5 days) until 
progression, withdrawal of consent, death, lost to follow‐up, or start of a subsequent anti‐cancer therapy 
 
FAll MRIs will be reviewed centrally by the investigators at Yale prior to confirmation of eligibility. For patients 
who will undergo local therapy on trial, investigators must identify a “clinically evaluable lesion(s)”. Brain MRI 
must be done within 28 days of intervention and should be repeated if more than 28 days will have lapsed by 
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the start of systemic therapy. For patients who previously underwent local therapy to a brain lesion and have 
tumor tissue available for analysis, only identification of “clinically evaluable lesion(s)” is necessary. 
GBrain MRI can be performed +/‐ 5 days. CNS response evaluation is performed using mRECIST criteria. MRIs 
should be done with perfusion, if possible. 
H Can be done at screening or any time prior to Cycle 1 Day 1 dosing 
iFollow‐up Visit should be 28 days after the last dose of trial treatment or before the initiation of a new anti‐ 
cancer treatment, whichever comes first. 
JIf a biopsy is done at any point during the subject’s participation in the trial, a sample of the tumor tissue will 
be taken for research. 
K If bevacizumab is held at any point it can be reinitiated when deemed safe for a total of four doses per 
patient 
L At screening, medications taken in the past 28 days need to be recorded, including over‐the‐counter 
medications and herbal supplements. Information on concomitant therapy including radiation therapy should 
be collected as well. 
M For all patients, archival tumor tissue will be requested. If archival tissue is not available patients on the 
NSCLC arm, or if intercurrent systemic therapy has been administered since the archival tissue was obtained, 
patients will need to have a fresh biopsy. 
N Subjects with PD‐L1 test results from outside the study are not required to undergo repeat testing for 
determination of eligibility as long as no systemic therapy was administered after the test results were 
obtained. Central and/or local testing of PD-L1 IHC by any FDA-approved assay or an assay performed in a CLIA 
laboratory is acceptable. If patients do not undergo PD‐L1 testing to determine eligibility, fresh or archival tissue 
is still required at study entry for correlative studies. 
O Plasma and PBMC are to be collected during the participant’s end of treatment visit in addition to those 
previously outlined. 
 
 
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7.0 TRIAL PROCEDURES 
 
The Trial Flow Chart - Section 6.0 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. 
 
7.1 Administrative Procedures 
 
7.1.1  Informed Consent 
 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
7.1.1.2 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. 
 
7.1.2 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. 
 
7.1.3 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 
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for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
 
7.1.4 Prior and Concomitant Medications Review 
 
 
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 28 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. 
 
 
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 7.6.3.1—Serious Adverse Events. 
 
7.1.5  Disease Details and Treatments 
 
Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
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. 
 
 
7.2 Clinical Procedures/Assessments 
 
7.2.1 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 5.0 (see Section 13.2). Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
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Please refer to section 7.6 for detailed information regarding the assessment and recording of 
AEs. 
 
7.2.2 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, on day 1 of each cycle, 
and at the follow-up visit. 
 
7.2.3 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. 
 
7.2.4 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 6.0). Vital signs should include temperature, pulse, respiratory 
rate, oxygen saturation, weight and blood pressure. Height will be measured at screening 
only. 
 
7.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (see Section 13.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart. 
 
7.2.6 Tumor Imaging and Assessment of Disease 
 
Tumor imaging and assessment of disease will be performed every 6 weeks for the first 3 
months of treatment, and then every 9 weeks thereafter. See section 12.0—Measurement of 
Response—for details. 
 
 
7.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
Before initiation of systemic therapy, a core biopsy will be obtained. This can be bypassed if 
there is archival tissue available. For NSCLC patients, it is acceptable to use archived tumor 
tissue rather than obtain a new biopsy to assess for PD-L1 status only if no intercurrent 
therapy was administered. In patients undergoing fresh biopsy, a minimum of two cores is 
required, and these will be formalin fixed and embedded in paraffin. These tissues will be 
stored for correlative studies mentioned below. Please see the Procedures Manual for tissue 
requirements and handling of tissue. 
 
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The stored tissue specimens will be analyzed at Yale University. In the context of a non- 
randomized trial, lack of validated assays and inability to identify and isolate tumor antigen 
specific T-cells, all correlative studies are considered exploratory. These are exploratory 
analyses that will be studying the tumor microenvironment and PBMC. Within the tumor 
microenvironment we will be assessing CD8+/IFNg+, PD-L1 expression, the ratio of 
CD8+/Treg and other assays (please see correlative section below). Within the PBMC, we 
will be studying CD8+/CD127+/PD-1+ (or PD-L1+)/IFNg+ cells, and PD-1/PD-L1 expression 
on central central memory and effector memory CD4+ subsets. Plasma will be stored for 
cytokine analyses. 
 
See section 11.0—Biomarker Studies—for details. 
 
7.3 Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6. 
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Table 6 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 
Total triiodothyronine (T3) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
Free tyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Carbon Dioxide 
results are noted 
Blood for correlative studies 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Uric Acid 
Partial Thromboplastin Time (PTT) or 
Activated Partial Thromboplastin Time 
(aPTT) 
Calcium 
Chloride 
Glucose 
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. 
 
 
 
 
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Laboratory tests for screening 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. 
 
7.4 Other Procedures 
 
7.4.1 Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable 
activities scheduled for the final trial visit should be performed at the time of 
discontinuation. Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.6—Assessing and Recording Adverse Events. 
Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if 
they meet the criteria specified in Section 5.7.1—Discontinuation of Study Therapy 
after CR. After discontinuing treatment following assessment of CR, these subjects 
should return to the site for a Safety Follow-up Visit (described in Section 7.5.1) 
and then proceed to the Follow-Up Period of the study (described in Section 7.5.2). 
 
7.5 Visit Requirements 
 
Visit requirements are outlined in Section 6.0—Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.0—Trial Procedures. 
 
7.5.1 Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 28 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. 
 
7.5.2 Follow-up Visits 
 
Subjects who discontinue trial treatment for a reason other than disease progression 
will move into the Follow-Up Phase and should be assessed every 9 weeks (± 7 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, or end of the study. Information regarding post- 
study anti-neoplastic treatment will be collected if new treatment is initiated. 
Survival Follow-up. 
 
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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. 
 
7.6 Assessing and Recording Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, 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, 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 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 will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and 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 7.6.3.1. 
 
 
 
 
 
 
 
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7.6.1 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). 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. Appropriate supportive treatment should be provided if clinically 
indicated. 
 
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) 
 
7.6.2 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), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days of completing the trial completing the trial, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. All subjects and female partners of male subjects who become pregnant 
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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7.6.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
 
Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck’s 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 a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
 
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 from the time the consent is signed through 90 days following cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether 
or not related to Merck product, must be reported within 24 hours to the Sponsor 
and within 2 working days to Merck Global Safety. 
 
Non-serious Events of Interest will be forwarded to Merck GS and will be handled 
in the same manner as SAEs. 
 
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 outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck. 
 
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.   
 
All subjects with serious adverse events must be followed up for outcome. 
 
 
 
 
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7.6.4 Reporting to the Food and Drug Administration 
 
This study will be conducted under an IND (Investigational New Drug application) that will 
be held by Harriet Kluger, M.D. The Principal Investigator will report in an expedited 
manner all SAEs meeting the criteria of “serious”, “unexpected” and “related to study 
treatment”.  Written safety reports will use a MedWatch Form 3500A.  A “fillable pdf” 
 
version with instructions is available at: http://www.fda.gov/medwatch/safety/FDA- 
3500A_Fillable_08-16-2006.pdf 
 
There are two types of expedited safety reports to the FDA: 
 
1. 7-Calendar-Day FDA Telephone or Fax Report:  The sponsor-investigator will 
directly notify the FDA, within 7 calendar days after his initial receipt of the 
information, of any adverse event that is ALL of the following: 
Death or immediately life-threatening 
Unexpected 
Associated with the use of study drug 
 
 
Notification to the FDA will be made directly to the new drug review division in the Center 
for Drug Evaluation and Research or in the product review division for the Center for 
Biologics Evaluation and Research, whichever was responsible for the review of the IND. 
[21CFR312.32(c)] A written report of the event is to follow within 15 calendar days. 
 
2. 15-Calendar-Day FDA Written Report:  The sponsor-investigator will directly 
notify the FDA within 15 calendar days of any adverse event that is ALL of the 
following: 
Serious (due to non-fatal and non-life threatening criteria) 
Unexpected 
Associated with the use of study drug 
Note: Serious Adverse Events which do not meet the criteria for expedited reporting will be 
reported to the FDA in the IND Annual Report. 
 
7.6.5 Reporting to the Yale Human Investigation Committee 
 
Sites will report to their IRB per local policy 
 
 
 
 
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7.6.6 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 5.0. 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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Table 7 
Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V50 
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 Merck 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
Is a new cancer; (that is not a condition of the study) or 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. 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. 
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 the Merck product to be discontinued? 
Relationship to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the 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 the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the 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 the 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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Relationship 
to Merck 
product 
(continued) 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable. The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
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7.6.7 Sponsor Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
 
7.6.8 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor. 
 
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 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 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent). 
 
Events of clinical interest for this trial include: 
• an overdose of Merck product, as defined in Section 7.6.1 – 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. 
 
• 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. 
 
8.0 STATISTICAL ANALYSIS PLAN 
 
8.1 Statistical Design 
 
This is a phase II study of patients with melanoma and a pilot study of NSCLC patients who 
have untreated brain metastases. Subjects must have at least 1 brain lesion that does not 
require immediate local therapy and can be assessed for response. Criteria for response are 
defined in Section 12.0. 
 
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The primary goal of this study is to determine the efficacy of pembrolizumab plus 
bevacizumab in patients with untreated brain metastases from melanoma or NSCLC. The 
primary endpoint is the brain metastasis response rate (BMRR). A drug with minimal 
activity would be expected to have a BMRR of 10%. The study was initially designed so that 
pembrolizumab and bevacizumab would be considered worthy of further study in patients 
with untreated brain metastases if its true BMRR is similar to the systemic response rate with 
pembrolizumab, which is 34% for melanoma and 25% for NSCLC. For this to occur, the 
study was originally planned to enroll a total of 53 eligible patients (20 with melanoma, 33 
with NSCLC). In the first stage of a Simon’s optimal two stage design, it was planned that 9 
patients with melanoma and 16 patients with NSCLC would be enrolled. If 2 or more of 9 
evaluable melanoma patients had a response in brain metastases, accrual would continue to 
enroll another 11 patients to that cohort. Similarly, in the NSCLC cohort, if a brain metastases 
response were to be seen in 2 more of the 16 eligible NSCLC patients, another 17 patients were 
planned to be accrued. 
 
Prior to February 2019, 20 patients were accrued to the melanoma cohort of the trial. We 
observed 11 brain metastasis responses in 20 patients (ORR=0.55, 95% CI: 0.32-0.77). For the 
melanoma cohort, we aimed to generate evidence that the true response rate of pembrolizumab 
plus bevacizumab in patients with untreated brain metastases is more than 30% and we 
expanded the cohort by another 20 patients. For the NSCLC cohort, we revised the statistics to 
conduct a pilot study as described below. 
 
In the study of the first 20 melanoma patients, we decided that the combination is not worthy 
of further investigation if the true response rate is <=10%. However, because we observed a 
BMRR of 55% in these patients, we raised this bar from 10% to 30%, which is the lower 
bound of the 95% CI from the first 20 melanoma patients who were enrolled on the study. 
 
For the melanoma cohort, the new null hypothesis that the true response rate is 30%.  was to 
be tested against a one-sided alternative, using Simon’s optimal two stage design, enrolling 
8 patients in the first stage and 12 in the second.  
 
Among the first six patients enrolled in the second melanoma cohort, one had a modified 
RECIST-defined complete response, and two had progression of disease due to initial tumor 
growth at six weeks or appearance of new lesions (one each), with subsequent tumor regression, 
remaining on study beyond progression. Two patients were unevaluable for intra-cranial 
response.  
 
Therefore, we are redesigning the analyses to remove the Simon’s optimal two stage design due 
to the possibility of delayed response and emerging evidence regarding the intra-cranial 
response rate to anti-PD-1 monotherapy (Long et.al, Lancet Oncology, 2018 64, in which 5 of 
25 patients responded and Kluger et al, Journal of Clinical Oncology 2019 65, in which 6 of 23 
patients responded), indicating that the response rate to anti-PD-1 alone is likely between 20-
26%. Long et al also reported a response rate to anti-PD-1 and anti-CTLA-4 combination 
therapy of 46%, and Tawbiet al reported a response rate to anti-PD-1 and anti-CTLA-4 of 56% 
(Tawbi et al, New England Journal of Medicine, 2018) 66.  
 
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The combination of pembrolizumab and bevacizumab, a significantly less toxic regimen, would 
be worthy of further study if the intracranial response rate was 46%. In the first melanoma 
cohort in this trial, the intracranial response rate was 55%, and the purpose of the second cohort 
was to verify this result.  
 
To account for the uncertainty of the historical response rate, we follow the approach proposed 
by Thall and Simon (1994) 63 and approximate the distribution of response rate to anti-PD-1 
monotherapy using a beta distribution with a mean of 23% (95% CI: 0.12-0.36), assuming there 
are 11 responses (5+6) out of 48 (25+23) patients in historical controls. That is, we assume the 
historical response rate 𝜃𝜃𝐻𝐻∼𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵( 𝑛𝑛𝐻𝐻 𝑝𝑝𝐻𝐻,    𝑛𝑛𝐻𝐻(1 − 𝑝𝑝𝐻𝐻), where  𝑛𝑛𝐻𝐻= 48 and  𝑝𝑝𝐻𝐻= 0.23. 
Assume the response rate of the combination has a uniform prior, that is, 𝜃𝜃𝐸𝐸∼𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵(1, 1). 
 
After enrolling and evaluating the outcomes of the 20 patients, we conclude the combination 
worthy of further study if 
𝑃𝑃(𝜃𝜃𝐸𝐸> 𝜃𝜃𝐻𝐻|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) > 0.936, 
 
i.e., we conclude the treatment is promising if there are at least 8 responses in 20 patients.  
 
The probability of false positive is 0.032, 0.067 and 0.122 if the true probability of response is 
0.20, 0.23 and 0.26, respectively. We achieve 78%, 87% and 94% power if the true probability of 
response is 0.46, 0.50 and 0.55, respectively.  
 
 
 
 
The beta distribution modelling the response rate to monotherapy in historical controls (Left panel) and 
the power function of the design (right panel). 
 
 
 
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For the lung cohort, we will conduct a pilot study which will decrease the number of planned 
enrolled patients from 33 to 13 patients. Under the null hypothesis, the response rate 
corresponding to drug with minimal activity is 10%. We therefore consider a drug is worthy of 
further investigation if the true response rate is at least 25% for NSCLC. 
 
Due to the pilot nature of this study, sample size calculation is not based on formal hypothesis 
testing. We provide the two-sided 90% confidence intervals for observing different number of 
responses. As shown by the table below, we can reject the null hypothesis if at least 4 responses 
are observed. 
 
Number of Responses 
Lower 90% CI 
Upper 90% CI 
3 
0.07 
0.49 
4 
0.11 
0.57 
5 
0.17 
0.65 
6 
0.22 
0.71 
7 
0.29 
0.78 
8 
0.35 
0.83 
 
 
Patients will be considered evaluable if they remain on treatment for the first 6-week scans or 
if they have unequivocal CNS progression prior to that. 
 
8.2 Analytic Plan for Primary Objectives: 
 
We will use mRECIST criteria to determine brain metastasis response rate (BMRR). The 
proportion of patients with a brain metastasis response in the clinically evaluable lesion(s) 
will be calculated along with a 95% confidence interval. 
 
8.3 Analytic Plan for Secondary Objectives: 
 
1) Objective: To determine the incidence of steroid use for control of cerebral 
edema during treatment with pembrolizumab and bevacizumab in combination in 
patients with metastatic melanoma or NSCLC. 
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The percentage of patients requiring corticosteroid use for control of perilesional 
edema will be compared that seen in a previous study with the same patient 
population using pembrolizumab alone. The proportion of patients using steroids 
for > 96 hours will be calculated with a 95% confidence interval. 
 
2) Objective: To determine the best overall response rate (ORR) in patients with 
brain metastases from melanoma or NSCLC treated with combination 
pembrolizumab and bevacizumab. 
 
Best overall response rate (ORR) is defined as the percentage of patients who 
experience a CR or PR in any metastases (clinically evaluable cerebral or 
systemic) as determined by mRECIST criteria in the brain or RECIST criteria in 
the body. The proportion of patients with an ORR will be calculated with a 95% 
confidence interval. A similar analysis will be performed using ir-mRECIST and 
ir-RECIST. 
 
 
3) Objective: To evaluate median progression free survival (PFS) and overall 
survival (OS) in patients with melanoma or NSCLC metastatic to the brain, treated 
with pembrolizumab plus bevacizumab. 
 
Progression-free survival will be calculated as the time from start of study drugs 
to progression (using mRECIST criteria for brain lesions and RECIST criteria for 
systemic disease) or death. Overall survival will be calculated as the time from 
start of pembrolizumab to death. Patients who do not meet the endpoint will be 
censored at the date of last follow-up. PFS and OS will be determined separate 
for each cohort and median survival will be estimated by using Kaplan-Meier 
methodology. 
 
8.4 Exploratory Objective 
 
(1) Objective: To study PD-L1 expression and other potential predictive biomarkers 
in CNS, tumors and blood, and correlate results with response to pembrolizumab 
plus bevacizumab. 
 
PD-L1 expression and other potential biomarkers will be correlated to clinical 
endpoints. Exploratory, hypothesis-generating analyses will be performed. Details of 
the statistical plan for the biomarker studies are provided in Section 11.0. 
 
(2) Objective: To determine the safety and toxicity of pembrolizumab in combination 
with bevacizumab in patients with untreated brain metastases 
 
Safety and toxicity will be assessed using CTC v4.0 criteria. All participants who 
receive any amount of study drug will be evaluable for toxicity. 
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9.0  
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
9.1 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 8. 
 
Table 8 Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
9.2 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
9.3 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. 
 
9.4 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. 
 
9.5 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. 
 
 
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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. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
10.1 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information. 
 
10.2 Quality Management System 
 
10.2.1 Monitoring 
 
The study principal investigator and YCCI are responsible for monitoring the performance of 
all of the participating sites. This will be performed by conducting a study site initiation 
visit, as well as regularly scheduled monitoring visits and/or remote monitoring throughout 
the life of the protocol. At the end of the trial, the monitor will then perform a study site 
close-out visit at all participating sites. 
 
YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. 
Following each site visit, a visit report will be generated containing information on site 
activities, and a summary of pertinent points and action items together with a copy of the 
follow-up letter will be sent to each investigative site. 
 
During these monitoring visits, some of the items that will be reviewed are the following: 
• Training of the sites 
• Site personnel qualifications to participate in the trial 
• That study related documents are current 
• That regulatory compliance is accomplished 
• That each subject has signed the informed consent 
• That the current and approved protocol is complied with (including reporting and 
logging of all protocol deviations) 
• That all SAEs and AEs have been reported to the local regulatory and Ethics/IRB 
Committees, YCCI, and Merck as appropriate 
• That source documentation matches CRFs 
• That required procedures for study drug accountability, distribution, and storage are 
followed. 
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YCCI will document the required study monitoring activities in a Study Monitoring Plan. 
 
10.2.2 Audit and inspection 
 
To ensure compliance with GCP and regulatory requirements, the YCCI Office of Quality 
Assurance and Training will audit the trial at least annually or as determined by the Yale 
Cancer Center DSMC. The overall principal investigator, study coordinator and/or data 
manager may request access to all source documents and other study documentation for on- 
site or remote monitoring, audit or inspection. 
 
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated by the 
Principal Investigator or Yale. The purpose of these audits or inspections is to examine 
study-related activities and documents to determine whether these activities were conducted 
and data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, and any applicable regulatory requirements. 
 
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection. 
The Sponsor-Investigator/institution and participating site investigators/institutions agree to 
allow the auditor or inspector direct access to all relevant documents and allocate their time 
and the time of their staff to the auditor/inspector to discuss findings and any issues. Audits 
and inspections may occur at any time during or after completion of the study. 
 
10.2.3 Data Safety Monitoring Committee (DSMC) 
 
The Yale Cancer Center DSMC will serve at the DSMC of record. The Yale DSMC will 
review and monitor compliance, toxicity and deviations from this study. The committee is 
composed of clinical specialists with experience in oncology and who have no direct 
relationship with the study. Information that raises any questions about participant safety will 
be addressed with the Principal Investigator. 
 
The DSMC will review this protocol at a minimum of once every six months. Information to 
be provided to the committee includes: a study narrative by the PI, a summary DSMC report 
produced by OnCore (which includes participant accrual, response, trial status history, SAEs, 
Adverse Events, Deviations and survival); audit results, and monitoring reports as applicable. 
Other information (e.g. scans, laboratory values) will be provided upon request. 
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11.0 BIOMARKER STUDIES 
 
11.1 Tissue-based correlative studies: 
 
Correlative studies will be conducted on the pre-treatment tissue specimens. When available 
we will include both cerebral and extra-cerebral samples. PD-L1 staining will also be 
determined by c entral and/or local testing of PD-L1 IHC by any FDA-approved assay or an 
assay performed in a CLIA laboratory on FFPE tissue. A number of additional biomarkers 
will be studied for their potential predictive value in pre- treatment specimens. These 
exploratory studies include (but are not limited to): 
 
1) Markers to be studied on tumor cells: PDL1, PDL2, B7-H2, B7-H3, B7-H4, Galactin- 
9, CEACAM-1, CD-70, HVEM, IDO, MHC class I antigens. 
2) Percent of tumor sample that constitutes CD3, CD4 and CD8 cells and macrophages 
(CD68) 
3) Markers  on  immune  infiltrating  cells:  LAG-3  on  CD4  cells,  PD1-H  (PD-1 
homologue), CTLA4, TIM3, PD-1, IDO, BTLA 
4) Vessel density will be determined by the area of CD34 staining in the sample. Tumor 
and vessel VEGF-receptor expression will be determined as previously described 52. 
 
Patients who undergo surgical procedures (either of the CNS or peripheral) while on systemic 
treatment will also be required, when feasible, to provide a research specimen to determine 
changes in the above markers in the context of response or resistance to therapy. 
 
Levels of all of the above markers will be measured by a method of Automated Quantitative 
Analysis (AQUA) of in situ protein levels in Dr. Kluger’s laboratory at Yale University. This 
method has been validated for epithelial cancers and melanoma, and has shown to be more 
precise than pathologist-based scoring of 3,3′-diaminobenzidine stain. AQUA is highly 
reproducible and quantitative, as reviewed 53. Tumors will be stained with a number of 
fluorophores: A tumor mask for melanoma will be made using a cocktail of anti-S100 and 
anti-Melan-A, and for NSCLC the mask will be generated by anti-cytokeratin antibodies. The 
methods for masking tumor have been described in the literature 52,54,55. The mask will by 
conjugated to Cy-2, and will be differentiated from the target antigen, which will be 
conjugated to Cy-5. Lymphocytes will be identified by the appropriate antigen conjugated to 
Cy-7. After fluorescent staining is completed, images are taken at the different wavelengths, 
and the images will be analyzed using algorithms that have been extensively described. A 
monochromatic, high-resolution images of each histospot will be obtained using the 10× 
objective of an Olympus AX-51 epifluorescence microscope (Olympus) with automated 
microscope stage and digital image acquisition driven by a custom program and macrobased 
interfaces with IPLabs software (Scanalytics, Inc.). Tumor will be distinguished from stromal 
elements by the tumor mask signal. The signal intensity of the target biomarker will be 
scored on a scale of 0-255 (the AQUA score). This will provide quantitative results. 
 
Biomarker analysis for individual markers will be conducted using standard statistical 
methods. Associations between continuous AQUA scores and dichotomized outcome 
variables (such as response) will be done by ANOVA. Cox univariate analysis will be used to 
study the associations between the survival endpoints and biomarker expression; Kaplan 
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Meier curves will be generated to depict the association between dichotomized biomarker 
levels and survival endpoints. Multivariable models will be generated to predict response. 
Biomarker selection will be done by determining area under the receiver operating 
characteristic (ROC) curves (AUCROC) at the time of each event in the testing set and we 
average these AUCROCs across all these events; this is a variant of the weighted average of 
time dependent ROC curve approaches 56-59. 
 
11.2 Blood-based studies: 
 
We will collect approximately 10 cc of blood from patients pre-treatment, after 6 weeks of 
therapy, 12 weeks of therapy, and every 9 weeks thereafter while on treatment, and at the 
end of treatment visit (5 cc of plasma and 5 cc of whole blood). We will immunophenotype 
cells from pre- and on- treatment blood samples to determine the array and activation status 
of different immune cell populations. We will do this using polychromatic flow cytometry 
which provides a powerful assessment of immune function based on differences in cell 
numbers, cell types and the expression of cell-associated surface and intracellular 
molecules related to immune perturbation 60. Lyophilized antibody cocktails have been 
developed in the form of lyoplates to improve standardization between different labs and will 
be utilized here, with a different panel to examine multiple immune cells types (see Table 
below for details). Approximately 5ml of blood will be used for this assay. 
 
We also will perform a multiplex cytokine analysis assay to determine the cytokines present 
pre-treatment and after 9 weeks on treatment with pembrolizumab 61. We will use the 
Luminex assay which multiplexes 25 cytokines from plasma. The cytokines in the panel 
include: GM-CSF, IFN-γ, IL-10, IL-12 (p70), IL-13, IL-15, IL-17A, IL-17E/IL-25, IL-17F, 
IL-1β, IL-2, IL-21, IL-22, IL-23,IL-27, IL-28A, IL-31, IL-33, IL-4, IL-5, IL-6, IL-9, MIP- 
3α/CCL20, TNFα, and TNFβ .This assay requires about 100ul of plasma and utilizes a bead 
set coated with a capture antibody specific for each cytokine. A second biotinylated antibody 
and streptavidin-phycoerythrin is used to detect the captured cytokine. The Luminex 200 
analyzer is a dual laser, flow-based, sorting and detection platform which can determine the 
specific cytokines present and the amount of cytokine bound. Both the immunophenotyping 
flow cytometry assay and the multiplex cytokine analysis are available through the Immune 
Monitor Core Facility at Yale under the direction of Dr. Lesley Devine, PhD. 
 
Blood-based immunophenotyping and cytokine assays: 
 
Antibody panels for immunophenotyping 
Lyoplate 
panel # 
FITC 
PE 
PE-Texas 
Red 
PerCP- 
Cy5.5 
PE-Cy7 
APC 
AlexaF- 
700 
APC-H7 
V450 
V500 
Purpose 
1 
CD27 
CCR7 
Viability 
Dye 
CD4 
CD45RA 
CD38 
CD28 
CD8 
CD3 
HLA- 
DR 
T cells 
2 
CXCR5 
CXCR3 
Viability 
Dye 
CCR4 
CCR6 
PD-1 
CD8 
CD3 
CD4 
TH1, TH2, TH17 cells 
3 
CD39 
CD25 
Viability 
Dye 
CD4 
CCR4 
CD127 
FoxP3 
CD45RO 
CD3 
HLA- 
DR 
TReg Cells 
4 
CD21 
CD24 
Viability 
Dye 
CD19 
CD27 
CD38 
CD10 
CD20 
CD3 
IgD 
B-cells 
5 
CD56 
Viability 
Dye 
CD123 
CD11c 
CD16 
CD3+19+20 
CD14 
HLA- 
DR 
DCs, monocytes and 
NK cells 
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Please note that the profile of biomarkers is likely to change as scientific knowledge evolves. 
 
11.3 Collection and Handling of Specimens 
 
Before initiation of systemic therapy, local surgical therapy may be performed when 
clinically appropriate, and samples of brain or extracerebral tumor will be obtained. After 
tissue is obtained, it will be formalin fixed and embedded in paraffin. These tissues will be 
stored for correlative studies mentioned in the biomarker spectrum. If a patient has previously 
undergone local therapy to a brain lesion and tissue is available for analysis, paraffin-
embedded tissue will be obtained from the sample. For patients who do not have tissue 
from a brain lesion available, tissue from a systemic lesion will be used to perform the planned 
studies. This tissue may include a FFPE specimen or SNAP frozen tissue. Please see the 
Procedures Manual for tissue requirements and handling of tissue 
 
12.0  MEASUREMENT OF RESPONSE 
 
Response will be evaluated with a CT chest/abdomen/pelvis and MRI brain every 6 weeks 
for the first 3 months of treatment and then every 9 weeks thereafter. If symptoms develop 
or clinical deterioration occurs, patients may be imaged prior to the pre-specified time 
points for imaging. 
 
12.1 Brain Metastasis Response Assessment 
 
RECIST criteria v1.1 will be modified to account for differences in measuring the response 
of clinically evaluable brain lesions as opposed to systemic lesions (modified RECIST, or 
mRECIST). Size is considered the tumor’s largest diameter. Measurements from multiple 
lesions are summed to calculate the sum of the diameters (SD). The SD calculated on a 
baseline scan performed within 28 days of study drug initiation will be used as a reference to 
determine the objective response of the clinically evaluable lesions. All responses must be 
confirmed at ≥6 weeks with an equivalent or better response. Please refer to the original 
RECIST criteria if further reference is necessary. 
 
 
12.2 Brain Metastasis Measurable disease 
 
Specification of a minimal lesion diameter for measurable lesions reduces the potential for 
variation in the measurement of smaller lesions due to slice selection and volume averaging. 
The minimal lesion diameter should be greater than or equal to 2 times the section thickness 
and a minimum of 5mm. A previously irradiated lesion will not be measured as a target 
lesion unless it is documented to have progressed since treatment. 
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12.3 Brain Metastasis Nonmeasurable disease 
 
Nonmeasurable lesions at baseline are important in clinical trials because tumor progression 
may occur at these sites. Nonmeasurable lesions include enhancing lesions that are less than 
the specified smallest measurable diameter (5mm when slice thickness is 2.5mm or twice the 
slice thickness), hemorrhagic or predominantly cystic or necrotic lesions that are difficult to 
accurately measure and track, and lesions that are indeterminate for metastatic disease. Intrinsic 
T1-hyperintensity is noted within hemorrhagic lesions that may be misinterpreted as enhancing 
tumor, and for this reason, the precontrast T1-weighted image must be examined at baseline 
to prevent this error. Nonmeasurable lesions should be briefly described on the imaging case 
report form for each study.62 
 
RECIST 1.1 limits the number of lesions measured to 5 in total, with 2 per organ. For our 
purposes, if there are multiple measurable lesions in the brain, the sum of diameters of up 
to a maximum of 5 of the largest lesions will be considered for response assessment. 
assessment. 
 
12.4 Modified Response Criteria for Brain Metastases 
Up to 5 CNS lesions can be selected as target lesions for response evaluation 
Complete Response (CR): Disappearance of all target 
lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum recorded since the treatment started or the 
appearance of one or more new lesions (new lesions must be greater than slice thickness). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters since the treatment started. 
 
Please refer to RECIST v1.1 for additional details regarding response criteria. 
 
12.5 Systemic Disease Response Assessment 
 
Response of all systemic, non-cerebral metastases will be evaluated in this study using the 
new international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee v1.1. Version 1.1 stipulates that the number of lesions required to 
assess tumor burden for response determination has been reduced to a maximum of five total 
lesions (two lesions maximum per organ). 
 
 
 
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Briefly, measurable lesions must have a minimum size of 10 mm by CT scan (CT scan slice 
thickness no greater than 5 mm) in at least one dimension. Lesions with a longest diameter of 
<10 mm are considered non-measurable lesions and will be tracked as non-target disease. 
Tumor lesions in a previously irradiated area, or in an area subject to other loco-regional 
therapy, are not considered measurable unless there has been demonstrated progression in the 
lesion. For complete definitions of measurable and non-measurable disease, please refer to 
the RECIST v1.1 criteria. 
 
12.6 Evaluation of Best Overall Response 
 
The Best Overall Response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. The best 
response will take into consideration both the clinically evaluable brain metastases and 
systemic metastases, and therefore will include measurements from both mRECIST criteria 
(in the brain) and RECIST criteria (in the body) as follows: 
 
Complete Response (CR): Disappearance of all target lesions in the brain and systemic 
disease. 
Partial Response (PR): Partial response in both the brain and the systemic disease, or if there 
is PR at one site and SD at the other, the sum of diameters from the brain and systemic 
disease will be added and the best overall response will be considered PR if there is at least a 
30% decrease, taking as reference the baseline sum diameters. 
Progressive Disease (PD): Progressive disease in either the brain or the systemic disease will 
qualify as PD as the best overall response. 
 
Stable Disease (SD): Stable disease in both the brain and systemic disease, or if the sum of 
diameters from the brain and systemic disease does not qualify for PR or PD (at least a 20% 
increase in the sum of diameters of target lesions), taking as reference the smallest sum 
diameters since the treatment started. 
 
Duration of overall response: The duration of overall response is measured from the time 
that measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. Please note that 
objective documentation implies confirmation of response by imaging. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started. 
 
 
 
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Progression-Free Survival (PFS): PFS is defined as the time from initiation of study drug 
until the first documented, confirmed progression of clinically evaluable brain metastases 
based on mRECIST criteria, systemic disease based on RECIST criteria, or death. If there is 
progression of disease that is then confirmed on a follow up scan at least 4 weeks later, the 
initial date of documented progression should be used in the PFS analysis. 
 
 
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13.0 APPENDICES 
 
13.1 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. 
 
 
13.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
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effectiveness of adoptive immunotherapy of cancer. Cancer research 2010;70:6171-80. 
29. 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 
on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 
blockade. Proceedings of the National Academy of Sciences of the United States of America 
2002;99:12293-7. 
30. 
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer research 2003;63:6501-5. 
31. 
Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients 
with metastatic melanoma. Cancer immunology research 2014;2:632-42. 
32. 
McDermott DF, Sznol M, Sosman JA, et al. 809OIMMUNE CORRELATES AND 
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ENGINEERED PD-L1 ANTIBODY, IN PATIENTS WITH METASTATIC RENAL CELL 
CARCINOMA (MRCC). Annals of Oncology 2014;25:iv280. 
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Lieu C, Bendell J, Powderly JD, et al. 1049OSAFETY AND EFFICACY OF 
MPDL3280A (ANTI-PDL1) IN COMBINATION WITH BEVACIZUMAB (BEV) 
AND/OR CHEMOTHERAPY (CHEMO) IN PATIENTS (PTS) WITH LOCALLY 
ADVANCED OR METASTATIC SOLID TUMORS. Annals of Oncology 2014;25:iv361. 
34. 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab 
for non-small-cell lung cancer. The New England journal of medicine 2006;355:2542-50. 
35. 
Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with 
non-small-cell lung cancer and brain metastases. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2009;27:5255-61. 
36. 
De Braganca KC, Janjigian YY, Azzoli CG, et al. Efficacy and safety of bevacizumab 
in active brain metastases from non-small cell lung cancer. Journal of neuro-oncology 
2010;100:443-7. 
37. 
Zustovich F, Ferro A, Lombardi G, Zagonel V, Fiduccia P, Farina P. Bevacizumab as 
front-line treatment of brain metastases from solid tumors: a case series. Anticancer research 
2013;33:4061-5. 
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Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. 
Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8:610-22. 
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Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination 
with irinotecan in recurrent glioblastoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2009;27:4733-40. 
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Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab 
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Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab 
safety in patients with central nervous system metastases. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2010;16:269-78. 
42. 
Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation 
necrosis of the brain. International journal of radiation oncology, biology, physics 
2007;67:323-6. 
43. 
Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial 
of bevacizumab therapy for radiation necrosis of the central nervous system. International 
journal of radiation oncology, biology, physics 2011;79:1487-95. 
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Furuse M, Kawabata S, Kuroiwa T, Miyatake S. Repeated treatments with 
bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report 
of 2 cases. Journal of neuro-oncology 2011;102:471-5. 
45. 
Torcuator R, Zuniga R, Mohan YS, et al. Initial experience with bevacizumab 
treatment for biopsy confirmed cerebral radiation necrosis. Journal of neuro-oncology 
2009;94:63-8. 
46. 
Yonezawa S, Miwa K, Shinoda J, et al. Bevacizumab treatment leads to observable 
morphological and metabolic changes in brain radiation necrosis. Journal of neuro-oncology 
2014;119:101-9. 
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Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment 
of advanced human cancer. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2013;19:1021-34. 
49. 
Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 Ligands, and Other 
Features of the Tumor Immune Microenvironment with Response to Anti-PD-1 Therapy. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research 2014. 
50. 
Zustovich F, Ferro A, Lombardi G, Farina P, Zagonel V. Bevacizumab-Based 
Therapy for Patients with Brain Metastases from Non-Small-Cell Lung Cancer: Preliminary 
Results. Chemotherapy 2015;60:294-9. 
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Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med 
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Kluger HM, Siddiqui SF, Angeletti C, et al. Classification of renal cell carcinoma 
based on expression of VEGF and VEGF receptors in both tumor cells and endothelial cells. 
Lab Invest 2008;88:962-72. 
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Jilaveanu L, Zito C, Lee SJ, et al. Expression of sorafenib targets in melanoma 
patients treated with carboplatin, paclitaxel and sorafenib. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2009;15:1076-85. 
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Berger AJ, Camp RL, Divito KA, Kluger HM, Halaban R, Rimm DL. Automated 
quantitative analysis of HDM2 expression in malignant melanoma shows association with 
early-stage disease and improved outcome. Cancer research 2004;64:8767-72. 
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Camp RL, Chung GG, Rimm DL. Automated subcellular localization and 
quantification of protein expression in tissue microarrays. Nat Med 2002;8:1323-7. 
56. 
Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival 
data and a diagnostic marker. Biometrics 2000;56:337-44. 
57. 
Heagerty PJ, Zheng Y. Survival model predictive accuracy and ROC curves. 
Biometrics 2005;61:92-105. 
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Parisi F, Gonzalez AM, Nadler Y, et al. Benefits of biomarker selection and clinico- 
pathological covariate inclusion in breast cancer prognostic models. Breast cancer research : 
BCR 2010;12:R66. 
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Haibe-Kains B, Desmedt C, Sotiriou C, Bontempi G. A comparative study of survival 
models for breast cancer prognostication based on microarray data: does a single gene beat 
them all? Bioinformatics 2008;24:2200-8. 
60. 
Maecker HT, McCoy JP, Nussenblatt R. Standardizing immunophenotyping for the 
Human Immunology Project. Nature reviews Immunology 2012;12:191-200. 
61. 
Djoba Siawaya JF, Roberts T, Babb C, et al. An evaluation of commercial fluorescent 
bead-based luminex cytokine assays. PloS one 2008;3:e2535. 
62. 
Henson JW, Ulmer S, Harris GJ. Brain tumor imaging in clinical trials. AJNR 
American journal of neuroradiology 2008;29:419-24. 
63. 
Thall PF, Simon R. Practical Bayesian guidelines for phase IIB clinical trials. 
Biometrics. 1994 Jun 1:337-49. 
64. 
Long GV1, Atkinson V2, Lo S3, Sandhu S, et al. Combination nivolumab and 
ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre 
randomised phase 2 study. Lancet Oncol. 2018 May;19(5):672-681 
 
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Kluger HM, Chainage V, Mahajan, A, et al. Long-Term Survival of Patients 
With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a 
Phase II Trial. Journal of Clinical Oncology 37, no. 1 (January 01, 2019) 52-60. 
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Tawbi, HA, Forsyth, PA, Algazi, A, et al.  Combined Nivolumab and 
Ipilimumab in Melanoma Metastatic to the Brain N Engl J Med 2018; 379:722-730 
 
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ICF_001.pdf: 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 1 of 24
YCC v18.0 (23-Apr-2024) 
COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL: 
SMILOW CANCER HOSPITAL
200 FR. 4 (2014-11) 
Study Title: A Phase 2 Trial of Pembrolizumab plus Bevacizumab in Patients with Metastatic 
Melanoma or Non-Small Cell Lung Cancer with Untreated Brain Metastases.
Principal Investigator: Harriet Kluger, MD
Principal Investigator’s Phone Number: 203-200-6622
24-Hour Phone Number: 203-200-6622
Principal Investigator’s Mailing Address: 333 Cedar St. PO BOX 20856, New Haven, CT 
06520
Funding Source: Yale Cancer Center and Merck and Co., Inc. and the NIH
Invitation to Participate and Description of Project
You are invited to take part in a research study. The research study is designed to look at whether 
or not the combination of pembrolizumab and bevacizumab has beneficial effects and is safe for 
use in subjects with metastatic melanoma or non-small cell lung cancer who also have untreated 
brain metastases. You have been invited to take part because you have been diagnosed with 
metastatic melanoma or non-small cell lung cancer and you have untreated brain metastases.
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed decision. This consent form gives you 
detailed information about the study, which a member of the research team will discuss with you. 
This discussion should go over all aspects of this research: the purpose and nature of the research 
study, the procedures that will be performed, the risks of the study drug(s) and procedures, possible 
benefits, possible alternative treatments, your rights as a participant and other information about 
the research study. You should take whatever time you need to discuss the research study with 
your physician and family. The decision to participate or not is yours. Once you understand the 
study, you will be asked if you wish to participate; if so, you will be asked to sign and date where 
indicated on this form.
If you choose to participate, you will be told of any significant new findings that develop during 
the course of your participation in this study that may affect your willingness to continue to 
participate.
The research study is being sponsored by Yale University. Yale is responsible for the conduct of 
the study. Merck and Co., Inc. (hereafter referred to as Merck) is the maker of pembrolizumab. 
Merck is providing funding and study drug for this research study. 
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APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
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Page 2 of 24
YCC v18.0 (23-Apr-2024) 
Dr. Harriet Kluger is the principal investigator of this study at Yale Cancer Center. The study 
doctors will not receive payment for any specific results from this study.
Purpose
The purpose of this study is to explore whether or not pembrolizumab combined with bevacizumab 
has beneficial effects and is safe for use in subjects diagnosed with metastatic melanoma or non-
small cell lung cancer (NSCLC) who also have untreated brain metastases. We will also study the 
effects of this combination on tumors outside of the brain (when present) and on survival.
The study drugs used that will be used in this research study, pembrolizumab and bevacizumab 
are approved for use by the United States Food and Drug Administration (FDA). 
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but may not be approved to treat your type of cancer. 
Pembrolizumab works by helping your immune system to fight your cancer. However, 
pembrolizumab can also cause your immune system to attack normal organs and tissues in your 
body and can affect the way they work, which can result in side effects. These side effects may be 
serious (i.e. causing hospitalization or be life-threatening), may result in death, and/or may occur 
after you stop taking pembrolizumab. Bevacizumab is widely used in the treatment of cancer and 
is FDA approved for use in advanced cancers of the colon, lung, breast, kidney and brain 
(glioblastoma). 
For the purposes of this study, the combination of pembrolizumab and bevacizumab is considered 
investigational. This means that the combination has not been approved for commercial use by the 
FDA in your type of cancer.
This will be a multi-institution trial, with a total approximate accrual of 53 subjects. It is expected 
that 40 subjects will have melanoma and 13 subjects will have NSCLC. It is expected that 
approximately 36 subjects will be enrolled at Yale Cancer Center. 
Study Procedures
You will be entered into one of 2 study groups (arms) based upon your diagnosis: Arm A is for 
melanoma subjects and Arm B is for NSCLC subjects. NSCLC subjects must be PD-L1 positive 
in order to be considered for participation in this clinical trial. PD-L1 is a protein and T-cell 
receptor which is thought to play a role in the ability of tumor cells to evade a person’s immune 
system. 
You may undergo some of the procedures listed below during Screening, Study drug treatment, 
and or Follow-up because you are in the research study and they are required by the sponsor as 
part of being in this study.  The standard of care is the procedures that are done and the tests that 
are done for patients who have your condition, whether they are in a study or not. Other procedures 
are done because you are in a research study and they are required by the sponsor for your 
participation in this study.
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APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 3 of 24
YCC v18.0 (23-Apr-2024) 

Procedures that are being performed for standard of care purposes include a 
medical history assessment, full physical exam (including weight), vital signs, 
performance status evaluation routine blood tests, urine sample, pregnancy test, 
CT & MRI scans, etc. 

Procedures that are being performed solely for research purposes include, blood 
sample for research purposes, tumor tissue collection, biobanking, review of 
medication and study drug administration.
Screening Period
If you agree to participate and sign and date this form, you will need to undergo a series of tests 
and procedures to determine if you are eligible to participate in the research study. You will come 
to the study site for screening tests and it is possible that more than one screening visit may be 
needed. The following tests or procedures will be performed during the visit(s) regardless of your 
kind of cancer (melanoma or NSCLC) unless otherwise indicated:

Physical Examination

Review of your medical history including medications you are taking and other medical 
conditions you have in addition to cancer

Measurement of height, weight and vital signs (including blood pressure, heart rate, 
temperature, breathing rate and oxygen measurement)

Performance status evaluation

Routine blood tests for safety:
o
Complete blood count
o
Blood chemistry
o
Liver function tests
o
Thyroid stimulating hormone (TSH)
o
Free T3 and Free T4

Urinalysis

Blood sample for research purposes; if you are found to not be eligible, but you still wish 
to provide a one-time blood sample, this sample may be banked for other future research 
studies. This sample is required for all subjects who are eligible to participate in this study 
and will be taken prior to your first dose of study drug. The blood samples will be tested to 
see what types of proteins the blood cells express, a technique called immunophenotyping. 
The samples will be stored, or banked, in a laboratory at Yale University until they are used 
by the researchers.

Pregnancy test (blood or urine) for women of child bearing potential only. If the results are 
positive, you will not be eligible to participate in this research study. Women of child 
bearing potential must agree to use an effective method of birth control or agree to remain 
abstinent during the course of the study. 

Computerized tomography (CT) scan of the chest and abdomen. CT scan of the pelvis will 
be done if clinically indicated.

Brain Magnetic Resonance Imaging (MRI) to assess Central Nervous System (CNS) tumor 
involvement. Your MRI will be reviewed by investigators at Yale University.
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 4 of 24
YCC v18.0 (23-Apr-2024) 

In order to participate in this research study, you must agree to provide tumor tissue from 
any prior surgical resections or biopsies, and any tumor that is removed or biopsied once 
on study. 

Blood sample for research purposes. A sample of your blood is required for all participants 
who are eligible to participate in this study and will be taken prior to your first dose of 
study drug. If you are found to not be eligible, but you still wish to provide a one-time 
blood sample, this sample may be banked for other future research studies. The blood 
samples will be tested to see what types of proteins the blood cells express, a technique 
called immunophenotyping. The samples will be stored, or banked, in a laboratory at Yale 
University until they are used by the researchers.

Review of Smoking Status 
Treatment Period
Prior to receiving the study drugs, subjects will have local therapy to a brain lesion by surgical 
resection or LITT (laser interstitial thermocoagulation therapy), when clinically needed. Surgical 
resection uses surgery to remove abnormal tissue in your brain. LITT is a surgical procedure that 
will require you to have general anesthesia (be put under). A small incision will be made in your 
scalp and a small (2.5 mm) hole will be drilled in your skull. A laser catheter (tube) will be inserted 
into your tumor and used to obtain a biopsy from the tumor and also to heat the tumor so that the 
tumor cells will no longer be alive. This thermocoagulation process typically lasts 2-3 minutes. 
LITT is FDA approved for use in the treatment of brain tumors. The tissue removed during surgical 
resection or LITT will be studied for PD-L1 expression and other biomarkers that may help 
researchers determine what types of tumors may or may not respond to pembrolizumab and 
bevacizumab. Melanoma tumors are not required to express PD-L1 in order for melanoma subjects 
to participate in this research study.
You will be required to provide a specimen from a tumor, if available, for research. Your study 
doctor will discuss with you which tumor specimen can be used and whether a new biopsy is 
necessary.
If at any time on study you have a surgical procedure or biopsy, you will be required to provide a 
portion of the tumor specimen for research.
For this research study, a cycle is three weeks (21 days). You will continue to receive the study 
drugs, pembrolizumab and bevacizumab, in three-week cycles until disease progression, 
unacceptable toxicity, withdrawal from the study or removal by the study team, termination of the 
study or if you develop an illness or complication that does not allow you to safely continue on 
study. Subjects will receive 200mg of pembrolizumab every 3 weeks intravenously (IV) (through 
your vein). Bevacizumab, at a dose of 7.5 mg/kg, will be administered intravenously on Day 1 of 
cycles 1, 2, 3, and 4 (or other cycles if bevacizumab is held during these cycles. Day 1 of the study 
will be defined as the first day a subject receives pembrolizumab.
If at any time during the study you experience symptoms related to your brain metastases, the 
study doctor may locally treat your lesions. 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
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YCC v18.0 (23-Apr-2024) 
The following is a list of evaluations that you will undergo during the treatment period of the study:
Day 1 of each Cycle (every 3 weeks):

Physical examination

Review of your medical history

Review the medications you have taken and are currently taking including treatment 
received for your cancer. If you are not already taking anti-convulsants, you will be started 
on medications to avoid seizures.

Performance status evaluation

Review of any side effects you may have had or may be having

Measurement of weight and vital signs (including blood pressure, heart rate, temperature, 
breathing rate and oxygen measurement)

Urinalysis (Cycles 1, 2, 3 and 4 only)

Pregnancy test (blood or urine) for women of child bearing potential only

Routine blood tests for safety:
o
Complete blood count
o
Blood chemistry
o
Liver function tests

Tumor response assessment by CT scan of the chest, abdomen and pelvis (Cycle 3 and 5 
and every 9 weeks thereafter)

Brain MRI (Cycle 3 and 5 and every 9 weeks thereafter)

Administration of pembrolizumab

Administration of bevacizumab (Cycles 1, 2, 3 and 4 only; or other cycles if bevacizumab 
is held during these cycles)

Blood samples for research purposes (Cycles 3 and 5)
Day 1 of Cycle 8 (and every 9 weeks thereafter):
The procedures listed above will be performed (unless otherwise specified) in addition to the 
following:

Blood sample(s):
o
Thyroid stimulating hormone (TSH)
o
Free T3 and Free T4 

Blood samples for research purposes

Brain MRI

Tumor response assessment by CT scan of the chest, abdomen and pelvis
End of Treatment
The following procedures will be performed within 28 days of your last dose of study drug:

Physical examination

Review the medications you have taken and are currently taking including treatment 
received for your cancer

Performance status evaluation

Review of any side effects you may have had or may be having
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 6 of 24
YCC v18.0 (23-Apr-2024) 

Measurement of weight and vital signs (including blood pressure, heart rate, temperature, 
breathing rate and oxygen measurement)

Routine blood tests for safety:
o
Complete blood count
o
Blood Chemistry
o
Liver function tests

Urinalysis

Blood sample for research purposes
Study Treatment Beyond Disease Progression
With most anti-cancer drugs, an increase in the size or number of tumors detected with CT or MRI 
scans or a physical exam is a signal that your disease has progressed and that you should consider 
switching to another therapy. However, an early increase in the size or number of tumors may not 
always be a sign of disease progression. Because of this possibility, you will have the option of 
continuing to receive study drug even after a scan in the course of your treatment shows an increase 
in the size or number of your tumors. A later scan will help to determine whether the increase was 
caused by real progression of your disease. Additional tests may help determine the cause for the 
increase in the size or number of your tumors and may be required to allow you to continue in the 
study. 
You may have other potentially beneficial approved treatments available to you. These treatments 
may include those that may shrink tumors, delay progression of cancer, provide symptom relief, 
or prolong your life. The option to continue pembrolizumab and bevacizumab treatment in spite 
of an apparent increase in tumor size should be carefully discussed with your study doctor. There 
are risks of continuing to receive pembrolizumab and bevacizumab treatment beyond an apparent 
increase in tumor size because of the possibility that it represents true progression of your disease. 
In that case, you may be exposed to an ongoing risk of side effects caused by the study drugs and 
delay the initiation of other treatment options that may have demonstrated benefit in clinical trials. 
In addition, your cancer may progress to the point that you are no longer able to receive other 
potentially effective therapies. If you show true progression of your disease, you will be 
discontinued from the study and the study doctor will ask you to visit the office for follow up 
exams.
If the size or number of your tumors show apparent progression, you will be asked to sign a 
separate consent form to continue receiving the study drugs. 
Follow-up Period
You will continue to have tumor assessments by CT scan of the chest, abdomen and pelvis and a 
Brain MRI every 9 weeks until disease progression, withdrawal of consent, start of a new anti-
cancer therapy, or death.
Long Term Follow-Up
You will be contacted by the study team every 3 months for survival follow-up information.
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 7 of 24
YCC v18.0 (23-Apr-2024) 
Optional Specimens for Future Storage/Genetic Testing
You are invited to allow some of your samples (called specimens) and related information to be 
stored (banked) for future research. This may help researchers in the future learn more about how 
to prevent, find and treat melanoma or NSCLC. Your specimens will be stored for an unlimited 
time, and may be used to make a cell line that will live indefinitely. 
Future research may look at your genes, which are the units of inheritance that are passed down 
from generation to generation. Genes are responsible for many things about you such as eye color, 
hair color, blood type and hundreds of other traits. Future genetic analysis may possibly include 
finding out the details of how your DNA is put together, such as whole exome or genome 
sequencing, or genome wide association studies (that is, looking at genes other than those 
associated with a specific disease). The materials at some point may be injected into animals in 
some of the research. We expect that there will be widespread sharing of these specimens and 
associated information. 
When your specimens and information are stored, we are careful to try to protect your identity 
from discovery by others. Your samples and information will receive a unique code. Other 
researchers will only receive coded samples and information, and will not be able to link the code 
to you. Strict security safeguards are in place to reduce the chance of misuse or unplanned release 
of information.
Using your specimens for research will probably not help you. We do hope the research results 
will help people in the future.
There is a risk that your information could be misused. The chance of this happening is very small. 
We have protections in place to lower this risk. There can also be a risk in uncovering genetic 
information. New health information about inherited traits that might affect you or your blood 
relatives could be found during a research study. Very rarely, health or genetic information could 
be misused by employers, health insurance companies, and others. A federal law called the Genetic 
Information Nondiscrimination Act (GINA) generally, makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your 
genetic information.
Your specimens and information will only be used for research and will not be sold. There is a 
possibility that this research may lead to development of products that will be commercialized. If 
this happens, there is no plan to share any financial gain with you or your family.
Research results will not be returned to you or your doctor. If research results are published, your 
name and other personal information will not be given.
The choice to take part is up to you. You may choose not to let us store and use your samples, and 
your care will not be affected by this decision. If you decide that your samples can be kept, you 
may change your mind at any time. To withdraw your samples from the study, you can call a 
member of the research team or you may write to the Principal Investigator using the contact 
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IRB #: 
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information on page one of this form at any time and tell them you do not want your samples used 
any longer. 
You will be asked to indicate your choice at the end of this form.
Potential Risks, Side Effects, Discomforts and Inconveniences
While in this study, you may have side effects. Anticipated side effects are listed here. In addition 
to the risks listed below, there may be risks that are currently unknown. If significant new risks 
develop during the course of study that might affect your willingness to participate, information 
will be reported to you as soon as possible. Possible side effects that you may experience during 
this study will be fully explained to you by the study staff. Please ask as many questions as you 
want so that you can understand the possible side effects of your specific treatment before you 
decide whether you want to be in this study. Please ask the study doctor or the study staff to explain 
any information or words that are not clear to you.
Risks Associated with Pembrolizumab
Pembrolizumab, which is approved in the USA and some other countries, is 
available by prescription to treat several different cancers but may not be approved 
to treat your type of cancer. 
Pembrolizumab works by helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal 
organs and tissues in your body and can affect the way they work, which can result 
in side effects. These side effects may be serious (i.e., causing hospitalization or be 
life-threatening), may result in death, and/or may occur after you stop taking 
pembrolizumab. These side effects can affect more than one of your normal organs and tissues at 
the same time. 
Very Common, Some May Be Serious (For Example, Causing Hospitalization, Life-
Threatening or Where Noted, May Cause Death)
Out of 100 people who receive pembrolizumab, 20 or more people may have the following:

Itching of the skin

Loose or watery stools

Cough
Common, Some May Be Serious (For Example, Causing Hospitalization, Life-Threatening, 
or Where Noted, May Cause Death)
Out of 100 people who receive pembrolizumab, at least 5 but less than 20 people may have 
the following:

Joint pain

Fever
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YCC v18.0 (23-Apr-2024) 

Back pain

Rash

Pain in your belly

Loss of skin color

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have infrequent 
or hard stools

Low levels of salt in the blood that may cause you to feel tired, confused, have a headache, 
muscle cramps and/or feel sick to your stomach
Uncommon, Some May Be Serious (For Example, Causing Hospitalization, Life-
Threatening, or Where Noted, May Cause Death)
Out of 100 people who receive pembrolizumab, at least 1 but less than 5 people may have the 
following:

Inflammation of the lungs so you may feel short of breath and cough. Rarely this might 
lead to death

Too much thyroid hormone so you may feel anxious, angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools

Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, feel 
short of breath, experience a decrease in your blood pressure at the time of receiving your 
infusion (IV) or just after, or pain at the site of infusion.

Inflammation of the bowels/gut that can cause pain in your belly with loose or watery 
stools, and black, tarry, sticky stools or stools with blood or mucus

Inflammation of the skin so you may have peeling of the skin, itching, and/or skin redness. 
The skin inflammation (for example peeling, itching and redness) could also be widespread 
throughout your body. More severe skin reactions may involve the inside of your mouth, 
the surface of your eye and genital areas, and/or may cause the top layer of your skin to 
peel from all over your body which can cause severe infection. These severe conditions 
can sometimes lead to death (epidermal necrolysis)
Rare, Some May Be Serious (For Example, Causing Hospitalization, Life-Threatening, or 
Where Noted, May Cause Death)
Out of 100 people who receive pembrolizumab, less than 1 person may have the following: 

Inflammation of the nerves that may cause pain, weakness or tingling in your hands and 
feet, and may spread to your legs, arms and upper body leading to severe muscle weakness

Inflammation of the muscles so you may feel weak or pain in the muscles

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you 
may have severe upper abdominal pain that may move to your back, feel sick to your 
stomach, and vomiting that gets worse when you eat

Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light, 
eye pain, see floaters or have headaches

Inflammation of the liver which may make you feel sick to your stomach and vomit, feel 
like not eating, feel tired, have a mild fever, have a pain in the right side of your belly, 
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IRB #: 
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YCC v18.0 (23-Apr-2024) 
yellow eyes and skin, and dark urine

Inflammation of the pituitary gland in the brain (a gland in the head), which may you to 
feel sick to your stomach or have headaches, changes in your behavior, double vision, few 
to no menstrual cycles, weakness, vomiting and dizziness or fainting. 

Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which 
could cause tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and belly 
aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes 
darkening of the skin like a suntan

Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling thirstier 
than usual, frequent urination and weight loss. You are likely to need regular insulin shots.

Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, and 
experience swelling and/or low back pain

Inflammation of the middle layer of your heart wall (myocarditis) that may cause your 
heart to have difficulty pumping blood throughout your body, which can cause chest pain, 
shortness of breath and swelling of the legs. You may experience a fast or irregular 
heartbeat that may cause dizziness or fainting. Sometimes this condition can lead to death

Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy.

A condition that may make you feel weak and tired and might have drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and 
legs, or difficulty breathing

The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin, or lungs (called sarcoidosis)

Inflammation of the brain (called encephalitis) with confusion and fever. This may also 
include: disorientation, memory problems, seizures (fits), changes in personality and 
behavior, difficulty speaking, weakness or loss of movement in some parts of your body, 
and loss of consciousness

Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms or 
legs, bladder or bowel problems including needing to urinate frequently, urinary 
incontinence, difficulty urinating, and constipation (myelitis).

Inflammation of the blood vessels (vasculitis).  Symptoms will depend on the particular 
blood vessels that are involved in the inflammatory process, for example; if it is your skin, 
you may get a rash. If your nerves are not getting enough blood, you could have numbness 
and weakness. You may also experience fever, weight loss, and fatigue.

Low levels of parathyroid hormone (a hormone made by 4 tiny glands in your neck) 
which may result in low blood calcium and cause muscle cramps or spasms; fatigue or 
weakness; numbness, tingling or burning in your fingertips, toes or lips 
(hypoparathyroidism)

Inflammation of the stomach (gastritis). You may have pain in your belly, feel full, or 
sick to your stomach. You may also experience nausea, vomiting or loss of appetite. 

Low number of red blood cells (cells that carry oxygen) due to destruction of red blood 
cells (hemolytic anemia). You may feel weak, tired, lightheaded, short of breath, or have 
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YCC v18.0 (23-Apr-2024) 
a fast heartbeat. You may also experience difficulty with physical exercise, pale or 
yellow skin, dark urine, or fever.

Not enough pancreatic enzymes (proteins that break down food) that leads to poor 
digestion of food (exocrine pancreatic insufficiency). You may have bloating, gas, 
discomfort in your belly, diarrhea, abnormal stool that is oily, or weight loss.
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in which 
a person receives blood-forming stem cells from a donor), you may experience graft versus host 
disease (GvHD), which may include diarrhea, skin rashes, and liver damage, after receiving 
pembrolizumab. Sometimes this condition can lead to death.
If you have had a solid organ transplant (for example, if you have received a kidney or heart 
transplant), you may experience rejection of the transplanted organ. Your doctor will monitor you 
and should tell you what signs and symptoms you should report depending on the type of organ 
transplant that you have had.
Additionally, since pembrolizumab was approved in September 2014, the following side effects 
have been reported by people receiving pembrolizumab. These side effects were voluntarily 
reported from a group of people of unknown size. It is not possible to estimate the frequency of 
these side effects:

Inflammation of the joints which may include joint pain, stiffness and/or swelling

Severe responses of the immune system that cause the body to attack its own blood cells, 
spleen, liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of 
the liver, yellowing of the skin, an enlarged liver and spleen, low blood counts, and 
enlarged lymph nodes. The nervous system may also be affected and cause confusion, 
seizures, and even coma

Changes in eyesight, eye pain, whitish patches on the skin and hearing loss (Vogt-
Koyanagi-Harada syndrome)

Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made in 
the liver). This can cause symptoms similar to those seen with inflammation of the liver 
(hepatitis) such as pain in right side of your belly, yellow eyes and skin, feeling tired, and 
itching (sclerosing cholangitis).

Inflammation or swelling of the nerve fibers of the eye which send visual information 
from your eye to your brain. This health condition often has a sudden onset of vision loss, 
loss of color vision, pain when moving your eyes, and/or loss of peripheral vision. It may 
affect one or both eyes at the same time (optic neuritis).
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Principal Investigator:
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IRB #: 
1512016953
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YCC v18.0 (23-Apr-2024) 
Risks Associated with Bevacizumab:
The addition of bevacizumab to anticancer therapies has led to an increased frequency of the side 
effects listed below.
Very common (occurring in greater than or equal to 10% of subjects):

High blood pressure (hypertension)

Numbness or loss of feeling in the fingers or toes (peripheral sensory neuropathy)

Low numbers of white blood cells (neutropenia, leucopenia) potentially associated with 
fever (febrile neutropenia)

Low numbers of platelets (thrombocytopenia), 

Shortness of breath (dyspnea)

Diarrhea

Bleeding from the rectum (rectal hemorrhage)

Nausea and vomiting

Pain, including headache and joint pain (arthralgia)

Constipation

Mucosal inflammation or inflammation of the mouth (stomatitis)

Protein in the urine

Mucocutaneous bleeding, which includes nosebleeds (epistaxis)Lack of energy and 
weakness (asthenia, fatigue)

Loss of appetite (anorexia)

Fever (pyrexia)

Runny nose (rhinitis)

Dry skin, flaking and inflammation of the skin (exfoliative dermatitis)

Change in skin color (skin discoloration)

Change in the sense of taste (dysgeusia)Eye disorder, watery eyes (lacrimation increased)

Abdominal pain

Weight loss

Low levels of magnesium in the blood (Hypomagnesemia) which could cause weakness 
and muscle cramping. Rarely heart rhythm abnormalities may occur

Decreased levels of sodium in the blood (Hyponatremia), which can cause confusion, 
seizures, fatigue and low levels of consciousness

Alteration in speech (dysarthria)

Fertility problems in women (ovarian failure)

Nail-related changes

Delay in wound healing, failure of a wound to heal, or spontaneous opening of a wound

Cough
Common (occurring in 1%10% of subjects):

Infection, presence of bacteria in the blood (sepsis), collection of pus in tissue or organs 
(abscess), and skin and soft tissue infection (cellulitis)

Infection in urine (urinary tract infection)

Tear or hole in the gut (perforation of the gastrointestinal tract)
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Principal Investigator:
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IRB #: 
1512016953
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YCC v18.0 (23-Apr-2024) 

Abnormal tube-like connection between internal organs and skin or other tissues that are 
not normally connected (fistula) including bowel and vagina (recto-vaginal fistulae)

Low numbers of red blood cells (anemia)

Bleeding, (hemorrhage) including bleeding associated with the tumor

Clogging of a blood vessel in the lung (pulmonary embolism)

Blocking of the arteries by a blood clot (arterial thromboembolism), including stroke 
(cerebral vascular accident) or heart attack

Heart failure, (congestive cardiac failure) especially in subjects who have received a certain 
type of chemotherapy in the past, such as mitoxantrone or other

chemotherapy drugs called anthracyclines (e.g. doxorubicin)

Blood clots in the veins (deep vein thrombosis)

Blockage in the intestine (ileus, intestinal obstruction)

Body water loss (dehydration)

Pain, tenderness, or blistering on the fingers or feet (hand-foot syndrome, palmar-plantar 
erythrodysesthesia syndrome)

Low levels of oxygen in the blood (hypoxia)

Fainting (syncope)

Allergic reaction, including allergic reaction to the drug during the infusion

Gastrointestinal disorder

Voice changes and hoarseness (dysphonia)

Muscular pain and muscular weakness (myalgia)

Pain, including rectal pain (proctalgia), back pain, and pelvic pain

Rapid beating of the heart (supraventricular tachycardia)

Sleepiness, feeling tired (somnolence, lethargy)
Less common (occurring in 0.1%1% of subjects):

Abnormal connection between the windpipe (trachea) and the esophagus (the tube that 
connects the mouth to the stomach) (tracheal-esophageal fistula)

Abnormal connection between the tubes within the gallbladder and surrounding organs 
(biliary fistula)
Rare but serious (occurring in 0.01%0.1% of subjects):

Medical condition that presents with symptoms of impaired brain function (headaches, 
vision changes, confusion, or seizures), and often, high blood pressure (posterior reversible 
leukoencephalopathy syndrome [PRES]

Serious infections of the skin or deeper layers under the skin, especially with participants 
who have had holes in the gut wall or problems with wound healing (necrotizing fasciitis)
Very rare but serious (occurring in less than 0.01% of subjects):

Medical condition that presents with symptoms that suggest changes in the normal brain 
function (headaches, vision changes, confusion, or seizures), and often, high blood pressure 
(Hypertensive encephalopathy)
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YCC v18.0 (23-Apr-2024) 
Unknown Frequency:

Abnormalities in the fetuses (unborn babies) of pregnant women treated with bevacizumab 
alone or in combination with chemotherapy that is known to be harmful to fetuses

Open sore or hole in the gut lining of the stomach or small intestine (gastrointestinal ulcers)

Hole in the nasal passage (nasal septum perforation)

Hole in the gallbladder (gallbladder perforation)

Abnormally high blood pressure in the blood vessels of the lungs that makes the right side 
of the heart work harder than normal (pulmonary hypertension)

Hypersensitivity infusion reaction – including shortness of breath (dyspnea), difficulty 
breathing, flushing, rash, redness of the skin (erythema), low blood pressure (hypotension) 
or high blood pressure (hypertension), oxygen reduction (desaturation), chest pain, 
shivering (rigors), and nausea and vomiting

Inflammation of eye caused by infection (Infectious endophthalmitis), may lead to 
blindness

Eye (Intraocular) inflammation (which may lead to blindness) including inflammation of 
the tissue of the eye (sterile endophthalmitis), inflammation of the iris of the eye 
(uveitis),and inflammation of the cells in the vitreous cavity (vitritis)

Separation of the retina from its connection at the back of the eye (Retinal detachment), 
Retinal pigment epithelial tear

Increased pressure in the eye (Intraocular pressure increased)

Bleeding into the eye (Intraocular hemorrhage –vitreous hemorrhage or retinal 
hemorrhage)

Bleeding in the tissue lining the eye (Conjunctival hemorrhage)

Weakened blood vessel that bursts or bleed into brain (Hemorrhagic stroke)
Other Relevant and Important Information and Risks Associated with Bevacizumab
Bevacizumab may also cause changes in laboratory tests, such as changes in kidney function
tests (increased blood creatinine), decreased blood potassium (hypokalemia) and sodium 
(electrolyte), increased blood sugar, or altered coagulation (how your blood clots) values.
Some side effects are more common in elderly subjects than in younger subjects. These side effects 
include blood clots in the arteries, which can lead to a stroke or a heart attack. In addition, elderly 
subjects have a higher risk of a reduction in the number of white cells in the blood (neutropenia, 
leucopenia) or platelets (thrombocytopenia), diarrhea, nausea, headache,
and fatigue.
Patients with a medical history of diabetes (diabetes mellitus) or a history of arterial 
thromboembolism have an increased risk of developing arterial thromboembolism.
Other Risks
Brain Biopsy:
A brain biopsy will be obtained while you undergo any surgical procedure (resection or LITT) that 
is necessary to treat the brain tumor. Although uncommon, infection or bleeding at the surgical 
site or brain could occur as well as the possibility of temporary or permanent neurological 
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YCC v18.0 (23-Apr-2024) 
problems. These risks depend on the location of the tumor in the brain and will be reviewed with 
you in detail by your study doctors before the procedure.
Blood Collection and Intravenous (IV) Catheter Placement:
The risks of taking blood may include pain, redness, swelling and/or bruising where the needle 
enters your body, light-headedness and fainting. On rare occasions, local blood clot formation or 
infection with redness and irritation of the vein has occurred. The blood pressure cuff may cause 
discomfort or bruising to the upper arm. Approximately 10 mL of blood will be taken during your 
participation in this research study pre-treatment, after 6 weeks of therapy, 12 weeks of therapy 
and every 9 weeks thereafter for research purposes only. 
Tumor Biopsy:
As with any procedure, there are risks and discomforts. You may feel some amount of pain or 
discomfort during a biopsy, including slight, stinging pain when a local anesthetic is injected by 
needle to numb the area, pressure and dull pain where the biopsy needle is inserted, discomfort 
from lying still for an extended time, and soreness, inflammation, bleeding, swelling, and/or 
infection at the biopsy site. With a tumor biopsy, there is a rare possibility of tumor cells spreading 
into the nearby area. If a general anesthetic is used, you will not feel pain during the procedure 
because you will be asleep. Your physician will explain the details of the procedure and the risks 
to you, depending on how the biopsy will be obtained. 
Brain MRI scan:
You may not have an MRI done if you have metal in your body, for example, some hip 
replacements, hearing aids, pacemakers, bullets, or jewelry that cannot be removed. You should 
inform the technologist or study doctor if you have any metal in your body. During the MRI exam, 
you may feel some heat and hear tapping noises but have no reason to worry. Some people may 
have a ‘closed in’ feeling while inside the machine. The injection may make you sick to your 
stomach or have pain, warmth, swelling, bruising, a small blood clot or infection at the injection 
site. Rarely, you may get a rash or other signs of allergy from the injection or get a rare disease 
where some of your body parts get scarred. If you have a history of kidney problems, you must 
inform the technologist or physician as you may not be able to receive an injection during the MRI 
exam. Please talk to your physician if you have any concerns or questions.
Risks associated with gadolinium contrast:
You may have a small IV catheter placed before the MRI scan so that gadolinium contrast can be 
injected into a vein as this may help to better determine if your cancer has spread. With gadolinium 
contrast severe reactions are rare. The FDA approves the contrast agent Gadolinium for use with 
human participants. You need to know that there are certain risks associated with the use of that 
contrast. Some healthy subjects (fewer than 3%) may experience mild nausea, headache or 
dizziness after the injection. These side effects usually resolve without need for treatment. There 
is also a risk of allergic reaction (less than 1%). An allergic reaction can cause hives and itching 
or difficulty breathing. In individuals with kidney dysfunction, the gadolinium can cause a serious 
condition called nephrogenic systemic fibrosis. Because of this, prior to your MRI scan you will 
have to undergo blood work to make sure that your kidney function is normal. 
Detailed information on the contrast agent Gadolinium can be provided to you at your request. 
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YCC v18.0 (23-Apr-2024) 
You should inform your study doctor: (1) if you are pregnant or breast feeding, (2) if you have a 
history of allergic reactions to MRI or CT contrast agents, (3) if you have a history of kidney 
disease, seizure, asthma, or allergic respiratory disorders, and (4) if you have anemia or disease 
that affects red blood cells. 
Reproductive Risks:
Female
It is not known if the study drugs may affect an unborn or nursing baby or has an adverse effect 
on sperm. Females who are pregnant, trying to become pregnant or breast-feeding, may not be in 
the study. The study doctor will perform a blood and/or urine pregnancy test before the start of 
and during the study, for females who are able to have a baby.
If you are able to have a baby, you must avoid having sex (abstinence) or use reliable birth control 
methods during the study and for a period of 120 days after your last dose of pembrolizumab. The 
following birth control methods are allowed during the study as per local regulations or guidelines:
Two (2) of the following barrier methods in combination:

Diaphragm 

Condom (by the partner)

Copper Intrauterine device (IUD)

Contraceptive sponge

Spermicide
OR One (1) of the above barrier methods in combination with:

Hormonal contraceptives (including oral, subcutaneous, intrauterine, or intramuscular) that 
are registered and marketed containing estrogen and/or a progestational agent
If you become pregnant during the study, or within 120 after the study, you must notify the study 
doctor right away. The study drug will be stopped, and you will be taken out of the study. 
Male
There may be risks if you are male and your partner is pregnant or trying to become pregnant. If 
you are male and your partner is able to have a baby, you and your partner must practice abstinence 
or use a reliable birth control method during the study and for a period of 120 days after the last 
dose of study drug. The following birth control methods are allowed during the study:
Two (2) of the following barrier methods in combination: 

Diaphragm 

Condom 

Copper Intrauterine device (IUD)

Contraceptive sponge

Spermicide
 
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Principal Investigator:
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IRB #: 
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YCC v18.0 (23-Apr-2024) 
OR One (1) of the above barrier methods in combination with: 

Hormonal contraceptives (including oral, subcutaneous, intrauterine, or intramuscular) that 
are registered and marketed containing estrogen and/or a progestational agent
If your partner becomes pregnant during or within 120 days after the study, you must notify the 
study doctor immediately. 
You must also agree to not donate sperm during the study and for a period 120 days after your last 
dose of study drug.
There may also be side effects, other than listed above that we cannot predict. Other drugs will be 
given to make side effects that occur less serious and less uncomfortable. Many side effects go 
away shortly after the study drug or procedure is stopped, but in some cases side effects can be 
serious, long lasting or permanent.
For more information about risks and side effects, ask the researcher or contact their office at 203-
200-6622. If you are a non-small cell lung cancer subject, you may also call Dr. Sarah Goldberg 
at 203-737-5649.
Benefits
If you agree to take part in this research study, we cannot guarantee that you will receive any 
benefits. We hope the information learned from this research study may benefit other patients who 
have metastatic melanoma or non-small cell lung cancer with untreated brain metastases in the 
future.
Economic Considerations/Cost
If you take part in this study, the sponsor pays the study doctor to conduct the study and covers 
the cost of  the study drug and the study-related tests and procedures (they are NOT part of your 
routine medical care). However, there may be additional costs to you. These can include costs of 
transportation and your time to come to the study visits. You or your health insurance must pay 
for services, supplies, procedures, and care that are part of your routine medical care. You will be 
responsible for any co-payments required by your insurance.
If you need assistance in answering financial questions related to your insurance, contact your 
study team who can connect you with a representative in the YCCI Clinical Research Billing and 
QA office at 1-877-874-2560.
For more information on clinical trials, you can visit the National Cancer Institute’s (NCI) web 
site at http://www.cancer.gov/aboutnci/organization/clinical-center-fact-sheet.
To learn more information about paying for clinical trials and insurance, you can visit the NCI 
web site at:
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
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• http://www.cancer.gov/clinicaltrials/learningabout/payingfor
• http://www.cancer.gov/clinicaltrials/learningabout/payingfor/insurance-coverage
Another way to get information is to call the NCI at 1-800-4-CANCER (1-800-422-6237) and 
talk to an Information Specialist, Monday-Friday 8am-8pm EST. You can request free 
information to be sent to you, such as the Cancer Clinical Trials FactSheet.”
Investigator Interest 
The Principal Investigator on this study has received financial compensation from the 
manufacturer of the study drug Pembrolizumab for providing services on an advisory board and 
lecturing.
Treatment Alternatives
You do not have to participate in this study. Your other choices may include:

Getting treatment or care for your cancer without being in a study. This includes taking 
pembrolizumab or bevacizumab alone without participating in this research study.

Taking part in another study.

Receiving no treatment at this time.

Getting comfort care, also called palliative care; this type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by the cancer. Comfort care does 
not treat the cancer directly but instead is meant to improve how you feel. Comfort care 
tries to keep you as active and comfortable as possible. 
Talk to your doctor about your choices and their risks and benefits before you decide if you will 
take part in this study.
This research is covered by a Certificate of Confidentiality from the National Institutes of Health.
The researchers with this Certificate may not disclose or use information, documents, or
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative,
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a
court subpoena, unless you have consented for this use. Information, documents, or biospecimens
protected by this Certificate cannot be disclosed to anyone else who is not connected with the
research except, if there is a federal, state, or local law that requires disclosure (such as to report
child abuse or communicable diseases but not for federal, state, or local civil, criminal
administrative, legislative, or other proceedings, see below); if you have consented to the
disclosure, including for your medical treatment; or if it is used for other scientific research, as
allowed by federal regulations protecting research subjects. 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 19 of 24
YCC v18.0 (23-Apr-2024) 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the National Cancer Institute which is funding this project.  You should 
understand that a Certificate of Confidentiality does not prevent you from voluntarily releasing 
information about yourself or your involvement in this research. If you want your research 
information released to an insurer, medical care provider, or any other person not connected with 
the research, you must provide consent to allow the researchers to release it.
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law of such as child abuse and neglect, or harm to self or others. 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document such as including your research data in your 
medical record and sharing your de identified data and specimens with other researchers 
Confidentiality and Authorization to collect, use and disclose Protected Health Information
For purposes of this study, Yale University, Yale-New Haven Hospital, and Dr. Harriet Kluger as 
the Principal Investigator will use medical information collected or created as part of the study, 
such as medical records and test results, which identifies you by name or in another way. Your 
consent to participate in the study means you agree that Yale University, Yale-New Haven 
Hospital, and Dr. Kluger may obtain your medical information that they request for study purposes 
from your physicians and your other health care providers from the past or during your 
participation in the study. 
The protected health information that will be collected in this study includes demographics, 
medical history, physical examinations, routine lab tests, review of adverse events and medications 
you take (past and present), vital signs, MRI scans, CT scans, pregnancy tests, blood or tissue 
samples for research purposes, survival follow-up information and records about any study drug(s) 
that you received.
Any identifiable information that is obtained in connection with this study will remain confidential 
and will be disclosed only with your permission or as permitted by U.S. or State law. Examples of 
information that we are legally required to disclose include abuse of a child or elderly person, or 
certain reportable diseases such as HIV or hepatitis. Positive results of HIV and Hepatitis will be 
reported to CT Department of Public Health. When the results of the research are published or 
discussed in conferences, no information will be included that would reveal your identity unless 
your specific consent for this activity is obtained. 
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information. If you decide to be in this 
study, the study staff will get information that identifies you and your protected health information. 
This may include information that might directly identify you, such as your name, date of birth, 
and medical record number. This information will be de-identified whenever possible prior to 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 20 of 24
YCC v18.0 (23-Apr-2024) 
providing it to the sponsor, meaning we will replace your identifying information with a code that 
does not directly identify you. The study doctor will keep a link that identifies you to your coded 
information, and this link will be kept secure and available only to the Principal Investigator or 
selected members of the study team. Any information that can identify you will remain confidential. 
The records for this trial will be stored in locked cabinets and/or offices and password protected 
computers. The study team will only give this coded information to others to carry out this research 
study or to sponsor representatives to comply with federal laws and regulations. It is anticipated 
that records containing the information that links you to your coded information will be maintained 
indefinitely, as there are no plans at this time to destroy these records at the end of the study. 
Information about your study participation will be entered into your Electronic Medical Record 
(EMR). Once placed in your EMR, these results are accessible to all of your providers who 
participate in the EMR system. Information within your EMR may also be shared with others who 
are appropriate to have access to your EMR (e.g., health insurance company, disability provider.)
Information about you and your health which might identify you may be used by or given to: 

The U.S. Department of Health and Human Services (DHHS) agencies

Representatives from Yale University and the Human Investigation Committee (the 
committee or Institutional Review Board that reviews, approves, and monitors research on 
human subjects), Yale Center for Clinical Investigation who are responsible for ensuring 
research compliance. These individuals are required to keep all information confidential

Your providers who are participants in the Electronic Medical Record (EMR) system

Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments

The study doctor, Harriet Kluger, MD, the Yale study team, and research team members at 
each participating institution

The U.S. Food and Drug Administration (FDA). This is done so that the FDA can review 
information about the new drug product involved in this research. The information may 
also be used to meet the reporting requirements of drug regulatory agencies. 

The manufacturer of study drug, Merck & Co. Inc. and/ or their representatives 

Drug regulatory agencies in other countries

Governmental agencies to whom certain diseases (reportable diseases) must be reported

Health care providers who provide services to you in connection with this study.

Laboratories and other individuals and organizations that analyze your health information 
in connection with this study, according to the study plan.

Data and Safety Monitoring Boards and others authorized to monitor the conduct of the 
study 
By signing this form, you authorize the use and/or disclosure of the information described above 
for this research study. The purpose for the uses and disclosures you are authorizing is to ensure 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 21 of 24
YCC v18.0 (23-Apr-2024) 
that the information relating to this research is available to all parties who may need it for research 
purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability Act) 
are required to protect the privacy of your information. The research staff at Yale School of 
Medicine and Yale-New Haven Hospital is required to comply with HIPAA and to ensure the 
confidentiality of your information. Some of the individuals or agencies listed above may not be 
subject to HIPAA and therefore may not be required to provide the same type of confidentiality 
protection. They could use or disclose your information in ways not mentioned in this form. 
However, to better protect your health information, agreements are in place with these individuals 
and/or companies that require that they keep your information confidential. 
Authorized representatives of the Food and Drug Administration (FDA) and the manufacturer of 
the study drug being tested, Merck & Co. Inc., may need to review records of individual subjects. 
As a result, they may see your name, but they are bound by rules of confidentiality not to reveal 
your identity to others.
The sponsor will see the research information we collect about you when they come to Yale to monitor 
the conduct of this research study. The “Sponsor” includes any persons that work for or are hired by 
the sponsor to conduct research activities related to this study.  For this study the sponsor is Merck & 
Co. Inc. Yale researchers will also send the sponsor your health information during the study or at the 
end of the study. When Yale researchers send information about you to the sponsor, they will not send 
information that directly identifies you such as your name.
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies. However, you will not be allowed to look 
at or copy your study related information until after the research is completed. 
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
In Case of Injury
If you are injured while on study, seek treatment and contact the study doctor as soon as you are 
able.
Yale University and Yale-New Haven Hospital do not provide funds for the treatment of research-
related injury. If you are injured as a result of your participation in this study, treatment will be 
provided. You or your insurance carrier will be expected to pay the costs of this treatment. No 
additional financial compensation for injury or lost wages is available.
You do not give up any of your legal rights by signing this form.
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 22 of 24
YCC v18.0 (23-Apr-2024) 
Voluntary Participation and Withdrawal
Participation in this study is voluntary. You are free to choose not to take part in this research 
study. Refusing to take part in this research study will not lead to penalty or loss of benefits to 
which you are otherwise entitled (such as your health care outside the study, the payment for your 
health care, and your health care benefits). However, you will not be able to enroll in this research 
study and will not receive study procedures as a study participant if you do not allow use of your 
information as part of this study.
Withdrawing from the Study:
If you decide to participate in this research study, you are free to stop and withdraw from this study 
at any time during its course. To withdraw from the study, you can call a member of the research 
team at any time and tell them that you no longer want to take part. They will make sure that proper 
procedures are followed and a final visit is made for your safety. This will cancel any future 
research study appointments. 
The researchers may withdraw you from participating in the research if necessary. You may be 
withdrawn by the researchers for progression of disease/poor response to treatment, development 
of serious side effects, or non-compliance (not following instructions from the study team). 
Withdrawing from the study will involve no penalty or loss of benefits to which you are otherwise 
entitled.
If you choose not to give your consent by not signing and dating this document, or if you cancel 
your consent later, then you will not be eligible to participate in this study and will not receive any 
study treatment provided as part of the study. Unless and until you do cancel the consent, it will 
remain valid and effective.
Withdrawing Your Authorization to Use and Disclose Your Health Information:
You may withdraw or take away your permission to use and disclose your health information at 
any time. You do this by telling the study staff or by sending written notice to the study doctor, 
Harriet Kluger, MD, at the address listed on page one of this form. If you withdraw your 
permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be gathered 
after that date. Information that has already been gathered may still be used and given to others 
until the end of the research study, as necessary to ensure the integrity of the study and/or study 
oversight. 
Questions
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the Investigator at the 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 23 of 24
YCC v18.0 (23-Apr-2024) 
telephone number listed on the first page of this consent document.  If you seek emergency care, 
or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects.  If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact:
Human Research Protection Program
Institutional Review Boards
FWA00002571
25 Science Park – 3rd Fl., 150 Munson St.
New Haven CT 06520-8327                   
If after you have signed this form you have any questions about your privacy rights, please contact 
the Yale Privacy Officer at (203) 432-5919. 
If you have further questions about this project or if you have a research-related problem, you may 
contact the Principal Investigator, Dr. Kluger at (203) 200-6622.
If you would like to talk with someone other than the researchers to discuss problems, concerns, 
and questions you may have concerning this research, or to discuss your rights as a research 
subject, you may contact the Yale Human Research Protection Program at (203) 785-4688 or email 
hrpp@yale.edu. 
We have used some technical terms in this form.  Please feel free to ask about anything you 
don't understand and to consider this research and the consent form carefully – as long as you 
feel is necessary – before you make a decision.
Optional Future Research
Please indicate your choice below by checking yes or no:
_____ Yes, I agree to allow my blood and tissue samples to be stored and used for future 
research.
_____ No, I do not agree to allow my blood and tissue samples to be stored and used for future 
research.
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024


APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024
Principal Investigator:
Harriet Kluger, MD
IRB #: 
1512016953
Sponsor ICF Template Version:
19.0
Funding Source:
Yale Cancer Center, Merck and Co., 
Inc 
Sponsor ICF Template Date:
19-APR_2024
Page 24 of 24
YCC v18.0 (23-Apr-2024) 
Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project as 
described above. Its general purposes, the particulars of my involvement and possible hazards and 
inconveniences have been explained to my satisfaction. My signature also indicates that I have 
received a copy of this consent form.
By signing this form, I give permission to the researchers to use and give out information about 
me for the purposes described in this form. By refusing to give permission, I understand that I will 
not be able to participate in this research. 
I also confirm that I have received a Trial Alert Card providing contact details of the study doctor 
and agree to carry this card with me at all times. 
Study Participant (print 
name)
Signature
Date
Person obtaining 
consent (print name)
Signature
Date
Person obtaining 
consent (print name) – 
only if applicable, 
otherwise blank
Signature
Date
Witness (print name) 
– only if applicable, 
otherwise blank
Signature
Date
 
APPROVED BY THE YALE UNIVERSITY IRB 5/9/2024