Conditions: Clear Cell Renal Carcinoma
Keywords: MK-3475 Pembrolizumab Bevacizumab
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 61
Healthy volunteers: no

Brief summary:
This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved.

Detailed description:
OUTLINE: This is a multi-center study.

The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease. The phase II trial will determine the activity of the combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic clear cell renal carcinoma.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

PHASE II INVESTIGATIONAL TREATMENT:

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months.

Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol therapy.

Life Expectancy: 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for protocol therapy:

Hematopoietic:

* Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L
* Platelets ≥ 100 × 10 9/L
* Hemoglobin (Hgb) ≥ 9.0 g/dL

Renal:

* Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
* OR, if serum creatinine \> 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

Hepatic:

* Total serum bilirubin ≤ 1.5 × ULN
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
* OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying malignancy

Coagulation:

* INR \< 1.5 × ULN
* OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.

Arms:
arm 1: Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. arm 2: The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle.

Interventions: intervention 1: MK-3475 intervention 2: Bevacizumab intervention 3: MK-3475 intervention 4: Bevacizumab
Intervention descriptions: intervention 1: Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV intervention 2: Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV intervention 3: Arm B: Phase II Treatment: 200mg IV intervention 4: Arm B: Phase II Treatment: administered at the maximum safe dose of 10mg or 15mg as established in the Phase 1b dose escalation cohort study.

Protocol document:
Prot_SAP_000.pdf: 
 
Page 1 of 70 
 
 
 
Phase Ib and Phase II Studies of anti-PD-1 Antibody Pembrolizumab (MK-3475) in 
Combination with Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma:  
Big Ten Cancer Research Consortium BTCRC-GU14-003 
 
 
Sponsor Investigator 
Arkadiusz Z. Dudek, MD, PhD  
University of Illinois at Chicago 
 
 
Co-Investigators  
Basharath Khan, MD 
University of Illinois at Chicago 
 
Statistician 
Hui Xie, PhD 
Associate Professor of Biostatistics 
Division of Epidemiology and Biostatistics School of Public Health 
University of Illinois-Chicago 
 
 
Trial Supported by  
Merck Sharp & Dohme Corp. 
 
Trial Management by 
BTCRC Administrative Headquarters at Hoosier Cancer Research Network 
500 North Meridian Street, Suite 100 
Indianapolis, IN 46204 
 
Investigational New Drug (IND) Application # 
125143 
 
Initial Protocol Version Date:  
22OCT2014 
 
Protocol Amendments: 
15JAN2015 
25MAR2015 
18JUN2015 
14SEP2015 
22AUG2016 
20MAR2017  
13OCT2017  
11OCT2018 (current) 
 
 


 
Page 2 of 70 
 
PROTOCOL SIGNATURE PAGE  
 
Phase Ib and Phase II Studies of anti-PD-1 Antibody Pembrolizumab (MK-3475) in Combination 
with Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma:  
Big Ten Cancer Research Consortium BTCRC-GU14-003 
 
VERSION DATE:  11OCT2018 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to 
the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual. I 
will accept the monitor’s overseeing of the study. I will promptly submit the protocol to applicable 
ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
____________________________________ 
 Investigator Name (printed) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO BTCRC ADMINISTRATIVE HEADQUARTERS  
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to BTCRC Administrative Headquarters and keep a record 
for your files. 


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STUDY SYNOPSIS 
 
TITLE 
Phase Ib and Phase II Studies of anti-PD-1 Antibody Pembrolizumab (MK-3475) 
in Combination with Bevacizumab for the Treatment of Metastatic Renal Cell 
Carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14-003
PHASE  
Phase Ib/II 
OBJECTIVES 
Primary Objectives: 
Phase Ib Dose Escalation Cohort:  To establish the maximum tested safe dose of 
study drug pembrolizumab (MK-3475) and bevacizumab in combination for 
subjects with metastatic clear cell renal carcinoma after failure of at least one 
systemic therapy for metastatic disease.  
 
Phase II Study:  To determine the activity of combination of pembrolizumab and 
bevacizumab in first line therapy for subjects with treatment naïve metastatic clear 
cell RCC as assessed by response rate (RR) (complete or partial response) based 
on RECIST 1.1.  
 
Secondary Objective(s): To evaluate: 
• 
progression-free survival (PFS) at 6 months using RECIST 1.1  
• 
PFS 
• 
clinical benefit rate (complete,  partial response, or stable disease) 
• 
toxicity of this combination therapy 
• 
2-year overall survival (OS) 
 
Correlative Objectives:  
 Correlate PD-L1 expression in archived diagnostic tumor tissue with 
clinical response. 
 Correlate tumor vascular density in archived diagnostic tumor tissue with 
clinical response during treatment. 
 Correlate CD4(+) and CD8(+) T-cell tumor infiltration in archived 
diagnostic tumor tissue with clinical response during treatment. 
 Correlate change in number of circulating tumor cells during therapy, 
relative to baseline expression, with clinical response. 
 Correlate change in soluble PD-L1 level in serum during therapy, relative 
to baseline level, with clinical response. 
 Correlate change in plasma VEGFc level during therapy, relative to baseline 
level, with clinical response. 
 To explore the association of proteomic and lipidomic tests at baseline with 
measures of response. 
STUDY DESIGN 
Single arm study with dose escalation phase Ib cohort followed by a phase II 
cohort 
TOTAL NUMBER 
OF SUBJECTS  
Up to 61 
KEY ELIGIBILITY 
CRITERIA  
1. Age ≥ 18 years 
2. Phase Ib dose escalation cohort study: subjects with histologically assessed 
metastatic clear cell RCC (defined as more than 50% clear cell component) 
after failure of at least one systemic therapy (including, but not limited to 
prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and 
mTOR) for metastatic disease. 


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NOTE: A biopsy to prove metastatic disease is not required. 
3. Phase II study: subjects with treatment-naïve histologically assessed 
metastatic clear cell RCC (defined as more than 50% clear cell component) 
and who are candidates for standard first-line therapy. 
NOTE: A biopsy to prove metastatic disease is not required. 
4. Measurable disease that can be monitored throughout the course of the study 
participation per RECIST 1.1 
5. Karnofsky Performance Status (KPS) ≥ 70% 
6. Life expectancy of 6 months or greater 
7. Adequate hematologic function, as defined by central laboratory values for all 
three of the following criteria: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, and 
b. Platelets ≥ 100 × 109/L, and 
c. Hemoglobin (Hgb) ≥ 9.0 g/dL 
8. Adequate renal function, as defined by either of the following criteria: 
a. Serum creatinine ≤ 3 mg/dL. 
b. OR, if serum creatinine > 3 mg/dL, estimated glomerular filtration rate 
(eGFR) ≥ 20 mL/min 
9. Adequate hepatic function, as defined by both of the following: 
a. Total serum bilirubin ≤ 1.5 × ULN 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 
2.5 × ULN 
− OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to 
underlying malignancy 
10. Adequate coagulation function as defined by either of the following criteria: 
a. INR < 1.5 × ULN 
b. For subjects receiving warfarin or LMWH, the subjects must, in the 
investigator’s opinion, be clinically stable with no evidence of active 
bleeding while receiving anticoagulant therapy. The INR for these subjects 
may exceed 1.5 × ULN if that is the goal of anticoagulant therapy. 
11. Negative pregnancy test for female subjects with reproductive potential, and 
agreement of all male and female subjects of reproductive potential to use a 
reliable form of contraception during the study and for 120 days after the last 
dose of study drug 
12. Able to abstain from taking prohibited drugs, either prescription or non-
prescription, during the treatment phase of the study 
13. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures 
14. Signed and dated informed consent document indicating that the subject (or 
legally acceptable representative) has been informed of all pertinent aspects of 
the trial prior to enrollment 
OUTCOME 
MEASURES 
Response rate  
STATISTICAL 
CONSIDERATIONS 
Phase Ib:  
A standard “3+3” design will be used with maximum number of subjects accrued to 
be 12. 
 


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Phase II: 
Phase II study endpoint will be response (PR or CR) as assessed by RECIST v1.1 
criteria. Clinical studies identified a response rate with pembrolizumab of 27% in 
kidney cancer. With assumptions of 80% power to detect a 55% improvement to a 
response rate of 42% in response by RECIST v1.1 in the combination arm over 
historic data on single agent pembrolizumab activity in RCC, and an alpha error is 
0.107, the optimal Simon’s two stage design proceeds as follows. After testing the 
drug on 22 patients in the first stage, the trial will be terminated if 6 or fewer 
respond. If at least 7 respond, the trial goes on to the second stage. A total of 49 
patients will be studied. If the total number responding is less than or equal to 16, 
the drug is rejected. Otherwise the drug will be accepted for further studies. 
ENROLLMENT 
PERIOD 
Estimated 24 months 
TOTAL STUDY 
DURATION  
Estimated 36 months 
 
 


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INDEX  
 
SECTION                                                                                                                 
PAGE 
PHASE Ib SCHEMA ....................................................................................................................... 7 
PHASE II SCHEMA........................................................................................................................ 8 
1. 
BACKGROUND & RATIONALE ................................................................................ 11 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................ 14 
2.1. 
Phase Ib Objectives ........................................................................................................... 14 
2.2. 
Phase II Objectives ............................................................................................................ 15 
3. 
ELIGIBILITY CRITERIA ............................................................................................ 16 
3.1. 
Inclusion Criteria ............................................................................................................... 16 
3.2. 
Exclusion Criteria .............................................................................................................. 18 
4. 
SUBJECT REGISTRATION ......................................................................................... 20 
5. 
TREATMENT PLAN ..................................................................................................... 21 
5.1. 
Overall Design and Study Plan ......................................................................................... 21 
5.2. 
Pre-medication .................................................................................................................. 23 
5.3. 
Drug Administration ......................................................................................................... 23 
5.4. 
Supportive Care ................................................................................................................. 24 
5.5. 
Concomitant Medications ................................................................................................. 26 
5.6. 
Diet/Activity/Other Considerations ................................................................................... 28 
6. 
DOSE DELAYS ............................................................................................................... 29 
6.1. 
Start of a New Cycle ......................................................................................................... 29 
6.2. 
Management of Allergic Reaction/ Hypersensitivity ........................................................ 29 
6.3. 
Other Adverse Event Guidelines ....................................................................................... 30 
6.4. 
Dose Modifications ........................................................................................................... 31 
7. 
STUDY CALENDAR & EVALUATIONS [Cycle = 21 days] ..................................... 34 
7.1. 
Screening ........................................................................................................................... 36 
7.2. 
On Treatment..................................................................................................................... 36 
7.3. 
Off Treatment .................................................................................................................... 37 
7.4. 
End of Treatment 30 days (+7 days) after final protocol therapy dose ............................. 38 
7.5. 
Follow-up (±14 days) ........................................................................................................ 38 
8. 
CRITERIA FOR DISEASE EVALUATION ............................................................... 38 
9. 
BIOLOGICAL CORRELATIVES ................................................................................ 47 
9.1. 
Evaluate PD-L1 expression of archived tumor tissue ....................................................... 47 
9.2. 
Assess tumor vascular density of archived tumor tissue ................................................... 47 
9.3. 
Assess CD4(+) and CD8(+) T-cell infiltration of archived tumor tissue .......................... 47 
9.4. 
Assess number of circulating tumor cells at baseline and during treatment ..................... 47 
9.5. 
Measure soluble PD-L1 level at baseline and during treatment ........................................ 48 
9.6. 
Measure VEGFc at baseline and during treatment ............................................................ 48 
9.7. 
Correlate baseline proteomic and lipidomic immune classifiers to clinical response. ...... 48 
9.8. 
Samples for future studies ................................................................................................. 48 
10. 
DRUG INFORMATION ................................................................................................ 49 
11. 
ADVERSE EVENTS ....................................................................................................... 56 
12. 
STATISTICAL CONSIDERATIONS .......................................................................... 60 
13. 
TRIAL MANAGEMENT ............................................................................................... 64 
14. 
REFERENCES ................................................................................................................ 68 
 


 
Page 7 of 70 
PHASE Ib SCHEMA 
 
Phase Ib and Phase II Studies of anti-PD-1 Antibody Pembrolizumab (MK-3475) in Combination 
with Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer 
Research Consortium BTCRC-GU14-003 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose 
Cohort 
# of Subjects 
Pembrolizumab 
(mg) 
Bevacizumab 
(mg/kg) 
1 
3-6 
200 
10 
2 
3-6 
200 
15 
Pembrolizumab + Bevacizumab 
Day 1  
(cycle = 21 days) 
 
CR, PR or SD 
Follow for progression 
and survival for 2 years 
(±2 months) from 
enrollment. 
Disease Assessment every 2 cycles 
Progression or 
significant toxicity 
Continue 
treatment. 
Discontinue 
treatment. 
Patients with metastatic clear cell renal cell carcinoma who have 
failed at least one prior systemic therapy for metastatic disease 


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PHASE II SCHEMA 
 
Phase Ib and Phase II Studies of anti-PD-1 Antibody Pembrolizumab (MK-3475) in Combination 
with Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer 
Research Consortium BTCRC-GU14-003 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will be treated with pembrolizumab at a 200 mg dose and bevacizumab at 15mg/kg (dose 
established by Dose Escalation Cohort to be safe).
Patients with metastatic clear cell renal cell carcinoma who are 
treatment naïve and are candidates for first-line therapy 
Pembrolizumab + Bevacizumab 
Day 1  
(cycle = 21 days) 
 
CR, PR or SD 
Follow for progression 
and survival for 2 years 
(±2 months) from 
enrollment. 
Disease Assessment every 2 cycles 
Progression or 
significant toxicity 
Continue 
treatment. 
Discontinue 
treatment. 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AHQ 
Administrative Headquarters 
ANC 
absolute neutrophil count 
Anti-PD-1 antibody 
anti-programmed death-ligand 1 antibody 
Anti-PD-L1 antibody 
anti-programmed death-ligand 1 antibody 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATE 
arterial thromboembolic event 
BMP 
basic metabolic panel 
BOR 
best overall response 
CA 
cancer antigen 
CBC 
complete blood cell count 
CIK 
cytokine-induced killer 
cm 
centimeter 
CR 
complete response 
CTC 
cytotoxic T cell 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTLA4 
cytotoxic T-lymphocyte-associated antigen 4 
dL 
deciliter 
DLT 
dose-limiting toxicity 
ECI 
event of clinical interest 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
Hgb 
hemoglobin 
HIF-1 
hypoxia-inducible factor-1 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hr 
hour 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
INR 
international normalized ratio 
I/O 
input/output 
IRB 
Institutional Review Board 
kg 
kilogram 
KPS 
Karnofsky Performance Status 
LAK 
lymphocyte-activated killer 


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Abbreviation 
Definition 
lb 
pound 
LDH 
lactate dehydrogenase 
LMWH 
low-molecular-weight heparin 
mCRC 
metastatic colorectal cancer 
MDSC 
myeloid-derived suppressor cell 
mg 
milligram 
min 
minute 
mL 
milliliter 
mm3 
cubic millimeters 
NCI 
National Cancer Institute 
NDC 
National Drug Code 
OS 
overall survival 
PD-1 
programmed death 1 
PD-L1 
programmed death ligand 1 
PD-L2 
programmed death ligand 2 
PFS 
progression-free survival 
PR 
partial response 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
RR 
response rate 
SAE 
serious adverse event 
SPM 
Study Procedures Manual 
SD 
stable disease 
TAA 
tumor-associated antigen 
TAM 
tumor-associated macrophage 
TIL 
tumor-infiltrating lymphocyte 
ULN 
upper limit of normal 
UPIRSO 
unanticipated problems involving risk to subjects or others 
US 
United States 
USP 
United States Pharmacopeia 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
WOCP 
women of childbearing potential 
wt 
weight 


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1. BACKGROUND & RATIONALE 
 
Introduction 
 
Anti-angiogenic treatment may improve efficacy of anticancer immunotherapies. 
In recent years, there has been an emergence of anticancer immunotherapies in treating various 
tumor types.1 These adoptive cell immunotherapies include tumor-infiltrating lymphocytes 
(TIL), cytokine-induced killer (CIK) cells, lymphokine-activated killer (LAK) cells, and tumor-
associated antigen (TAA)-specific cytotoxic T cell (CTL).2 Despite the renewed hope for 
cancer immunotherapy, survival benefits from adoptive cell immunotherapy alone remain 
modest. One of the critical challenges that adoptive cell immunotherapy faces is the 
immunosuppressive tumor microenvironment. The tumor microenvironment contains a 
vasculature that is structurally and functionally abnormal. In certain regions of tumors, the 
vessels are leaky, twisted, and lack stabilizing pericytes and basement membrane. The 
structurally abnormal tumor vessels do not provide nutritive blood flow. The immature tumor 
vessels contribute to an abnormal tumor microenvironment with one of the key characteristics 
being that of hypoxia.3 Abnormal tumor vasculature and subsequent tumor hypoxia contribute 
to immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor 
parenchyma and inhibiting their antitumor efficacy.4 These obstacles might explain why the 
promising approach of adoptive cell immunotherapy does not exert significant antitumor 
activity.5 Hypoxia contributes to immune suppression by activating hypoxia-inducible factor 
(HIF-1) and the vascular endothelial growth factor (VEGF) pathway, which plays a determining 
role in promoting tumor cell growth and survival.6 Tumor hypoxia creates an 
immunosuppressive microenvironment via the accumulation and subsequent polarization of 
inflammatory cells toward immune suppression phenotypes, such as myeloid-derived 
suppressor cells (MDSC)7, tumor-associated macrophages (TAM)8, and dendritic cells9. 
Adoptive cell immunotherapy alone is not efficient enough to decrease tumor growth as its 
antitumor effect is inhibited by the immunosuppressive hypoxic tumor microenvironment. 
Antiangiogenic therapy could normalize tumor vasculature and decrease hypoxic tumor 
area and thus may be an effective modality to potentiate immunotherapy3.  
 
Recent studies have demonstrated that there is an interaction between immune response and 
tumor angiogenesis. Huang et al. demonstrated that lower doses of an anti-VEGF receptor 2 
(VEGFR2) antibody treatment enhanced the anti-cancer efficacy of a vaccine therapy in a 
model of immune tolerant breast cancer.10 Furthermore, it was demonstrated that lower doses 
of the same anti-angiogenic treatment normalized breast tumor vasculature and improved tissue 
distribution of functional vasculature within the tumor. As stated earlier, myeloid-derived 
suppressor cells (MDSC) and tumor-associated macrophages (TAM) promote tumor 
progression by suppressing innate anti-cancer immunity. Low doses of this treatment decreased 
the number of MDSCs and increased the number of TAMs. On profile analysis, however, these 
TAMs were polarized from an immunosuppressive (M2-like) to an immune-stimulatory (M1-
like) phenotype. A low dose of the anti-angiogenic treatment was also demonstrated to enhance 
tumor infiltration by CD4+ and CD8+ T-cells. An improvement in tumor vasculature and 
polarization of TAMs was shown to reduce immune-regulatory signals, and facilitated 
recruitment of activated CD8 (+) T cells that could exact an anti-tumor effect.  
 


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Similarly, Shi et al. demonstrated that using an anti-angiogenic agent rh-endostatin improved 
the anti-cancer effect of adoptive cytokine-induced killer (CIK) cells against lung carcinoma3. 
The proposed mechanism was a synergistic therapeutic effect in which endostatin contributed 
to structural normalization of tumor vasculature. They also demonstrated that the addition of 
endostatin augmented homing of the CIK cells and subsequently intratumoral CD3(+) T 
lymphocytes, suggesting that the addition of an anti-angiogenic agent normalized vasculature, 
reduced hypoxia, and altered the tumor microenvironment  to enhance tumor infiltration by 
transferred CIK cells and T-lymphocytes.    
 
The Programmed Death (PD-1) Receptor, Its Ligand PD-L1, and a Novel 
Immunotherapy: Anti-PD-1 Antibody 
The Programmed death 1 (PD-1) receptor is expressed on activated T- and B-cells.12 Its major 
ligand PD-L1 (B7-H1) is typically expressed on a subset of macrophages, but can be induced 
by inflammatory cytokines in a variety of tissue types.13-17 When activated T-cells expressing 
PD-1 encounter PD-L1, T-cell effector functions are diminished. PD-1 also binds PD-L2 (B7-
DC), which is expressed selectively on macrophages and dendritic cells.17-19 These unique 
expression patterns suggest that PD-L1 promotes self-tolerance in peripheral tissues, while PD-
L2 may function in lymphoid organs, although the role of PD-L2 in immunomodulation is not 
as well understood.20 Multiple tumor types have been shown to express PD-L1 and PD-L2, 
effectively co-opting a native tolerance mechanism.21-24 It has been postulated that antibodies 
that block the interaction between PD-1 and PD-L1 in tumors may preferentially release the 
cytotoxic function of tumor-specific T cells with fewer systematic toxic effects than those that 
are seen with other immune checkpoint inhibitors, such as CTLA-41  
Two large, dose-escalation, phase 1 clinical trials evaluating the safety of the anti–PD-1 
antibody nivolumab (formerly known as BMS936558)  and the anti–PD-L1 antibody 
BMS936559 showed significant antitumor activity in subjects with advanced melanoma, lung 
carcinoma, and renal cell carcinoma, among other cancers, thus validating the PD-1–PD-L1 
axis as a therapeutic target.25-27  Most clinical responses were durable beyond 1 year.26,27 Toxic 
effects were generally of low grade. Especially relevant to this protocol, cumulative response 
rate among subjects with renal cell carcinoma was 27% (9/33 subjects).27  
 
Pembrolizumab (MK-3475) is a highly selective, humanized monoclonal IgG4–kappa isotype 
antibody against PD-1 that is designed to block the negative immune regulatory signaling of 
the PD-1 receptor expressed by T cells.28 The variable region sequences of a very-high-affinity 
mouse antihuman PD-1 antibody (dissociation constant, 28 pM) were grafted into a human 
IgG4 immunoglobulin with a stabilizing S228P Fc alteration. The IgG4 immunoglobulin 
subtype does not engage Fc receptors or activate complement, thus avoiding cytotoxic effects 
of the antibody when it binds to the T cells that it is intended to activate. In T-cell activation 
assays that used human donor blood cells, the 50% effective concentration was in the range of 
0.1 to 0.3 nM.29 The first dose escalation phase 1 study involving subjects with solid tumors 
showed that MK-3475 was safe at the dose levels tested (1 mg per kilogram of body weight, 3 
mg per kilogram, and 10 mg per kilogram, administered every 2 weeks) without reaching a 
maximum tolerated dose. In addition, clinical responses were observed at all the dose levels.30 
In a recent multicenter study of 135 subjects with advanced melanoma, treatment with MK-
3475 was demonstrated to have a high rate of sustained tumor regression with mainly grade 1 
or 2 toxicities, and a very low incidence of grade 3 or 4 toxicities.29 


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The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer trials. 
Available PK results in subjects with melanoma, NSCLC, and other solid tumor types support 
a lack of meaningful difference in PK exposures obtained at a given dose among tumor types. 
An open-label Phase 1 trial (PN001) in melanoma subjects is being 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 maximum tolerated dose (MTD) has been 
identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The clinical 
efficacy and safety data demonstrate a lack of clinically important differences in efficacy 
response or safety profile at these doses.  For example, in Cohort B2, advanced melanoma 
subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 26% 
(21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)).  
The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, 
serious drug-related AEs, death or discontinuation due to an AE was comparable between 
groups or lower in the 10 mg/kg group.   
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab to a clinically 
meaningful extent.  Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data supporting the dose 
selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within 
the exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.   The distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to 
range slightly higher with the 200 mg fixed dose.   The slight increase in PK variability 
predicted for the fixed dose relative to weight-based dosing is not expected to be clinically 
important given that the range of individual exposures is well contained within the range of 
exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar efficacy and 
safety.  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 


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indications. Therefore, there are no anticipated changes in exposure between different tumor 
types and indication settings.  
 
Bevacizumab has gained approval for the treatment of metastatic renal cell carcinoma, when it 
was combined with Interferon Alfa-2a as reported by the AVOREN study. In the study 649 
patients with previously untreated mRCC were randomized to treatment with either IFN+ 
Bevacizumab or IFN+ Placebo. In that study overall response rate (ORR) was 31% vs 13% 
respectively (p<0.001). This was associated with an improvement in PFS and a trend towards 
improvement in OS. In a similar trial CALGB 90206, 732 previously untreated patients were 
also randomized to IFNa + Bevacizumab vs IFNa + placebo. This trial also showed an 
improvement in ORR of 25.5% vs 13.1% respectively.   
 
Study Rationale 
There is recent promising evidence that anti-PD-1 antibodies have efficacy in treating 
metastatic RCC.27 However as reviewed in the Introduction, immunotherapies such as anti-PD-
1 antibodies must contend with a tumor microenvironment that is immunosuppressant, in part 
because of angiogenesis that results in hypoxia, diminishing the ability of the antibodies to 
infiltrate the tumor.3,10,11 One of the front-line treatments for metastatic RCC is the anti-
angiogenic agent, bevacizumab.31-33 We hypothesize that through the strategy of adding the 
anti-VEGF agent bevacizumab to the anti-PD-1 agent pembrolizumab, tumor vasculature can 
be normalized (by reducing the area of the tumor that is hypoxic), thereby allowing tumor 
infiltration by T-lymphocytes. We will conduct two studies based on this premise. The first 
study is a Phase Ib dose escalation trial to establish the safe dose of pembrolizumab in 
combination with bevacizumab for subjects with metastatic clear cell RCC after failure of at 
least one systemic therapy of the disease. Once that safe dose is determined, we will conduct a 
Phase II study to assess superiority of disease response by adding bevacizumab to 
pembrolizumab in subjects with treatment naïve metastatic RCC.  
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1.Phase Ib Objectives 
 
2.1.1. Primary Objective 
The primary objective of the Phase Ib dose escalation cohort study is to establish the safe 
dose of study drug pembrolizumab when used in combination with bevacizumab for 
subjects with metastatic clear cell renal cell carcinoma (RCC) after failure of at least one 
systemic therapy for metastatic disease. 
 
2.1.2. Secondary Objectives 
 Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab 
in subjects with metastatic RCC after failure of at least one systemic therapy. 
 Evaluate clinical benefit rate (complete, partial response, or stable disease) measured by 
RECIST 1.1 of pembrolizumab in combination with bevacizumab in subjects with 
metastatic RCC after failure of at least one systemic therapy. 
 Measure Progression-Free Survival (PFS) at 6 months in subjects with metastatic RCC 
after failure of at least one systemic therapy treated with pembrolizumab in combination 
with bevacizumab. 


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 Measure overall survival (OS) at 2 years in subjects with metastatic RCC after failure of 
at least one systemic therapy treated with pembrolizumab in combination with 
bevacizumab. 
 
2.1.3. Correlative Objectives 
 Correlate PD-L1 expression in archived diagnostic tumor tissue with clinical 
response. 
 Correlate tumor vascular density in archived diagnostic tumor tissue with clinical 
response during treatment. 
 Correlate CD4(+) and CD8(+) T-cell tumor infiltration in archived diagnostic tumor 
tissue with clinical response during treatment. 
 Correlate change in number of circulating tumor cells during therapy, relative to 
baseline expression, with clinical response. 
 Correlate change in soluble PD-L1 level in serum during therapy, relative to baseline 
level, with clinical response. 
 Correlate change in plasma VEGFc level during therapy, relative to baseline level, 
with clinical response. 
 To explore the association of proteomic and lipidomic tests at baseline with measures 
of response. 
 
2.2.Phase II Objectives 
 
2.2.1. Primary Objective 
The primary objective of the Phase II trial is to determine the activity of the combination of 
pembrolizumab and bevacizumab as a first line therapy for subjects with treatment naïve 
metastatic clear cell RCC as assessed by response rate (RR) (complete or partial response) 
based on RECIST 1.1. 
 
2.2.2. Secondary Objectives 
 Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab 
in subjects with treatment-naïve metastatic RCC. 
 Evaluate clinical benefit rate (complete, partial response, or stable disease) of 
pembrolizumab in combination with bevacizumab in subjects with treatment-naïve 
metastatic RCC. 
 Measure Progression-Free Survival (PFS) using RECIST 1.1 at 6 months in subjects with 
treatment-naïve metastatic RCC treated with pembrolizumab in combination with 
bevacizumab. 
 Measure overall survival (OS) at 2 years in subjects with treatment-naïve metastatic RCC 
treated with pembrolizumab in combination with bevacizumab. 
 
2.2.3. Correlative Objectives 
 Correlate PD-L1 expression in archived diagnostic tumor tissue with clinical 
response. 
 Correlate tumor vascular density in archived diagnostic tumor tissue with clinical 
response during treatment. 


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 Correlate CD4(+) and CD8(+) T-cell tumor infiltration in archived diagnostic tumor 
tissue with clinical response during treatment. 
 Correlate change in number of circulating tumor cells during therapy, relative to 
baseline expression, with clinical response. 
 Correlate change in soluble PD-L1 level in serum during therapy, relative to baseline 
level, with clinical response. 
 Correlate change in plasma VEGFc level during therapy, relative to baseline level, 
with clinical response. 
 To explore the association of proteomic and lipidomic tests at baseline with measures 
of response. 
 
3. ELIGIBILITY CRITERIA 
 
Study entry is open to adults regardless of gender or ethnic background. While there will be 
every effort to seek out and include women and minorities, the subject population is expected to 
be no different than that of other advanced solid tumor cancer studies at each participating 
institution. 
 
3.1.Inclusion Criteria 
 
3.1.1 Male or female ≥ 18 years of age at time of consent. 
 
3.1.2 Phase Ib dose escalation cohort study: subjects with histologically assessed metastatic 
clear cell RCC (defined as more than 50% clear cell component) after failure of at least one 
systemic therapy (including, but not limited to prior therapy with interleukin 2, interferon, 
bevacizumab, VEGF TKI, and mTOR) for metastatic disease. 
NOTE: A biopsy to prove metastatic disease is not required. 
 
3.1.3 Phase II study: subjects with treatment-naïve histologically assessed metastatic clear cell 
RCC (defined as more than 50% clear cell component) and who are candidates for standard 
first-line therapy. 
NOTE: A biopsy to prove metastatic disease is not required. 
 
3.1.4 Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion 
according to RECIST 1.1 (Section 8), and obtained by imaging within 28 days prior to 
registration for protocol therapy. 
 
3.1.5 Karnofsky Performance Status ≥ 70% within 28 days prior to registration for protocol 
therapy. 
 
3.1.6 Life expectancy of 6 months or greater as determined by the treating physician. 
 
3.1.7 Adequate hepatic function within 28 days prior to registration for protocol therapy defined 
as meeting all of the following criteria: 
 total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for 
subjects with total bilirubin levels > 1.5 x ULN 


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 and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with 
known hepatic metastases 
 and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with 
known hepatic metastases 
 
3.1.8 Adequate renal function within 28 days prior to registration for protocol therapy defined by 
either of the following criteria:  
 serum creatinine ≤ 3 mg/dL 
 OR if serum creatinine > 3 mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 
mL/min 
 
3.1.9 Adequate hematologic function within 28 days prior to registration for protocol therapy 
defined as meeting all of the following criteria: 
 hemoglobin ≥ 9 g/dL 
 and absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
 and platelet count ≥ 100 × 109/L 
 
3.1.10 Adequate coagulation functioning within 28 days prior to registration for protocol therapy 
defined by either of the following criteria:  
 INR < 1.5 × ULN 
 OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator’s 
opinion, be clinically stable with no evidence of active bleeding while receiving 
anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the 
goal of anticoagulant therapy. 
 
3.1.11 Provided written informed consent and HIPAA authorization for release of personal health 
information, approved by an Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
NOTE: HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
3.1.12 Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A 
negative serum or urine pregnancy test is required within 72 hours of study registration. If 
the urine test cannot be confirmed as negative, a serum pregnancy test will be required. 
 
3.1.13 Women of childbearing potential (WOCP) must be willing to use two effective methods of 
birth control such as an oral, implantable, injectable, or transdermal hormonal 
contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms, 
sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence 
for the course of the study until 120 days after the last dose of study drug.  
NOTE: Women are considered to be of childbearing potential unless they are 
postmenopausal for at least 12 consecutive months or surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy). 
 
3.1.14 Men who are not surgically sterile (vasectomy) must agree to use an acceptable method of 
contraception. Male subjects with female sexual partners who are pregnant, possibly 


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pregnant, or who could become pregnant during the study must agree to use condoms from 
the first dose of study drug through at least 120 days after the last dose of study drug. Total 
abstinence for the same study period is an acceptable alternative. 
 
3.1.15 Availability of tissue if applicable (from the primary tumor or metastases) for correlative 
studies. 
 
3.1.16 Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures. 
 
3.2. Exclusion Criteria 
 
3.2.1 Phase Ib: Received prior monoclonal antibody therapy other than bevacizumab within 4 
weeks of study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events of such agents administered more than 4 weeks earlier. 
 
3.2.2 Phase II: has had prior therapy for metastatic RCC. 
 
3.2.3 Surgery within 4 weeks prior to study treatment except for minor procedures.  
NOTE: Hepatic biliary stent placement is allowed. 
NOTE: Subject must have adequately recovered from the toxicity and/or complications of 
major surgery prior to study registration, as determined by the treating physician.   
 
3.2.4 Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
Subjects with neurological symptoms must undergo a head CT scan or brain MRI to 
exclude brain metastasis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have returned 
to baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study registration.  This exception does not include 
carcinomatous meningitis, which is excluded regardless of clinical stability.   
 
3.2.5 Previously received an organ or allogeneic progenitor/stem cell transplant.   
 
3.2.6 Received a live vaccine within 30 days prior to the first dose of trial treatment. 
Examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed. 
 
3.2.7 History of blood clots, pulmonary embolism, or deep vein thrombosis unless controlled by 
anticoagulant treatment. 
 
3.2.8 Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies]. 
 
3.2.9 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 


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3.2.10 Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to study registration. 
 
3.2.11 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).   
NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment. 
 
3.2.12 Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events from previously administered agents.  
NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and can still 
be considered for the study. 
 
3.2.13 Any clinically significant infection defined as any acute viral, bacterial, or fungal infection 
that requires specific treatment.  
NOTE: Anti-infective treatment must be completed ≥ 7 days prior to study registration. 
 
3.2.14 Evidence of interstitial lung disease, history of (non-infectious) pneumonitis that required 
steroids, or current pneumonitis 
 
3.2.15 Known history of active tuberculosis. 
 
3.2.16 Any other severe, uncontrolled medical condition, including uncontrolled diabetes mellitus 
or unstable congestive heart failure 
 
3.2.17 Known allergy to pembrolizumab or any of its excipients 
 
3.2.18 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies 
 
3.2.19 Any condition that, in the opinion of the treating physician, would exclude the subject 
from receiving bevacizumab. Examples may include but are not limited to: 
 Hemoptysis (defined as > ½ teaspoon of blood) 
 Pre-existing bleeding diathesis, coagulopathy or hemorrhage 
 Myocardial infarction or cerebrovascular accident within 6 months prior to study 
registration 
 Any drugs or supplements that interfere with blood clotting can raise the risk of 
bleeding during treatment with bevacizumab. These drugs include vitamin E, non-
steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), 
and naproxen (Aleve, Naprosyn), warfarin (Coumadin), ticlopidine (Ticlid), and 
clopidogrel (Plavix). These agents should be used with caution. 
 
3.2.20 Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 


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administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the subject inappropriate for enrollment in this study. 
 
3.2.21 Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study 
registration. 
 
3.2.22 Any condition that, in the opinion of the investigator, might jeopardize the safety of the 
subject or interfere with protocol compliance. 
 
3.2.23 Any mental or medical condition that prevents the subject from giving informed consent or 
participating in the trial. 
3.2.24 No prior malignancy is allowed except for adequately treated basal cell or squamous cell 
skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or other cancer for 
which the subject has been disease-free for at least 5 years. 
 
3.2.25 Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab 
or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
 
3.2.26 Treatment with any investigational agent within 28 days prior to registration for protocol 
therapy and the subject must have recovered from the acute toxic effects of the regimen. 
 
4. SUBJECT REGISTRATION  
All subjects must be registered through BTCRC Administrative Headquarters’ electronic data 
capture (EDC) system. A subject is considered registered when an ‘On Study’ date is entered 
into the EDC system. 
 
Subjects must be registered after signing consent but prior to starting protocol therapy. Protocol 
therapy must begin therapy within 5 business days of registration.   
 
Subjects Who Do Not Begin Study Treatment 
If a subject signs consent, is registered to the study, and later is not able to begin the planned 
study treatment, for whatever reason, the subject will be removed from study and treated at the 
physician’s discretion. The subject will be considered a screen/baseline failure and be replaced. 
The reason for removal from study will be clearly indicated in EDC system.   
If a subject begins treatment, and then is discontinued for whatever reason, the subject must be 
followed per section 7.5. 
 


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5. TREATMENT PLAN 
 
5.1. Overall Design and Study Plan 
 
5.1.1. Phase Ib Dose Escalation Study 
This phase Ib dose escalation study will evaluate pembrolizumab in combination with 
bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least 
one systemic therapy for metastatic disease. Both drugs are given on Day 1 of the 21-day 
cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. 
Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or 
subject death either from progression of disease, the therapy itself, or from other causes. 
Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities 
will be followed for up to 24 months.  
 
The primary objective of the Phase Ib portion is to determine the maximum safe dose of 
pembrolizumab when given in combination with bevacizumab in subjects with metastatic 
clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.  
 
Dose 
Cohort 
# of Subjects 
Pembrolizumab 
(mg)  
Bevacizumab 
(mg/kg) 
1 
3-6 
200 
10.0 
2 
3-9 
200 
15.0 
 
The maximum safe dose of pembrolizumab in combination with bevacizumab will be 
determined using a standard “3+3” design.  
 
 Three subjects will be enrolled at dose level 1. If none of the 3 subjects experience a dose 
limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be 
enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of 
therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects 
have a DLT. There will be no further escalation beyond dose level 2. 
 
 Alternatively, if 1 of the first 3 subjects experiences a dose limiting toxicity (DLT), the 
cohort will be expanded to 6 subjects. If only 1 of the total 6 subjects in a dose level 
experience DLT, the study will proceed to dose level 2. If there are 2 DLTs experienced 
during first cycle of therapy (>33% of subjects experiencing DLT), the cohort will be 
deemed unsafe. If this occurs at dose level 2, dose level 1 will be expanded to 6 subjects 
(if applicable). If there are 2 DLTs experienced during the first cycle of therapy at dose 
level 1, the combination will be considered unsafe for further development.  
 The maximum safe dose of pembrolizumab in combination with bevacizumab is the dose 
of pembrolizumab combined with bevacizumab with dose limiting toxicity of less than 
33% in first cycle of therapy. That dose will be recommended for the Phase II study.  
 An expansion cohort of 6 patients will be allowed at the maximum safe dose prior to 
opening Phase II portion of the study. This will ensure ample safety data of the 


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combination and provide pilot activity data from 12 patients in the second-line RCC 
setting. 
 
Dose limiting toxicity (DLT) is defined as one of the following events occurring during cycle 
1:   
 
Grade 4 or greater treatment-related hematologic toxicity for > 7 days during the first 
cycle (21 days) of therapy. 
 
Febrile neutropenia 
 
Grade 4 or greater thrombocytopenia of any duration. 
 
Grade 3 thrombocytopenia with significant hemorrhage of any duration. 
 
Grade 3 or greater treatment-related clinical non-hematological toxicity 
Excluding: 
o Grade 3-4 nausea, vomiting in the absence of maximal medical therapy that 
resolves in 72 hours. 
o Grade 3-4 laboratory abnormalities that are not clinically significant and which 
resolve in 72 hours. 
o Grade 3 fatigue lasting < 5 days. 
o Grade 3 hypertension that can be controlled with medical therapy. 
 
Delay of cycle 2 treatment start by more than 2 weeks due to incomplete hematologic 
recovery (ANC > 1.5 x 109/L or platelets 100 x 109/L) or unresolved treatment related 
grade 3 or greater non-hematologic toxicity. 
 
DLTs will be counted based on the number of subjects with DLT at a given dose level, not 
the absolute number of DLTs. No single subject can trigger more than one DLT event.  
 
Additional subject cohorts will not be enrolled at the second dosing level until all subjects 
at the initial dosing level complete all planned treatment for cycle 1 (defined as 2 doses of 
pembrolizumab, and two doses of bevacizumab) and are able to start cycle 2 with no more 
than a 2-week delay. 
 
Intra-subject dose escalation is not permitted. 
 
Once the maximum tested safe dose of pembrolizumab in combination with bevacizumab is 
determined, enrollment will continue until at least 9 subjects total are accrued at the 
maximum tested safe dose. 
 
Correlative research analyses includes examining the relationship between clinical response 
at the end of Cycle 2 (Week 6) with PD-L1 expression, tumor vascular density, and CD4(+) 
and CD8(+) T-cell tumor infiltration of the archived diagnostic tumor tissue. Research 
analyses also include examining the relationship between changes in number of circulating 
tumor cells, soluble PD-L1 levels, and VEGFc levels from baseline to the end of Cycle 2 
(Week 6) of the treatment period and clinical response at that time. Correlative samples will 
continue to be collected every 6 or 9 weeks for exploratory analysis of circulating tumor 
cells, soluble PD-L1 levels, and VEGFc levels. Correlative sample analysis will also explore 
the association of proteomic and lipidomic tests at baseline with measures of response. 


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5.1.2. Phase II Study 
The primary objective of the Phase II trial is to determine the activity of the combination of 
pembrolizumab and bevacizumab in first line therapy for subjects with metastatic clear cell 
RCC as assessed by response rate (RR) (complete or partial response) based on RECIST 1.1. 
The maximum safe dose of pembrolizumab in combination bevacizumab will be given on 
Days 1 of each 21 day cycle. Treatment will continue until disease progression, unacceptable 
toxicity, subject refusal, or subject death either from progression of disease, the therapy 
itself, or from other causes. Subjects who voluntarily stop the study, have progressive 
disease, or unacceptable toxicities will be followed for a total of 24 months.  
 
Correlative research analyses includes examining the relationship between clinical response 
at the end of Cycle 2 (Week 6) with PD-L1 expression, tumor vascular density, and CD4(+) 
and CD8(+) T-cell tumor infiltration of the archived diagnostic tumor tissue. Research 
analyses also include examining the relationship between changes in number of circulating 
tumor cells, soluble PD-L1 levels, and VEGFc levels from baseline to the end of Cycle 2 
(Week 6) of the treatment period and clinical response at that time. Correlative samples will 
continue to be collected every 6 or 9 weeks for exploratory analysis of circulating tumor 
cells, soluble PD-L1 levels, and VEGFc levels. Correlative sample analysis will also explore 
the association of proteomic and lipidomic tests at baseline with measures of response. 
5.2.Pre-medication  
Pre-medication is not required but may be administered per physician discretion. 
 
5.3. Drug Administration 
 
5.3.1. Pembrolizumab + Bevacizumab Administration 
 
Phase Ib 
Dosing will occur in 21-day cycles. Pembrolizumab in the Phase Ib dose escalation study 
will be dosed at 200 mg  IV followed by bevacizumab at either 10 mg/kg or 15 mg/kg IV on 
day 1 of a 21 day cycle.  
 
Phase II 
In Phase II, the pembrolizumab dose will be 200 mg administered via IV followed by 
bevacizumab at 15mg/kg (dose established in the Phase Ib study) administered via IV. 
Pembrolizumab will be administered as a 30-minute intravenous infusion. Bevacizumab will 
be administered as a one-hour intravenous infusion. All treatment will be administered 15-
30 minutes apart. Subsequent cycles must meet the criteria found in section 6.1 and may 
begin 1 day earlier or up to 2 days later to accommodate scheduling issues. 
 
Monitoring 
Vital signs including blood pressure, pulse, temperature, respirations, and pulse oximetry, 
will be measured as follows: 
 Pembrolizumab infusion: before and after the infusion and every 30 minutes (±5 min) 
until the bevacizumab infusion is complete.  
 During bevacizumab infusion: every 30 minutes (±5 min) for one hour during infusion. 


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Subjects will be closely monitored for toxicities. Toxicity will be assessed using CTCAE 
version 4.  
 
Drug 
Administration 
Sequence 
Dose 
Length and 
route of 
administration 
Frequency of 
administration 
Length 
of cycle 
pembrolizumab 
1st  
200 mg 
30-min (-5/+10), 
IV 
Day 1 
21 days 
bevacizumab 
2nd  
(15-30 min post 
pembrolizumab)
10 mg/kg 
1-hra, IV 
Day 1 
15 mg/kg 
a: Length of first infusion and subsequent infusion will be per institutional standards. 
 
NOTE: Infusions may be given -1 day or +2 days for reasons such as observed holidays, 
inclement weather, scheduling conflicts, etc. It should be clearly documented in subject’s 
chart and case report forms. 
 
The body surface area and bevacizumab dose should be recalculated if the subject’s weight 
changes by ≥ 10% during the course of the study. 
 
5.4. Supportive Care 
Optimal patient care is to be given to all subjects. 
 
Subjects should receive full supportive care during the study, including transfusion of blood 
and blood products, treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, 
when appropriate.  
 
Although acetaminophen at doses of ≤2 grams/day is permitted, it should be used with caution 
in subjects with impaired liver function. 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below).  
 


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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 
Management of Pembrolizumab Infusion Related Reactions 
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. 
 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 5  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, 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 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; 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics
 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
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. 
**In cases of anaphylaxis, epinephrine should 
be used immediately. 
Subject is permanently discontinued from 
further trial treatment administration.
An appropriate resuscitation plan should in place 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 
(CTCAE) at http://ctep.cancer.gov 
 
5.5. Concomitant Medications 
 
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 sponsor-investigator by contacting the BTCRC Project Manager. The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  
 
Permitted Concomitant Medications and Procedures 
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 medications will be recorded on the electronic case report form 
(eCRF). 
 
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 medications 
administered beyond 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 11. 
 
Myeloid growth factors to treat subjects with neutropenia according to the American Society 
of Clinical Oncology (ASCO) Guidelines are permitted. Myeloid growth factors should be 
avoided (if medically appropriate) in Cycle 1 until subjects have developed a DLT or dose-
limiting Grade 4 neutropenia. 
 


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Antiemetic agents may be administered at the discretion of the investigator but are not 
commonly required as a prophylactic agent. All other manifestations of the subject’s 
malignancy should be treated at the discretion of the investigator. 
 
Medications with potential CNS effects are not prohibited in this study, but it is recommended 
that their use be minimized to avoid confusion in the interpretation of CNS effects should they 
occur during the course of treatment with pembrolizumab and bevacizumab.   
 
In appropriate settings, such as combinations with agents known to produce frequent 
thrombocytopenia, restricted uses of anticoagulants should be considered. 
 
All other medical conditions should be treated at the discretion of the investigator in accordance 
with local community standards of medical care. 
 
The Effects of Other Drugs on Bevacizumab 
Any drugs or supplements that interfere with blood clotting can raise the risk of bleeding during 
treatment with bevacizumab. These drugs include vitamin E, non-steroidal anti-inflammatory 
drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Naprosyn), 
warfarin (Coumadin), ticlopidine (Ticlid), and clopidogrel (Plavix).These agents should be 
used with caution. 
 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy not specified in this protocol 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with sponsor-investigator. Please contact the BTCRC 
Project Manager.  
 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, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed.  
 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 sponsor-investigator 
via the BTCRC Project Manager.  
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.   
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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5.6. Diet/Activity/Other Considerations 
 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 
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 drug.  
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 requirements described above for the duration 
of the study and 120 days following the last dose of study drug. 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. 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to BTCRC Administrative 
Headquarters (AHQ) and to Merck immediately and within 24 hours 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 BTCRC AHQ. If a male subject impregnates his female partner, he 
must immediately inform the site study personnel and the pregnancy reported to BTCRC AHQ 
and to Merck and followed as described above and in Section 11. 


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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. 
 
6. DOSE DELAYS  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 will be used 
to grade adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Section 7. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring protocol therapy interruption or discontinuation at each study visit for the 
duration of their participation in the study.   
 
Subjects discontinued from the treatment phase of the study for any reason will be evaluated at 
least 30 days (+ 7) after the last dose of protocol therapy. 
 
6.1.Start of a New Cycle 
 
A new treatment cycle will only be initiated when all of the following conditions are met: 
 
ANC ≥ 1,500× 109/L  
 
platelets ≥ 100× 109/L  
 
non-hematologic treatment related toxicities have improved to ≤ Grade 1 or to the subject’s 
baseline values (except alopecia) 
 
If blood counts are below this threshold, blood work is to be repeated weekly until counts are 
at an acceptable level. If treatment is unable to restart within 12 weeks of the planned treatment 
date, the subject will be permanently discontinued from study therapy.   
 
NOTE:  For cycle 1 only, the inability to restart therapy within 2 weeks of the planned date is 
a DLT (per section 5.1.1); however, the subject is allowed an additional week of recovery and 
is allowed to remain on study if treatment restarts within 12 weeks. 
 
Any delay to the start of pembrolizumab will result in the same delay to bevacizumab (and vice 
versa) so that both treatments are given together. Study procedures associated with each cycle 
of therapy will also be delayed accordingly (including scans for tumor assessment). Blood tests 
and/or clinical evaluations should occur at the discretion of the treating investigator to monitor 
these parameters. If one drug is permanently discontinued the other drug can be continued. 
 
6.2. Management of Allergic Reaction/ Hypersensitivity 
 
Description 
Action 


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CTCAE Grade I Allergic 
Reaction/Hypersensitivity: (Transient 
flushing or rash, drug fever < 38°C):  
Supervise without further treatment for 
allergic reaction/hypersensitivity. 
CTCAE Grade 2 Allergic 
Reaction/Hypersensitivity: (Rash, 
flushing, dyspnea, urticaria, drug fever 
greater than or equal to 38°C) and/or 
asymptomatic bronchospasm: 
Interrupt the infusion. If symptoms abate, 
attempt re-infusion at a slower rate. If the 
symptoms recur, discontinue infusion and 
follow for recurrent allergic 
reaction/hypersensitivity in the next 
paragraph.
Recurrent CTCAE Grade 2 or 
CTCAE Grade 3 or 4 Allergic 
Reaction/Hypersensitivity: 
Stop the infusion. Administer additional 
doses of H1 and H2 blockers 
intravenously. Administer IV steroids and 
consider epinephrine and bronchodilators 
as clinically indicated.
CTCAE Grade 3 or 4 Allergic 
Reaction/Hypersensitivity: 
Will be permanently discontinued from 
study treatment.
 
Prior to re-challenge of Grade 2 allergic reaction/ hypersensitivity reaction and with all 
subsequent cycles, give both an H1 and H2 blocker intravenously plus dexamethasone 20 mg 
× 2 doses (orally or intravenously) 12 and 6 hours before the chemotherapy session. 
Dexamethasone could be used at the investigator’s discretion in subsequent cycles for recurrent 
(i.e. occurring despite slowing infusion as discussed above) Grade 2 reactions but would not be 
mandated. 
 
6.3. Other Adverse Event Guidelines 
 
Description 
Treatment Delay 
Any other grade 3 non-hematologic toxicity 
Up to 4 week delay 
Any other grade 4 non-hematologic toxicity 
Discontinue treatment 
Neutrophils 999-500 cells/mm3 
Up to 4 week delay 
Neutrophils <500 cells/mm3 
Discontinue treatment 
Febrile Neutropenia 
Discontinue treatment 
Platelets 50,000 /mm3 to 75,000/mm3 
Up to 4 week delay 
Platelets <50,000/mm3 
Discontinue treatment 
Any other grade 4 hematologic toxicity  
Discontinue treatment 
 
If treatment delay necessitates a period longer than 12 weeks, treatment is stopped and the 
subject is discontinued from the study.  
 
 


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6.4. Dose Modifications 
 
There will be no dose modification of bevacizumab in the Phase Ib study. Once the doses are 
established for the Phase II study, there will be no dose modification of bevacizumab. 
 
Pembrolizumab Dose Modifications  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly 
after the first dose or several months after the last dose of pembrolizumab treatment and may 
affect more than on body system simultaneously. Therefore, early recognition and initiation 
of treatment is critical to reduce complications. Based on existing clinical study data, most 
irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. 
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and 
administer corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in Table 3 below.  
 
Other allowed dose interruptions for pembrolizumab 
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 BTCRC Project Manager. The 
reason for interruption should be documented in the patient's study record.


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Table 3: Dose modification and toxicity management guidelines for immune-related adverse events associated with 
pembrolizumab. 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced 
to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 Monitor participants for signs and 
symptoms of pneumonitis 
 Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
 Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2 
Permanently discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids (initial 
dose of 1-2 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.  
 Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes should 
be substituted via IV infusion.
Grade 4 
Permanently discontinue 
AST / ALT elevation or 
Increased bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper
 Monitor with liver function tests 
(consider weekly or more frequently 


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Grade 3 or 4  
Permanently discontinue  Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
until liver enzyme value returned to 
baseline or is stable 
Type 1 diabetes mellitus 
(T1DM) or 
Hyperglycemia 
Newly onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with evidence 
of -cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants with 
T1DM  
 Administer anti-hyperglycemic 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 
discontinue1  
Hyperthyroidism 
Grade 2 
Continue  
 Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
 Monitor for signs and symptoms of 
thyroid disorders.  
Grade 3 or 4  
Withhold or permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care
 Monitor for signs and symptoms of 
thyroid disorders.  
Nephritis and Renal 
dysfunction 
Grade 2 
Withhold  
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
 Monitor changes of renal function 
Grade 3 or 4  
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinue 
All other immune-
related AEs 
Intolerable/ persistent 
Grade 2 
Withhold 
 Based on type and severity of AE 
administer corticosteroids  
 Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis
Grade 4 or recurrent 
Grade 3  
Permanently discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 


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7. STUDY CALENDAR & EVALUATIONS [Cycle = 21 days] 
Study Day 
Screening 
Cycle 1
Cycle 2+ 
Every 6 or 9 
weeks
End of treatment 
visit
Follow Up until 2 yrs 
from registration
-28 days 
Day 15 
Day 1 
(±3)
 
30 days (+7) post last 
protocol therapy dose
Every 3 months 
(±14 days)
REQUIRED ASSESSMENTS 
Informed Consent/ HIPAA auth. 
X
Medical history including prior therapies and pathology
X
Substance use: smoking history (amnt, freq, start/stop)
X
Physical examination, height, weight 
X
X
X
X
Vital Signs 
X
X12
X
X
Karnofsky Performance status 
X
X12
X
X
Blood Chemistries1 
X
X12
X
Thyroid Function (TSH, T3, T4) 
X
PT/INR and aPTT 
X
X12
Platelets, ANC & Hgb 
X
X12
X
Urinalysis for protein2 
X
X12
X
X
Pregnancy test for WOCP10 
X
AE, ECI and irAE assessment 
X12
X
X6
Concomitant medications 
X
X
X
X
Survival 
X
DISEASE ASSESSMENT 
CT chest, abdomen/pelvis 
X3
X (± 7 days)3
X13
CT or MRI Brain, if indicated 
[X]
TREATMENT 
Pembrolizumab 
X
X
Bevacizumab 
X
X
CORRELATIVE STUDIES 
Unstained slides from an archived tumor tissue4 -  
Mandatory 
 
X 
 
 
 
 
Whole blood for circulating tumor cells - Mandatory
X11
X11
Serum for soluble PD-L1 analysis - Mandatory
X11
X11
Plasma for VEGFc levels - Mandatory 
X11
X11
BANKING SAMPLES 
Whole Blood7  
X
Unstained slides from archived tumor tissue8
X
Serum and plasma9  
X
X


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Footnotes: 
 
1: Blood Chemistries to include: sodium, potassium, serum creatinine (or GFR; see 3.1.8), calcium, albumin, ALT, AST, bilirubin, alkaline 
phosphatase, total protein 
2: Urinalysis for protein to be performed within one week of study enrollment. If urine dipstick is 2+, then 24-hr urine for protein must demonstrate < 
1 g protein in 24 hr to allow participation in the study. 
3: Appropriate scans to assess disease status will be obtained within 4 weeks of study enrollment including CT chest, abdomen/pelvis. Disease 
imaging will be performed every 6 weeks through Cycle 9 (cycle 3, 5, 7, 9). Thereafter, imaging will be performed every 9 weeks (cycle 12, 15, 18, 
etc.).  
4: Mandatory submission of unstained slides from an archived tumor tissue for PD-L1 expression, tumor vascular density and CD4(+) and CD8(+) T-
cell infiltration are to be submitted after the patient is registered to the trial. These must be submitted prior to Cycle 2. If archived tumor tissue is not 
available, the patient does not need to undergo a biopsy to obtain tissue. See SPM for collection, labeling and shipping instructions. 
5: For cycle 1 only: labs do not need to be repeated if done within 7 days of day 1. 
6: For subjects with unresolved treatment related toxicity, follow as medically appropriate until resolution or stabilization 
7: Submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See SPM for collection, processing, labeling and shipping 
instructions. 
8: Submission of unstained slides for banking from an archived FFPE tumor block is requested. See SPM for collection, labeling, and shipping 
instructions. 
9: Submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the End of Treatment visit. See SPM for 
collection, labeling, processing, and shipping instructions. 
10: A negative serum or urine pregnancy test is required within 72 hours of study registration. If the urine test cannot be confirmed as negative, a 
serum pregnancy test will be required. 
11: Mandatory submission of whole blood (circulating tumor cell analysis), plasma (VEGFc analysis) and serum (soluble PD-L1 analysis) will be 
collected pre-dose Cycle 1 Day 1 and every 6 or 9 weeks thereafter (i.e. pre-dose Cycle 3 Day 1, pre-dose Cycle 5 Day 1, etc.). Correlative samples 
will be collected every 6 weeks through Cycle 9 (cycle 3, 5, 7, 9). Thereafter, samples will be collected every 9 weeks (cycle 12, 15, 18, etc.). See 
SPM for collection, processing, labeling and shipping instructions.  
12: Phase Ib only: To be performed weekly during Cycle 1 (DLT evaluation period).  
13: Disease assessment will be performed during the 6-month follow up visit for subjects who did not progress during treatment. 


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7.1. Screening 
 
7.1.1. Within 28 days prior to registration for protocol therapy:  
 Informed consent, HIPAA authorization 
 Medical history including prior therapies and pathology 
 Substance use: smoking history. To include: amount, frequency, start and stop dates of 
cigarette, cigar and pipe usage.  
 Physical exam, height, weight 
 Vital signs (blood pressure, heart rate, temperature) 
 Karnofsky performance status 
 Blood chemistries (sodium, potassium, serum creatinine [or GFR; see 3.1.8], calcium, 
albumin, ALT, AST, bilirubin, alkaline phosphatase, total protein) 
 PT/INR and aPTT 
 Thyroid function (TSH, T3 and T4) 
 Platelets, ANC and hemoglobin 
 Urinalysis (urine protein, white blood cells, red blood cells). Urinalysis for protein to 
be performed within one week of study enrollment. If urine dipstick is 2+, then 24-hr 
urine for protein must demonstrate < 1 g protein in 24 hr to allow participation in the 
study. 
 Concomitant medications 
 CT chest, abdomen, pelvis 
 CT or MRI of brain, if indicated 
 
7.1.2. Within 72 hours prior to registration for protocol therapy:  
 Pregnancy test for women of childbearing potential (WOCP). A negative serum or 
urine pregnancy test is required within 72 hours of study registration. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
7.2. On Treatment 
 
7.2.1. Day 1 of Cycle 1: 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
 Physical exam, weight 
 Vital signs 
 Karnofsky performance status 
 Blood chemistries (sodium, potassium, serum creatinine [or GFR; see 3.1.8], calcium, 
albumin, ALT, AST, bilirubin, alkaline phosphatase, total protein) 
 Platelets, ANC and hemoglobin 
 Urinalysis for protein. If urine dipstick is 2+, then 24-hr urine for protein must 
demonstrate < 1 g protein in 24 hr. 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related 
adverse events (irAE) 
 Concomitant medications 
 Pembrolizumab 


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 Bevacizumab 
 Correlative and Banking samples. See Study Procedures Manual for specific 
instructions. 
 
7.2.1.1. Weekly during Cycle 1 of Phase Ib only: 
The following will be performed weekly during Cycle 1 (DLT evaluation period): 
 Vital signs (blood pressure, heart rate, temperature) 
 Karnofsky performance status 
 Blood chemistries (sodium, potassium, serum creatinine [or GFR; see 3.1.8], calcium, 
albumin, ALT, AST, bilirubin, alkaline phosphatase, total protein) 
 PT/INR and aPTT 
 Platelets, ANC and hemoglobin 
 Urinalysis (urine protein, white blood cells, red blood cells). If urine dipstick is 2+, 
then 24-hr urine for protein must be collected. If protein is < 2 g, bevacizumab may 
resume but continue to monitor until 24-hr protein demonstrates < 1 g of protein. 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related 
adverse events (irAE) 
 
7.2.2. Day 1 of Cycle 2+ (±3 days): 
 Physical exam, weight 
 Vital signs 
 Karnofsky performance status 
 Blood chemistries (sodium, potassium, serum creatinine [or GFR; see 3.1.8], calcium, 
albumin, ALT, AST, bilirubin, alkaline phosphatase, total protein) 
 Platelets, ANC and hemoglobin 
 Urinalysis. If urine dipstick is 2+, then 24-hr urine for protein must be collected. If 
protein is < 2 g, bevacizumab may resume but continue to monitor until 24-hr protein 
demonstrates < 1 g of protein. 
 Assess adverse events, events of clinical interest and immune-related adverse events 
 Concomitant medications 
 Pembrolizumab 
 Bevacizumab 
 
7.2.3. Every 6 or 9 weeks: 
Disease imaging and correlative sample collection will be performed every 6 weeks 
through Cycle 9 (cycle 3, 5, 7, 9). Thereafter, they will be performed every 9 weeks (cycle 
12, 15, 18, etc.). 
 CT chest, abdomen, pelvis (±7 days) 
 Correlative samples (pre-dose Cycle 3 Day 1, pre-dose Cycle 5 Day 1, etc.). See 
Study Procedures Manual for specific instructions. 
 
7.3. Off Treatment 
 
7.3.1. Protocol therapy discontinuation: 
A subject will be discontinued from the protocol therapy under the following 
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 
If there is evidence of disease progression  
 
If the treating physician thinks a change of therapy would be in the best interest of 
the subject 
 
If the subject requests to discontinue protocol therapy 
 
If the protocol therapy exhibits unacceptable toxicity 
 
If a female subject becomes pregnant  
 
If there is a ≥ 12-week delay between cycles due to a treatment related adverse 
event.  
 
Subjects can stop study participation at any time. However, if they decide to stop, subjects 
will continue to be followed for survival for 24 months after discontinuation.  
 
7.4. End of Treatment 30 days (+7 days) after final protocol therapy dose 
 Physical exam, weight 
 Vital signs 
 Karnofsky performance status 
 Urinalysis. If urine dipstick is 2+, then 24-hr urine for protein must be collected. 
Continue to monitor until 24-hr protein demonstrates < 1 g of protein. 
 Assess adverse events, events of clinical interest and immune-related adverse events 
 Concomitant medications 
 Banking samples. See Study Procedures Manual for specific instructions. 
 
7.5. Follow-up (±14 days) 
 
Administration of study medication may continue until disease progression, unacceptable 
toxicity, or subject withdrawal. A final study visit will occur at least 30 days (+ 7 days) after 
the last dose of study drugs.  
 
Subjects will continue to be followed for survival every 3 months for 24 months after 
registration.  
 
Disease assessment will be performed during the 6-month follow up visit for subjects who did 
not progress during treatment. 
 
8. CRITERIA FOR DISEASE EVALUATION 
 
Response assessments will be made both using the Immune Related Response Criteria (irRC), and 
using RECIST v1.1, allowing additional comparisons among these criteria for disease response 
assessment. The same measurable and non-measurable lesions will be followed by both RECIST 
v1.1 & irRC. Disease progression will be determined using RECIST 1.1 criteria. 
 
 


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8.1. Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 
 
8.1.1. Measurable disease: The presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
8.1.1.1. Measurable lesions: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
8.1.1.2. Non-measurable lesions: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
8.1.1.3. Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
8.1.1.4. Baseline documentation of “Target” and “Non-Target” lesions:  
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum.  The baseline sum diameters will be used as reference to 


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further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
8.2. Response Criteria for Target Lesions 
 
8.2.1. Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study
 
8.2.2. Evaluation of non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
* Complete Response (CR) 
Disappearance of all non-target 
lesions and normalization of tumor 
marker level 
* Incomplete Response/ Stable Disease (SD) 
Persistence of one or more non-
target lesion(s) or/and maintenance 
of tumor marker level above the 
normal limits 
* Progressive Disease (PD) 
Appearance of one or more new 
lesions and/or unequivocal 
progression of existing non-target 
lesions*
 
* Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Sponsor-Investigator. 


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8.3. 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 PD the smallest measurements 
recorded since the treatment started). In general, the subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
8.4. Definitions for Response Evaluation –RECIST version 1.1 
 
8.4.1. First Documentation of Response: 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.4.2. Confirmation of Response: 
To be assigned a status of complete or partial response, changes in tumor measurements 
must be confirmed by repeat assessments performed no less than four weeks after the 
criteria for response are first met. 
 
8.4.3. Duration of Response: 
Duration of overall response—the period measured from the time that measurement 
criteria are met for complete or partial response (whichever status is recorded first) until 


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the date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since treatment 
started). 
 
8.4.4. Duration of Overall Complete Response: 
The period measured from the time that measurement criteria are met for complete 
response until the first date that progressive disease is objectively documented. 
 
8.4.5. Response Rate:  
The response rate is the proportion of all subjects with confirmed PR or CR according to 
RECIST v1.1. 
 
8.4.6. Clinical Benefit Rate 
The proportion of patients with a confirmed complete response, a partial response or stable 
disease based on RECIST 1.1. 
 
8.4.7. Progression-Free Survival: 
A measurement from the start of the treatment until the criteria for disease progression is 
met as defined by RECIST 1.1 or death occurs. Patients who have not progressed or died 
will be right-censored at the date of the last disease evaluation.   
 
8.4.8. Overall Survival 
A measurement from the start of the treatment until death from any cause. Patients alive at 
last time of contact will be right-censored. 
 
8.5. Methods of Measurement 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment. 
 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. The same 
imaging modality must be used throughout the study to measure disease. 
 
8.5.1. CT and MRI: 
CT and MRI are the best currently available and most reproducible methods for measuring 
target lesions. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 


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type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, 
the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed. 
 
8.5.2. Chest X-Ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by an aerated lung (CT is preferable).   
 
8.5.3. Clinical Examination: 
Clinically detected lesions will only be considered measurable when they are superficial 
(e.g. skin nodules and palpable lymph nodes). For skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended. Photographs 
should be retained at the institution. 
 
8.5.4. Cytology and Histology: 
Cytologic and histologic techniques can be used to differentiate between complete and 
partial responses in rare cases (e.g. after treatment to differentiate residual benign lesions 
and residual malignant lesions in germ cell tumors). Cytologic confirmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required when 
the measurable tumor has met response or stable disease criteria. 
 
8.6. Immune Related Response Criteria: 
This study will evaluate concordance of the Immune Related Response Criteria (irRC) with 
RECIST 1.1 and OS. These response criteria were developed to overcome the variable and 
unusual patterns of response to immunotherapeutic agents, in particular, ipilimumab [34]. The 
development of the guidelines were prompted by observations, mostly in subjects with 
metastatic melanoma, of initial disease progression followed by later response, late responses, 
and mixed responses with an overall decrease in tumor burden.  
 
8.6.1. Antitumor response based on total measurable tumor burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast to 
conventional WHO criteria, which do not require the measurement of new lesions, nor do 
they include new lesion measurements in the characterization of evolving tumor burden). 
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 


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diameters (SPD) of all index lesions (5 lesions per organ, up to 10 visceral lesions) is 
calculated. At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (up to 5 new lesions per organ; 10 visceral lesions) are added together 
to provide the total tumor burden:  
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions  
Table 8: Comparison of WHO and irRC criteria 
 
WHO 
irRC 
New, 
measurable 
lesions  
Always represent PD 
Incorporated into tumor burden 
New, non-
measurable 
lesions  
Always represent PD 
Do not define progression (but preclude 
irCR) 
Non-index 
lesions 
Changes contribute to defining BOR of CR, PR, 
SD, and PD 
Contribute to defining irCR (complete 
disappearance required) 
CR 
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart 
Disappearance of all lesions in two 
consecutive observations not less than 4 
wk apart 
PR 
≥50% decrease in SPD of all index lesions 
compared with baseline in two observations at 
least 4 wk apart, in absence of new lesions or 
unequivocal progression of non-index lesions  
≥50% decrease in tumor burden 
compared with baseline in two 
observations at least 4 wk apart 
SD 
50% decrease in SPD compared with baseline 
cannot be established nor 25% increase compared 
with nadir, in absence of new lesions or 
unequivocal progression of non-index lesions  
50% decrease in tumor burden compared 
with baseline cannot be established nor 
25% increase compared with nadir 
PD 
At least 25% increase in SPD compared with nadir 
and/or unequivocal progression of non-index 
lesions and/or appearance of new lesions (at any 
single time point)  
At least 25% increase in tumor burden 
compared with nadir (at any single time 
point) in two consecutive observations at 
least 4 wk apart  
 
8.6.2. Time-point response assessment using irRC 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the 
change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed 
relative to baseline measurements (i.e., the SPD of all index lesions at screening). The irRC 
were derived from WHO criteria and, therefore, the thresholds of response remain the same. 
However, the irRC response categories have been modified from those of WHO criteria as 
detailed in Tables 8 and 9.  
 
8.6.3. Overall response using the irRC 
The sum of the products of diameters at tumor assessment using the immune-related 
response criteria (irRC) for progressive disease incorporates the contribution of new 
measurable lesions. Each net Percentage Change in Tumor Burden per assessment using 


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irRC criteria accounts for the size and growth kinetics of both old and new lesions as they 
appear. 
Definition of Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of 
the products of the 2 largest perpendicular diameters of all index and all new measurable 
lesions (ie, Percentage Change in Tumor Burden). Note: the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not automatically qualify as 
progressive disease until the SPD increases by ≥ 25% when compared to SPD at nadir. 
 irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
 irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden 
(i.e., taking sum of the products of all index lesions and any new lesions) when compared to 
SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
 irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not 
constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir of the index lesions increases by the required 
amount). 
 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However, their 
contribution to total tumor burden is included in the SPD, which in turn feeds into the irRC 
criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria (see Table 9): 
 Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and non-index together with no new measurable/unmeasurable lesions) for at 
least 4 weeks from the date of documentation of complete response.  
 Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline. 
At each subsequent tumor assessment, the sum of the products of the two largest 
perpendicular diameters of all index lesions and of new measurable lesions are added 
together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, 
relative to baseline of the irSPD compared to the previous SPD baseline, of 50% or greater 
is considered an immune Partial Response (irPR).  


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 Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease.  
 Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 
o At least 25% increase in the sum of the products of all index lesions over nadir SPD 
calculated for the index lesions. 
o At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between 
the date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per subject are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 4 weeks 
after the criteria for response are first met. 
 
Table 9: Derivation of irRC overall responses 
Measurable response 
Nonmeasurable response 
Overall 
response
Index and new, measurable lesions (tumor 
burden),*% 
Non-index lesions 
New, 
nonmeasurable 
lesions 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal progression
Any 
irPR† 
↓≥50 
Absent/Stable 
Any 
irPR† 
↓≥50 
Unequivocal progression
Any 
irPR† 
↓<50 to <25↑ 
Absent/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal progression
Any 
irSD 
≥25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), including measurable 
lesions only  
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at 
least 4 wk apart.  
 
 
 


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9. BIOLOGICAL CORRELATIVES  
 
9.1. Evaluate PD-L1 expression of archived tumor tissue and correlate to clinical response. 
Expression of PD-L1 in archived diagnostic tumor tissue will be determined by IHC by 
referring laboratory used by Merck, and will be correlated with clinical response assessed by 
imaging. Unstained slides are to be submitted; a tumor block is not acceptable.  
 
A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, bone, bone 
marrow or cytologic specimen are not be acceptable for PD-L1 analysis.  
 
Refer to the Study Procedures Manual (SPM) for collection, labeling and shipping 
instructions. 
 
9.2. Assess tumor vascular density of archived tumor tissue and correlate to clinical 
response. 
Tumor vascular density of archived diagnostic tumor tissue will be determined by IHC in the 
Department of Pathology at UI-Health and will be correlated with clinical response assessed 
by imaging. Unstained slides are to be submitted; a tumor block is not acceptable. 
 
Refer to the Study Procedures Manual (SPM) for collection, labeling and shipping 
instructions. 
 
9.3. Assess CD4(+) and CD8(+) T-cell infiltration of archived tumor tissue and correlate to 
clinical response. 
Using archived diagnostic tumor tissue, CD4(+) and CD8(+) T-cell infiltration of the tissue  
will be determined by IHC in the Department of Pathology at UI-Health and will be correlated 
with clinical response assessed by imaging.  Unstained slides are to be submitted; a tumor block 
is not acceptable. 
 
Refer to the Study Procedures Manual (SPM) for collection, labeling and shipping 
instructions. 
 
9.4. Assess number of circulating tumor cells at baseline and during treatment and correlate 
to clinical response. 
Whole blood will be collected at pre-dose Cycle 1 Day 1 and every 6 or 9 weeks thereafter (i.e. 
pre-dose Cycle 3 Day 1, pre-dose Cycle 5 Day 1, etc.) for subsequent analysis of circulating 
tumor cells. Samples will be collected every 6 weeks through Cycle 9 (cycle 3, 5, 7, 9). 
Thereafter, samples will be collected every 9 weeks (cycle 12, 15, 18, etc.). Change in number 
as a result of treatment will be examined in relation to the best clinical response assessed by 
imaging. This analysis will be conducted at the University of Illinois Cancer Center.  
 
Refer to the Study Procedures Manual (SPM) for collection, processing, labeling and shipping 
instructions. 
 


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9.5. Measure soluble PD-L1 level at baseline and during treatment and correlate to clinical 
response. 
Whole blood for serum submission will be collected at pre-dose Cycle 1 Day 1 and every 6 or 
9 weeks thereafter (i.e. pre-dose Cycle 3 Day 1, pre-dose Cycle 5 Day 1, etc.) for subsequent 
analysis of soluble PD-L1 levels. Samples will be collected every 6 weeks through Cycle 9 
(cycle 3, 5, 7, 9). Thereafter, samples will be collected every 9 weeks (cycle 12, 15, 18, etc.). 
Change in soluble PD-L1 levels as a result of treatment will be examined in relation to the best 
clinical response assessed by imaging. This analysis determined by ELISA assay will be 
conducted at the University of Illinois Cancer Center.  
 
Refer to the Study Procedures Manual (SPM) for collection, processing, labeling and shipping 
instructions. 
 
9.6. Measure VEGFc at baseline and during treatment and correlate to clinical response. 
Whole blood for plasma submission will be collected at pre-dose Cycle 1 Day 1 and every 6 or 
9 weeks thereafter (i.e. pre-dose Cycle 3 Day 1, pre-dose Cycle 5 Day 1, etc.) for subsequent 
analysis of VEGFc levels. Samples will be collected every 6 weeks through Cycle 9 (cycle 3, 
5, 7, 9). Thereafter, samples will be collected every 9 weeks (cycle 12, 15, 18, etc.). Change in 
VEGFc levels as a result of treatment will be examined in relation to the best clinical response 
assessed by imaging. This analysis will be conducted at the University of Illinois Cancer 
Center. 
 
Refer to the Study Procedures Manual (SPM) for collection, processing, labeling and shipping 
instructions. 
 
9.7. Correlate baseline proteomic and lipidomic immune classifiers to clinical response. 
Subjects who consent to allow future analysis of left over correlative samples will have 
baseline serum analyzed for immune classifiers. Predictive tests to aid in therapeutic decision 
making are critical for optimizing patient outcomes while minimizing toxicity and associated 
treatment costs. These samples will provide data for proteomics and biomarker development 
via mass spectroscopy. This can be accomplished with a process of proteomic profiling, 
followed by targeted assay development, and then measuring the identified target proteins. 
These samples may also provide data for metabolomics guided by functional groups. This 
approach, known as multiple reaction monitoring (MRM)-profiling, uses specific metabolite 
fragmentations related to functional groups and classes to interrogate the metabolome. 
Immunotherapy mechanisms are dependent upon the interactions between the tumor, tumor 
microenvironment, and the host immune system. As such, a successful predictive test will 
reflect the complex interplay between tumor and host. Pre-treatment serum and/or plasma 
samples will be used to explore the association of proteomic and lipidomic tests at baseline 
with measures of response. 
 
9.8. Samples for future studies 
Subject consent will be obtained for additional samples collected for future Big Ten Cancer 
Research Consortium studies. Hoosier Cancer Research Network, as Administrative 
Headquarters for the BTCRC, will manage the banked samples. Samples will be banked 
indefinitely in the Hoosier Cancer Research Network Biorepository.  
 


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This includes: 
 Whole blood: 
o 
Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: 
o 
Whole blood for plasma will be collected prior to treatment on Cycle 1 Day 1 and at 
End of Treatment.  
 Pre- and Post-treatment serum:  
o 
Whole blood for serum will be collected prior to treatment on Cycle 1 Day 1 and at 
End of Treatment. 
 Unstained slides: 
o 
Unstained slides will be obtained from the subject’s archived formalin fixed paraffin 
embedded tumor sample.  
 
Please refer to the Study Procedures Manual for all sample collection, processing, labeling, 
and shipping instructions. 
 
 
10. DRUG INFORMATION  
 
10.1. Drug Name 
Bevacizumab (Avastin®) 
 
Classification 
Recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic 
activity of human vascular endothelial growth factor. 
 
Mechanism of Action 
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and 
KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads 
to endothelial cell proliferation and new blood vessel formation in in vitro models of 
angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in 
nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic 
disease progression. 
 
How Supplied 
Bevacizumab is supplied in sterile single-use vials individually packaged in a carton (one 
vial to a carton) containing either 100 mg per 4 mL vial (NDC: 50242-060) or 400 mg per 
16 mL vial (NDC: 50242-061)  
 
Availability 
Commercial supplies of bevacizumab will be used in this study and billed to third party 
payers or the subject.   
 
 
 


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Storage, Handling, and Accountability 
Unopened vials of bevacizumab are stable until the expiration date indicated on the package 
when stored at 2° to 8ºC (36° to 46ºF). Bevacizumab vials should be protected from light. Do 
not freeze or shake. Diluted bevacizumab solutions may be stored at 2° to 8ºC (36° to 46ºF) 
for up to 8 hours. Store in the original carton until time of use. No incompatibilities between 
bevacizumab and polyvinylchloride or polyolefin bags have been observed. 
 
Description 
Bevacizumab is supplied in a sterile form for intravenous use only. Bevacizumab is a clear 
to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous 
infusion. Bevacizumab is supplied in 100 mg and 400 mg preservative-free, single-use vials 
to deliver 4 mL or 16 mL of bevacizumab (25 mg/mL). The 100 mg product is formulated 
in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 
4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for 
Injection, USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 
mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, 
anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP. 
 
Administration 
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. Withdraw necessary amount of bevacizumab and dilute in a total volume of 100 mL 
of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the 
product contains no preservatives. 
 Do not administer as an intravenous push or bolus. Administer only as an intravenous 
(IV) infusion.  
 Do not initiate bevacizumab until at least 28 days following major surgery.  
 Administer bevacizumab after the surgical incision has fully healed.  
 First infusion and subsequent infusions duration as per institutional standards.  
 
Risks 
 
Please refer to the package insert for a complete list of adverse events.  
 
Delayed toxicities which occur within hours to days include bleeding gums, blood in urine or 
stools, burning, crawling, itching, numbness, prickling, "pins and needles", or tingling 
feelings, chest pain, cloudy urine, coughing up blood, cough or hoarseness, diarrhea, difficult 
or labored breathing, difficulty in moving, difficulty in swallowing, dizziness, fever or chills, 
general feeling of discomfort or illness, headache, increased menstrual flow or vaginal 
bleeding, joint pain, lack or loss of strength, loss of appetite, lower back or side pain, muscle 
aching or cramping, muscle pains or stiffness, nausea, nosebleeds, painful or difficult 
urination, pale skin, paralysis, pinpoint red spots on skin, prolonged bleeding from cuts, red 
or black, tarry stools, red or dark brown urine, runny nose, shivering, shortness of breath, 
sores, ulcers, or white spots on lips or in mouth, sore throat, sweating, swelling of hands, 
ankles, feet, or lower legs, swollen glands, swollen joints, tightness in chest, troubled 
breathing with exertion, trouble sleeping, unusual bleeding or bruising, unusual tiredness or 
weakness, vomiting, weight loss, and wheezing. 


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Less common toxicities include blurred vision, chest discomfort, fainting, fast, slow, or 
irregular heartbeat, headache (sudden and severe), inability to speak, nervousness, noisy 
breathing, pain or discomfort in arms, jaw, back or neck, pounding in the ears, seizures, 
slurred speech, temporary blindness, weakness in arm and/or leg on one side of the body 
(sudden and severe), and wheezing. 
 
Rare toxicities include allergic reactions, confusion, lightheadedness, and rapid, shallow 
breathing. 
 
Warnings and Precautions 
 
Please refer to the package insert for a complete list of adverse events. 
 
Gastrointestinal Perforations 
Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in 
bevacizumab treated patients compared to controls. The incidence of gastrointestinal 
perforation ranged from 0.3 to 2.4% across clinical studies.  
 
The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. 
Perforation can be complicated by intra-abdominal abscess and fistula formation. The 
majority of cases occurred within the first 50 days of initiation of bevacizumab. 
 
Discontinue bevacizumab in subjects with gastrointestinal perforation. 
 
Surgery and Wound Healing Complications 
Bevacizumab impairs wound healing in animal models. In clinical trials, administration of 
bevacizumab was not allowed until at least 28 days after surgery. In a controlled clinical trial, 
the incidence of wound healing complications, including serious and fatal complications, in 
patients with mCRC who underwent surgery during the course of bevacizumab treatment was 
15% and in patients who did not receive bevacizumab, was 4%. 
 
Bevacizumab should not be initiated for at least 28 days following surgery and until the 
surgical wound is fully healed. Discontinue bevacizumab in subjects with wound healing 
complications requiring medical intervention. 
 
The appropriate interval between the last dose of bevacizumab and elective surgery is 
unknown; however, the half-life of bevacizumab is estimated to be 20 days. Suspend 
bevacizumab for at least 28 days prior to elective surgery. Do not administer bevacizumab 
until the wound is fully healed. 
 
Necrotizing fasciitis, including fatal cases, has been reported in patients treated with 
bevacizumab, usually secondary to wound healing complications, gastrointestinal 
perforation, or fistula formation. Discontinue bevacizumab therapy in subjects who develop 
necrotizing fasciitis.  
 


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Hemorrhage 
Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most 
commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. 
Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, 
CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in 
patients receiving bevacizumab compared to patients receiving only chemotherapy. Across 
indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving 
bevacizumab ranged from 1.2 to 4.6%. 
 
Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous 
cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer 
receiving bevacizumab and chemotherapy compared to none of the 32 (0%) patients receiving 
chemotherapy alone. 
In clinical studies in non–small cell lung cancer where patients with CNS metastases who 
completed radiation and surgery more than 4 weeks prior to the start of bevacizumab were 
evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented 
in one of 83 bevacizumab -treated patients (rate 1.2%, 95% CI 0.06%–5.93%). 
 
Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; 
two patients had Grade 3–4 hemorrhage. 
 
Do not administer bevacizumab to subjects with recent history of hemoptysis of ≥ 1/2 
teaspoon of red blood. Discontinue bevacizumab in subjects with hemorrhage.  
Non-Gastrointestinal Fistula Formation 
Serious 
and 
sometimes 
fatal 
non-gastrointestinal 
fistula 
formation 
involving 
tracheoesophageal, bronchopleural, biliary, vaginal, renal, and bladder sites occurs at a higher 
incidence in bevacizumab -treated patients compared to controls. The incidence of non-
gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the 
first 6 months of bevacizumab therapy. 
 
Discontinue bevacizumab in subjects with fistula formation involving an internal organ.  
 
Arterial Thromboembolic Events  
Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral 
infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other 
ATE occurred at a higher incidence in patients receiving bevacizumab compared to those in 
the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the bevacizumab 
containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving 
bevacizumab in combination with chemotherapy, the risk of developing ATE during therapy 
was increased in patients with a history of arterial thromboembolism, diabetes, or age greater 
than 65 years.  
 
The safety of resumption of bevacizumab therapy after resolution of an ATE has not been 
studied. Discontinue bevacizumab in subjects who experience a severe ATE.  


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Hypertension 
The incidence of severe hypertension is increased in patients receiving bevacizumab as 
compared to controls. Across clinical studies, the incidence of Grade 3 or 4 hypertension 
ranged from 5-18%. 
 
Monitor blood pressure every two to three weeks during treatment with bevacizumab. Treat 
with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to 
monitor blood pressure at regular intervals in subjects with bevacizumab -induced or -
exacerbated hypertension after discontinuation of bevacizumab. 
 
Temporarily suspend bevacizumab in subjects with severe hypertension that is not controlled 
with medical management. Discontinue bevacizumab in subjects with hypertensive crisis or 
hypertensive encephalopathy.  
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of 
symptoms occurred from 16 hours to 1 year after initiation of bevacizumab. RPLS is a 
neurological disorder, which can present with headache, seizure, lethargy, confusion, 
blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be 
present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. 
 
Discontinue bevacizumab in subjects developing RPLS. Symptoms usually resolve or 
improve within days, although some patients have experienced ongoing neurologic sequelae. 
The safety of reinitiating bevacizumab therapy in patients previously experiencing RPLS is 
not known.  
 
Proteinuria 
The incidence and severity of proteinuria is increased in patients receiving bevacizumab as 
compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving 
bevacizumab in clinical trials, in some instances with fatal outcome. In a published case 
series, kidney biopsy of six patients with proteinuria showed findings consistent with 
thrombotic microangiopathy. 
 
Monitor proteinuria by dipstick urine analysis for the development or worsening of 
proteinuria with serial urinalyses during bevacizumab therapy. Subjects with a 2 + or greater 
urine dipstick reading should undergo further assessment with a 24-hour urine collection. 
 
Suspend bevacizumab administration for ≥ 2 grams of proteinuria/24 hours and resume when 
proteinuria is < 2 gm/24 hours. Continue to monitor until 24-hr protein demonstrates < 1 g of 
protein. Discontinue bevacizumab in subjects with nephrotic syndrome. Data from a post-
marketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine 
Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).  
 
Infusion Reactions 
Infusion reactions reported in the clinical trials and post-marketing experience include 
hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, 


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oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. 
In clinical studies, infusion reactions with the first dose of bevacizumab were uncommon (< 
3%) and severe reactions occurred in 0.2% of subjects. 
 
Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.  
 
Ovarian Failure 
The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving 
bevacizumab in combination with mFOLFOX chemotherapy as compared to those receiving 
mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which 
bevacizumab is not approved. Inform females of reproductive potential of the risk of ovarian 
failure prior to starting treatment with bevacizumab.  
Nursing Considerations 
Advise subjects: 
 To undergo routine blood pressure monitoring and to contact their health care provider 
if blood pressure is elevated. 
 To immediately contact their health care provider for unusual bleeding, high fever, 
rigors, sudden onset of worsening neurological function, or persistent or severe 
abdominal pain, severe constipation, or vomiting. 
 Of increased risk of wound healing complications during and following bevacizumab. 
 Of increased risk of an arterial thromboembolic event. 
 Of the potential risk to the fetus during and following bevacizumab and the need to 
continue adequate contraception for at least 6 months following last dose of 
bevacizumab. 
 Of the increased risk for ovarian failure following bevacizumab treatment. 
 
10.2. Drug Name 
Keytruda® (Pembrolizumab; MK-3475 [Anti-PD-1 Antibody MK-3475]) 
 
Chemical name and properties 
Humanized X PD-1_mAb (H409A11) IgG4 
 
Availability 
Merck will supply pembrolizumab at no charge to subjects participating in this clinical trial.  
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. 
 
Storage 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 


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Dosage and Administration 
Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab 
preparation. 
 
Merck & Co. Inc. will supply pembrolizumab directly to sites at no cost to patients in this 
clinical trial. Pembrolizumab is provided as a white to off-white lyophilized powder (50 
mg/vial) or as a liquid solution (100 mg/vial) in Type I glass vials intended for single use 
only. Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is reconstituted with 
sterile water for injection prior to use. Pembrolizumab is formulated with L-histidine as 
buffering agent, polysorbate 80 as surfactant, sucrose as stabilizer/tonicity modifier, and 
hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for pH adjustment (if necessary). 
The drug product is stored as a stable lyophilized powder or liquid solution under 
refrigerated conditions (2°C - 8°C). 
 
The product after reconstitution with sterile water for injection and the liquid drug product 
is a clear to opalescent solution, which may contain extraneous and proteinaceous 
particulates. The reconstituted product and liquid product is intended for IV administration. 
The reconstituted drug product solution and liquid drug product can be further diluted with 
normal saline in IV containers made of polyvinyl chloride (PVC) or non-PVC material. 
Reconstituted vials should be immediately used to prepare the infusion solution in the IV 
bag and the infusion solution should be immediately administered. If not used immediately, 
vials and/or IV bags may be stored at 2-8 °C for up to a cumulative time of 20 hours. If 
refrigerated, the vials and/or IV bags should be allowed to equilibrate to room temperature 
prior to subsequent use. Pembrolizumab solutions may be stored at room temperature for a 
cumulative time of up to 4 hours. This includes room temperature storage of reconstituted 
drug product solution and liquid drug product in vials, room temperature storage of infusion 
solution in the IV bag and the duration of infusion. 
 
Side Effects 
Please refer to the current version of the Investigator’s Brochure for a complete list of adverse 
events. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on 
this mechanism of action, immune mediated adverse events are of primary concern. 
Important identified risks for pembrolizumab are of an immune mediate nature, including: 
pneumonitis, colitis, hepatitis, nephritis, endocrinopathies that include hypophysitis 
(including hypopituitarism and secondary adrenal insufficiency), thyroid disorder 
(hypothyroidism, hyperthyroidism and thyroiditis), Type I diabetes mellitis, uveitis, 
myositis, Guillain-Barré syndrome, pancreatitis, myocarditis, myasthenic syndrome, 
encephalitis, sarcoidosis, severe skin reactions including Stevens-Johnson syndrome (SJS) 
and toxic epidermal necrolysis (TEN), some with fatal outcome; and “solid organ transplant 
rejection following pembrolizumab treatment in donor organ recipients” (risk applicable to 
post-marketing setting only, as such patients are currently excluded from Merck clinical 
trials with pembrolizumab). 
 


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The majority of immune-mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of therapy.  
 
Since the last IB (v15) update, the safety profile for pembrolizumab also includes 2 
important potential risks – i.e. increased risk of severe complications (such as early severe 
graft versus host disease and veno-occlusive disease) of allogeneic transplant in patients 
with hematologic malignancies who have previously been treated with PD-1 inhibitors; and 
GVHD after pembrolizumab administration in patients with a history of allogeneic HSCT. 
 
No new identified or potential risks have been added to the safety profile for 
pembrolizumab since IBv15. 
 
However, based upon additional information received from the clinical study and post-
marketing environments after release of IBv15, the following changes have been made to 
the safety information for pembrolizumab:  
1. further information was added to product labeling to note that immune-mediated 
adverse drug reactions may be fatal and may occur after discontinuation of 
pembrolizumab therapy; and  
2. a new ADR of “arthritis” was identified based primarily on post-marketing experience. 
 
Further details around frequency, reporting, and management of immune-related adverse 
events (irAEs) can be found in the current version of the Investigator’s Brochure.  
 
In addition to the previously noted identified risks, infusion-related reactions are a risk but 
are not considered immune mediated; these are also further described in the current IB. 
 
 
11. ADVERSE EVENTS  
 
11.1. Definitions of Adverse Events 
 
11.1.1. Adverse Event (AE): 
Any untoward medical occurrence in a patient or clinical trial subject administered an 
investigational product and which does not necessarily have a causal relationship with 
the treatment. An adverse event (AE) can, therefore, be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not related to the investigational 
product. 
 
11.1.2. Serious Adverse Event (SAE): 
A serious adverse event is any untoward medical occurrence resulting in one or more of 
the following: 
 
Results in death 
 
Is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
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 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but,  based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or 
the development of drug dependency or drug abuse. 
 
Pembrolizumab overdose. For purposes of this trial, an overdose will be defined as 
any dose exceeding the prescribed dose for pembrolizumab by 20% over the 
prescribed dose. 
 
11.1.3. Unexpected Adverse Event: 
An adverse event not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's Brochure or 
package insert. 
 
11.2. Adverse Event (AE) Reporting 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days 
after treatment discontinuation, regardless of whether or not the event(s) are considered 
related to trial medications. All AEs considered related to trial medication will be followed 
until resolution, return to baseline, or deemed clinically insignificant, even if this occurs 
post-trial. All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. 
 
11.3. Definition and Reporting of an Overdose 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 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 1 
working day to BTCRC Administrative Headquarters (AHQ). BTCRC AHQ will report 


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the event within 1 working day to Merck Global Safety (Attn: Worldwide Product Safety; 
FAX 215-993-1220). 
 
11.4. Reporting of Pregnancy and Lactation 
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, 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 1 working day to BTCRC AHQ. BTCRC AHQ will 
report the event within 1 working day to Merck Global Safety (Attn: Worldwide Product 
Safety; FAX 215-993-1220). 
 
11.5. Definition and Reporting of Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported to BTCRC AHQ within 1 working day of the event. 
 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined above, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*NOTE:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event. Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes. If no other cause is found, then it is assumed to be immune-related.  
 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck’s product, must be reported within 1 working day to 


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BTCRC AHQ. BTCRC AHQ will report the event within 1 working day to Merck Global 
Safety (Attn: Worldwide Product Safety; FAX 215-993-1220). 
 
11.6. Serious Adverse Event (SAE) Reporting 
 
11.6.1. Study Center (Site) Requirements for Reporting SAEs: 
Progression of the cancer under study is not considered an adverse event unless it results 
in hospitalization or death. 
 
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 1 working day to BTCRC AHQ.  
Non-serious Events of Clinical Interest will be reported to BTCRC AHQ and will be 
handled in the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator to be related to the 
Merck product, which is brought to the attention of the investigator at any time outside of 
the 90-day time period specified in the previous paragraph, also must be reported 
immediately to BTCRC AHQ.  
 
The completed SAE Report Form (see SPM) must be sent to Big Ten Cancer 
Research Consortium (BTCRC) Administrative Headquarters (AHQ) within 1 
working day of discovery of the event.  The form will be sent electronically to Big Ten 
CRC AHQ at safety@hoosiercancer.org.The investigator is responsible for informing the 
IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
The original copy of the SAE Report and the email correspondence must be kept within 
the Trial Master File at the study site. 
 
Follow-up information will be sent electronically to BTCRC AHQ, using a new SAE 
Report Form stating that this is a follow-up to the previously reported SAE and giving the 
date of the original report. Each re-occurrence, complication, or progression of the original 
event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not (if applicable), and whether the 
subject continued or withdrew from study participation. All subjects with serious adverse 
events must be followed up for outcome. Sites will electronically submit follow up SAE 
Submission Forms within a reasonable timeframe to Big Ten CRC AHQ at 
safety@hoosiercancer.org. 
 
11.6.2. Death and Immediately Life-Threatening Events: 
Any death and immediately life-threatening event from any cause while a subject is 
receiving trial treatment on this protocol or up to 30 days after the last dose of trial 
treatment, or any death and immediately life-threatening event occurring more than 30 


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days after trial treatment has ended but which is felt to be treatment related must be 
reported within one business day of discovery of the event. All deaths must be reported 
primarily for the purposes of SAE reporting; however, deaths due unequivocally to 
progression are not SAEs.   
 
Participating sites are responsible for informing their IRB and/or the Regulatory 
Authority of the SAE as per local requirements. The completed SAE Reporting Form 
should be emailed to BTCRC AHQ (safety@hoosiercancer.org) within one working 
day of discovery of the event. 
 
11.6.3. 
BTCRC AHQ Requirements for Reporting SAEs: 
BTCRC AHQ will submit all immediately reportable events (e.g. SAEs, ECIs, overdose, 
pregnancy, etc.) received from sites to Merck within one working day of receipt of the 
SAE Reporting Form and to regulatory authorities (FDA) per federal guidelines.   
 
BTCRC AHQ will fax a MedWatch for all SAE reports and any other relevant safety 
information to Merck Global Safety (Attn: Worldwide Product Safety) at: 
Facsimile number:  +1-215-993-1220 
 
BTCRC AHQ will provide follow-up information to Merck as reasonably requested. 
 
BTCRC AHQ will submit 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 to Merck. The sponsor-investigator 
will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally, BTCRC AHQ will submit a copy of these reports to Merck & Co., Inc. 
(Attn: Worldwide Product Safety; FAX 215-993-1220) at the time of submission to 
FDA. 
 
11.7. IND Safety Reports Unrelated to This Trial 
IND safety reports not occurring on this trial but involving the study intervention (outside 
SAEs) received from outside sources will be forwarded to participating sites for 
submission to their Institutional Review Boards per their guidelines.   
 
 
12. STATISTICAL CONSIDERATIONS 
12.1. Study Design 
Phase Ib: 
The primary objective of the Phase Ib dose escalation cohort study is to establish the safe 
dose of study drug pembrolizumab when used in combination with bevacizumab for 
subjects with metastatic clear cell renal cell carcinoma (RCC) after failure of at least one 
systemic therapy for metastatic disease. A standard “3+3” design will be used to establish 
the safe dose. An expansion cohort of 6 patients will be carried out during the Phase Ib 
study at the maximum safe dose, prior to opening the Phase II portion. This will ensure 


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ample safety data of the combination and provide pilot activity data from 12 patients in the 
second-line RCC setting. 
 
Phase II: 
The primary objective of the Phase II trial is to determine the activity of the combination of 
pembrolizumab and bevacizumab in first line therapy for subjects with metastatic clear cell 
RCC as assessed by response rate (RR) (complete or partial response) based on RECIST 1.1. 
The maximum safe dose of pembrolizumab in combination bevacizumab will be given on 
day 1 of each 21 day cycle. Treatment continues until disease progression, unacceptable 
toxicity, subject refusal, or subject death either from progression of disease, the therapy 
itself, or from other causes. Subjects who voluntarily stop the study, have progressive 
disease, or unacceptable toxicities will be followed for a total of 24 months.  An optimal 
two-stage design is used to determine whether the new treatment has sufficient biological 
activity against the disease under study to warrant future development.  
 
Correlative research analyses includes examining the relationship between clinical response 
at the end of Cycle 2 (Week 6) of the treatment period with PD-L1 expression, tumor 
vascular density, and CD4(+) and CD8(+) T-cell tumor infiltration of the archived diagnostic 
tumor tissue. Research analyses also include examining the relationship between changes in 
number of circulating tumor cells, soluble PD-L1 levels, and VEGFc levels from baseline to 
the end of Cycle 2 (Week 6) of the treatment period and clinical response at that time.  
 
12.2. Criteria for Stopping Study 
The Phase Ib portion of the study will be stopped if 2 or more DLTs occur at dose level 1. 
 
The Phase II portion of the study will be stopped if ≥ 2 subjects in first 20, or ≥ 3 in first 30 
subjects, or ≥ 4 in first 40 subjects develop grade 5 toxicity during first 4 cycles of therapy.  
 
 
12.3. Analysis Datasets 
 
Methods of Statistical Analysis 
The definitions of the study populations are listed below. The appropriate study population for 
each analysis should be chosen and defined in the protocol. 
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the 
eligibility criteria and are registered onto the study.  
Evaluable 
This will comprise all subjects who receive at least 
one dose of trial drug and either undergo at least one 
post-baseline assessment or die before any 
evaluation.  
Safety 
This will comprise all subjects who received at least 
one dose of study drug.  
 


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Intention-To-Treat Principle - The principle that asserts that the effect of a treatment policy 
can be best assessed by evaluating on the basis of the intention to treat a subject (i.e. the 
planned treatment regimen) rather than the actual treatment given. It has the consequence 
that subjects allocated to a treatment group should be followed up, assessed, and analyzed 
as members of that group irrespective of their compliance to the planned course of treatment. 
 
12.4. Sample Size 
 
Phase Ib:  
A standard “3+3” design will be used with maximum number of subjects accrued to be 12. 
An expansion cohort of 6 patients will be carried out during the Phase Ib study at the 
maximum safe dose, prior to opening the Phase II portion. 
 
Phase II:  
Study endpoint will be response (PR or CR) as assessed by the RECIST v1.1 criteria. Clinical 
studies identified a response rate with pembrolizumab of 27% in kidney cancer. With 
assumptions of 80% power to detect a 55% improvement to a response rate of 42% in 
response by RECIST v1.1 in the combination arm over historic data on single agent 
pembrolizumab activity in RCC, and an alpha error is 0.107, the optimal Simon’s two stage 
design proceeds as follows. After testing the drug on 22 patients in the first stage, the trial 
will be terminated if 6 or fewer respond. If at least 7 respond, the trial goes on to the second 
stage. A total of 49 patients will be studied. If the total number responding is less than or 
equal to 16, the drug is rejected. Otherwise the drug will be accepted for further studies. The 
sample size analyses are conducted using the software PASS 13 (NCSS, Kaysville, Utah, 
USA.) 
 
12.5. Analysis of Primary Objectives/Aims 
 
Phase Ib Analysis of Primary Endpoint  
The primary endpoint is determination of the maximum safe dose. The maximum safe dose 
will be defined as that dose of pembrolizumab combined with bevacizumab with the highest 
clinical benefit rate, i.e., complete response + partial response + stable disease (CR+PR+SD) 
(RECIST v1.1, Section 8) after 2 cycles of therapy, and best safety profile in the first 6-week 
treatment period. 
 
Phase II Analysis of Primary Endpoint 
The primary endpoint is determination of the activity of the combination of pembrolizumab 
and bevacizumab in first line therapy for metastatic disease as assessed by response rate 
(RR) (complete or partial response) based on RECIST 1.1. The response rate and 95% 
confidence interval for the response rate will be computed using PROC FREQ in SAS (Cary, 
NC).  
 
12.6. Analysis of Secondary Endpoints 
 
Phase Ib Analysis of Secondary Endpoints 
 


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Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in 
subjects with metastatic RCC after failure of at least one systemic therapy. 
 Proportion of subjects with each grade of adverse events as defined by CTCAE v4 will 
be computed along with 95% confidence intervals, and reported in a tabular and 
descriptive manner. 
 
Evaluate clinical benefit rate (complete, partial response, or stable disease) of 
pembrolizumab in combination with bevacizumab in subjects with metastatic RCC after 
failure of at least one systemic therapy. 
 Clinical benefit rate (complete, partial response, or stable disease) will be assessed every 
6 or 9 weeks +/- 1 week while on study treatment using the Response Evaluation Criteria 
In Solid Tumors version 1.1 (RECIST 1.1- Section 8).  Response will be recorded as 
clinical benefit rate, or stable disease plus partial response plus complete response, and 
reported via waterfall plot. The response rate and 95% confidence interval for the 
response rate will be computed using PROC FREQ in SAS (Cary, NC).  
 
Measure Progression-Free Survival (PFS) at 6 months in subjects with metastatic RCC after 
failure of at least one systemic therapy treated with pembrolizumab in combination with 
bevacizumab. 
 Median PFS times will be computed, and PFS rate at 6 months +/- 1 month will be 
calculated with associated 95% confidence intervals. Kaplan-Meier curves will be 
plotted. Data will be analyzed using the PROC FREQ and PROC LIFETEST in SAS. 
 
Measure overall survival (OS) at 2 years from registration in subjects with metastatic RCC 
after failure of at least one systemic therapy treated with pembrolizumab in combination 
with bevacizumab. 
 Median OS times will be computed, and OS rate at 2 years +/- 3 months will be 
calculated with associated 95% confidence intervals. Kaplan-Meier curves will be 
plotted. Data will be analyzed using the PROC FREQ and PROC LIFETEST in SAS. 
 
Phase II Analysis of Secondary Endpoints 
 
Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in 
subjects with treatment-naïve metastatic RCC. 
 Proportion of subjects with each grade of adverse events as defined by CTCAE v4 will 
be computed along with 95% confidence intervals and reported in a tabular and 
descriptive manner. 
Evaluate clinical benefit rate (complete, partial response, or stable disease) of 
pembrolizumab in combination with bevacizumab in subjects with treatment-naïve 
metastatic RCC. 
 Clinical benefit rate (complete, partial response, or stable disease) will be assessed every 
6 or 9 weeks +/- 1 week while on study treatment using the Response Evaluation Criteria 
In Solid Tumors version 1.1 (RECIST 1.1- Section 8). Response will be recorded as 
clinical benefit rate, or stable disease plus partial response plus complete response, and 
reported via waterfall plot.  
 


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Measure Progression-Free Survival (PFS) at 6 months in subjects with treatment-naïve 
metastatic RCC treated with pembrolizumab in combination with bevacizumab. 
 Median PFS times will be computed, and PFS rate at 6 months +/- 1 month will be 
calculated with associated 95% confidence intervals. Kaplan-Meier curves will be 
plotted. Data will be analyzed using the PROC FREQ and PROC LIFETEST in SAS. 
 
Measure overall survival (OS) at 2 years after registration in subjects with treatment-naïve 
metastatic RCC treated with pembrolizumab in combination with bevacizumab. 
 Median OS times will be computed, and OS rate at 2 years +/- 2 months will be 
calculated with associated 95% confidence intervals. Kaplan-Meier curves will be 
plotted. Data will be analyzed using the PROC FREQ and PROC LIFETEST in SAS.  
 
12.7. Analysis of Phase II Correlative Endpoints 
 
 PD-L1 expression by IHC of archived diagnostic tumor tissue will be correlated with the 
best clinical response (RECIST v1.1). Spearman correlation will be computed using 
PROC CORR in SAS (Cary, NC).  
 Tumor vascular density of archived diagnostic tumor tissue will be correlated with the 
best clinical response (RECIST v1.1). Spearman correlation will be computed using 
PROC CORR in SAS (Cary, NC).  
 CD4(+) and CD8(+) T-cell tumor infiltration of archived diagnostic tumor tissue will be 
correlated with the best clinical response (RECIST v1.1). Spearman correlation will be 
computed using PROC CORR in SAS (Cary, NC).  
 Change in PD-L1 expression on circulating tumor cells during therapy relative to 
baseline will be examined in relation to the best clinical response (RECIST v1.1). 
Spearman correlation will be computed using PROC CORR in SAS (Cary, NC).  
 Change in soluble PD-L1 level during therapy relative to baseline will be examined in 
relation to the best clinical response (RECIST v1.1). Spearman correlation will be 
computed using PROC CORR in SAS (Cary, NC).  
 Change in VEGFc level during therapy relative to baseline will be examined in relation 
to the best clinical response (RECIST v1.1). Spearman correlation will be computed 
using PROC CORR in SAS (Cary, NC).  
 Proteomic and lipidomic test results from pre-treatment blood samples will be correlated 
with measures of response (RECIST v1.1). Spearman correlation will be computed using 
PROC CORR in SAS (Cary, NC). 
 
13. TRIAL MANAGEMENT 
 
13.1. Quality Controls and Quality Assurance 
 
13.1.1. Study Monitoring: 
Study monitoring will include a risk-based monitoring strategy as defined in the Data 
Management Plan associated with this protocol. Monitoring visits to the trial sites will be 
made periodically during the trial, to ensure all aspects of the protocol are followed. 
Source documents will be reviewed for verification of agreement with data as submitted 


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via the data collection system. The investigator/institution guarantee access to source 
documents by BTCRC AHQ or its designee and appropriate regulatory agencies. 
 
The trial site may also be subject to quality assurance audit by Merck or its designee as 
well as inspection by appropriate regulatory agencies. 
 
It is important for the investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
13.1.2. Data and Safety Monitoring Plan: 
The study will be conducted in accordance with the University of Illinois Cancer 
Center’s Data and Safety Monitoring Plan. The University of Illinois Cancer Center Data 
Safety and Monitoring Committee will review and make recommendations on this trial. 
BTCRC AHQ will provide the University of Illinois Cancer Center DSMC with periodic 
data reports to comply with the UICC DSMC review requirements.  
 
In addition, BTCRC AHQ data and safety monitoring activities include: 
 
Conduct review of clinical trial for progress and safety 
 
Review of all adverse events requiring expedited reporting as defined in the 
protocol 
 
Provide the Sponsor Investigator with trial progress and safety data as 
required 
 
Notification of participating sites of adverse events requiring expedited reporting 
and subsequent committee recommendations for study modifications 
 
Data and Safety Monitoring and Reporting Guidelines: 
BTCRC AHQ will compile data summary reports for this trial and submit these reports 
monthly to the Sponsor Investigator. BTCRC AHQ will submit data summary reports at 
minimum twice per year for review by the University of Illinois Cancer Center Data 
Safety Monitoring Committee (DSMC).  
 
13.2. Data Handling and Record Keeping 
 
13.2.1. Case Report Forms: 
 
An electronic case report form (eCRF) is required and must be completed for each 
included subject. The completed dataset is housed at BTCRC AHQ and is the sole 
property of the sponsor-investigator’s institution. It should not be made available in any 
form to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without written permission from the sponsor-investigator 
and BTCRC AHQ. After the initial publication, the complete data set will be available to 
all BTCRC institutions. 
13.2.2. Record Retention: 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records; e.g., hospital records), all original signed 


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informed consent forms, copies of all source documents, and detailed records of drug 
disposition. To comply with international regulations, the records should be retained by 
the investigator in compliance with regulations. 
 
During data entry, range and missing data checks will be performed on-line. The checks 
to be performed will be documented in the Data Monitoring Plan for the study. A 
summary report (QC Report) of these checks together with any queries resulting from 
manual review of the eCRFs will be generated for each site and transmitted to the site 
and the site monitor. Corrections will be made by the study site personnel. This will be 
done on an ongoing basis. 
 
13.3. Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records 
identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.   
 
Information collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure locations 
only accessible to the study team. Samples that are collected will be identified by a subject 
study number assigned at the time of registration to the trial. Any material issued to 
collaborating researchers will be anonymized and only identified by the subject study 
number. 
 
Subjects will be informed in writing that some organizations including the sponsor-
investigator and his/her research associates, BTCRC AHQ, Merck, IRB, or government 
agencies, like the FDA, may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled 
in strictest confidence and in accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
13.4. Changes to the Protocol 
Study procedures will not be changed without the mutual agreement of the Sponsor 
Investigator, BTCRC AHQ, and Merck. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version of 
the study protocol (amended protocol) will be generated by BTCRC AHQ and must be 
approved by each IRB, Merck, and if applicable, also the local regulatory authority. Local 
requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then the 
IRB must be notified. Approval of the revised Written Informed Consent Form by the IRB 
is required before the revised form is used.  
The principal investigator is responsible for the distribution of these documents to his or 
her IRB, and to the staff at his or her center. The distribution of these documents to the 
regulatory authority will be handled according to local practice. 


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Merck’s willingness to supply study drug is predicated upon the review of the protocol. 
BTCRC AHQ agrees to provide written notice to Merck of any modifications to the 
protocol or informed consent. 
 
13.5. Ethics 
 
13.5.1. Ethics Review 
The final study protocol, including the final version of the Written Informed Consent 
Form, must be approved or given a favorable opinion in writing by an IRB. The 
investigator must submit written approval to the BTCRC AHQ office before he or she can 
enroll any subject into the study.   
 
The principal investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the 
IRB annually, as local regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be 
provided to the IRB according to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious 
adverse drug reactions from any other study conducted with the investigational product. 
Merck will provide this information to the Sponsor Investigator. These reports will be 
reviewed by the Sponsor-Investigator and will be forwarded to participating sites every 2 
weeks for submission to their Institutional Review Boards per their guidelines.  
 
13.5.2. Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH Good Clinical Practice, and 
applicable regulatory requirements. 
 
13.5.3. Written Informed Consent 
The investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects 
must also be notified they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The investigator must store the original, signed 
Written Informed Consent Form. A copy of the signed Written Informed Consent Form 
must be given to the subject. 
 
 


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