Phase Ib Study to Test the Safety and Potential Synergy of Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Dana-Farber Cancer Institute

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (Ang-2)) in patients with advanced solid tumor 
Version 5.0 –  August 12, 2021 
 
0 
 
 
 
 
Title: Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 
(angiopoietin-2 (Ang-2)) in patients with advanced solid tumor 
 
 NCT Number: NCT03239145 
 IRB Approval Date: Version 5.0 Protocol Version Date 12Aug2021 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
1 
 
Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and 
AMG386 (angiopoietin-2 (Ang-2)) in patients with advanced solid tumor 
 
 
Protocol Version Date:  
August 12, 2021 
 
 
Protocol Version No.: 
5.0 
 
DF/HCC Protocol No.: 
17-217  
 
  
 
 
  
 
 
Study Disease(s): 
1. Solid Tumors 
2. Melanoma   
3. Ovarian Cancer  
4. Kidney cancer   
5. Colorectal Adenocarcinoma  
 
 
*Principal Investigator (PI): 
 F. Stephen Hodi, MD 
 
Dana-Farber Cancer Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
    
                                                                        
                    
 
 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
2 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Agent(s):   
Pembrolizumab (KEYTRUDA®): Merck & Co., Inc. 
                   
Trebananib (AMG386): Amgen, Inc. 
 
IND #:   
133954 
 
   
 
 
 
 
 
 
 
 
 
 
 
 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
5 
 
 
 
TABLE OF CONTENTS 
 
STUDY SCHEMA...............................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Study Design ............................................................................................................8 
1.2 
Primary Objectives...................................................................................................8 
1.3 
Secondary Objectives...............................................................................................9 
1.4 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Background: Pembrolizumab...................................................................................9 
2.2 
Trebananib (AMG386) ........................................................................................233 
2.3 
Rationale ..............................................................................................................277 
2.4 
Correlative Studies Background ............................................................................30 
3. 
PARTICIPANT SELECTION ...........................................................................................31 
3.1 
Eligibility Criteria ..................................................................................................31 
3.2 
Exclusion Criteria ..................................................................................................34 
3.3 
Inclusion of Women and Minorities ......................................................................37 
4. 
REGISTRATION PROCEDURES ...................................................................................37 
4.1 
General Guidelines for DF/HCC Institutions ........................................................37 
4.2 
Registration Process for DF/HCC Institutions .......................................................37 
5. 
TREATMENT PLAN ........................................................................................................38 
5.1 
Treatment Regimen ................................................................................................38 
5.2 
Trial Treatments .....................................................................................................39 
5.3 
Agent Administration.............................................................................................40 
5.4 
Criteria to Resume Treatment ..............................................................................499 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
6 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) ........................................................50 
5.6 
Definition of Maximum Tolerated Dose..............................................................511 
5.7 
Trial Blinding/Masking ........................................................................................511 
5.8 
Stratification .........................................................................................................511 
5.9 
General Concomitant Medication and Supportive Care Guidelines ....................511 
5.10 
Pembrolizumab Rescue Medications & Supportive Care ....................................533 
5.11 
Diet/Activity/Other Considerations .....................................................................533 
5.12 
Duration of Therapy and Criteria for Taking a Participant Off Protocol 
Therapy/Participant Withdrawal ..........................................................................555 
5.13 
End of Treatment Evaluation and Follow-Up ......................................................577 
5.14 
Long-Term Follow-Up and Study Completion....................................................588 
5.15 
Discontinuation of Study Therapy after CR ..........................................................58 
5.16 
Clinical Criteria for Early Trial Termination .........................................................58 
5.17 
Participant Replacement Strategy ..........................................................................59 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................59 
6.1 
Definition of an Overdose for Pembrolizumab and Reporting of Overdose 
to the Sponsor and to Merck ................................................................................600 
6.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck and 
Amgen ....................................................................................................................60 
6.3 
Immediate Reporting of Adverse Events to the Sponsor and to Merck ..............611 
6.4 
Evaluating Adverse Events ..................................................................................633 
6.5 
Sponsor Responsibility for Reporting Adverse Events .......................................666 
7. 
PHARMACEUTICAL INFORMATION ..........................................................................66 
7.1 
Product Descriptions ............................................................................................666 
8. 
ADMINISTRATIVE AND REGULATORY DETAILS ................................................700 
8.1 
Confidentiality .....................................................................................................700 
8.2 
Compliance ..........................................................................................................711 
8.3 
Quality Management System ...............................................................................733 
8.4 
Data Management ................................................................................................733 
9. 
STUDY CALENDAR .....................................................................................................733 
10. 
Trial Procedures and assessments ....................................................................................777 
10.1 
Administrative Procedures ...................................................................................771 
10.2 
Prior and Concomitant Medications Review .........................................................78 
10.3 
Disease Details and Treatments .............................................................................78 
10.4 
Other Procedures ..................................................................................................811 
10.5 
Post Treatment Visits ...........................................................................................811 
11. 
MEASUREMENT OF EFFECT......................................................................................833 
11.1 
Antitumor Effect – Solid Tumors ........................................................................833 
11.2 
Antitumor Effect ..................................................................................................911 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
7 
 
12. 
Tumor tissue collection and correlative studies blood sampling .....................................933 
12.1 
Fresh tumor biopsies: ...........................................................................................933 
12.2 
Peripheral blood: ....................................................................................................98 
12.3 
Integrated Correlative Studies............................................................................1011 
12.4 
Exploratory/Ancillary Correlative Studies ........................................................1044 
12.5 
Sites Performing Correlative Study .................................................................10505 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................10505 
13.1 
Data Reporting .................................................................................................10505 
13.2 
Data Safety Monitoring....................................................................................10505 
14. 
STATISTICAL CONSIDERATIONS.........................................................................10606 
14.1 
Study Design/Endpoints...................................................................................10606 
14.2 
Sample Size, Accrual Rate and Study Duration ..............................................10606 
14.3 
Patient Characteristics ......................................................................................10707 
14.4 
Treatment Compliance .....................................................................................10707 
14.5 
Endpoint Definitions ........................................................................................10707 
14.6 
Efficacy Analysis .............................................................................................10808 
14.7 
Safety Analysis ................................................................................................10808 
14.8 
Proposed analyses of correlative endpoints .....................................................10909 
15. 
PUBLICATION PLAN ...............................................................................................10909 
16. 
REFERENCES ..............................................................................................................1100 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..............................................1200 
ECOG Performance Status ............................................................................................1200 
 
 
 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
8 
 
1. OBJECTIVES 
 
 
1.1 
Study Design 
 
This is a prospective trial which will accrue participants with solid tumors to evaluate the safety, 
clinical, and immunological effect of the combination of pembrolizumab (MK-3475) and  
trebananib (AMG386). The treatment will include an induction phase of pembrolizumab and 
trebananib for 4 cycles (12 weeks) followed by pembrolizumab alone for 2 years. The study will 
accrue up to 60 participants. This trial will be conducted in 2 parts. Part I will use a standard 3+3 
dose escalation design in all solid tumors. The goal of Part I will be to identify the recommended 
part 2 (expansion cohort) doses (RP2D) for the combination of pembrolizumab plus trebananib . 
Dose escalation will begin in dose cohort +1. If two or more patients in dose cohort +1 experience 
a DLT, the next cohort of patients will be enrolled into dose cohort -1.  Should dose cohort -1 
prove too toxic, enrollment to the study will stop.  If the toxicity profile of dose cohort +1 is 
acceptable, the next cohort will be enrolled into dose cohort +2.  Should dose cohort +2 have 
acceptable toxicity, that will be the RP2D; otherwise, dose cohort +1 will be the RP2D. 
Part II has 4 dose expansion cohorts to be treated at the RP2D, which was determined to be 200 
mg pembrolizumab every 3 weeks + 30 mg/kg trebananib every week:  
 melanoma  
 renal cell carcinoma (RCC)  
 ovarian cancer  
 colorectal cancer (CRC)   
 
Initially, 12 patients were to be treated in each cohort. However, as of protocol amendment Version 
4.0, no patients were enrolled to the melanoma cohort and only 4 patients were enrolled to the 
RCC cohort. Due to slow accrual in these specific cohorts, the melanoma and RCC cohorts will 
no longer be open to accrual. Accrual will continue in the ovarian cohort, and the CRC cohort will 
be expanded to allow enrollment of 37 patients total.  
 
Safety assessments will include all patients receiving one or more doses of the study drug 
combinations. Secondary and correlative endpoints will be based on the cohorts of patients 
enrolled in Part II of the trial.  We will summarize secondary and correlative endpoints according 
to disease indication and, in an exploratory fashion, with all patients combined. Pre-and on-
treatment biopsies will be obtained for all patients enrolled in the dose expansion cohorts and 
archival tissue will be collected for selected dose escalation patients when available. 
 
1.2 
Primary Objectives 
 
 Part 1: To determine the safety, tolerability, and RP2D for trebananib when given with 
pembrolizumab in patients with metastatic solid tumor. 
 Part 2 (expansion cohort): To determine the safety and tolerability of the RP2D of 
trebananib, determined in Part 1, when given with pembrolizumab in patients 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
9 
 
withunresectable stage III or stage IV melanoma, metastatic renal cell, ovarian, or 
colorectal cancer. 
 
1.3 
Secondary Objectives 
 
 To obtain preliminary estimates of progression free survival (PFS) at 6 months. 
 To obtain preliminary estimates of the rate of 1-year overall (OS).  
 To obtain preliminary estimates of the response rate (RR).  
  To obtain preliminary estimates of time to progression. 
  
1.4 
Exploratory Objectives 
 To determine the effect of the combination on vasculopathy, immune infiltration, and 
tumor necrosis by staining pathologic specimens for VEGF/VEGFR expression, 
phosphoTie-2 and other targets. 
 To investigate immune responses in the periphery to VEGFR, Tie-2, and other angiogenic 
molecules and tumor-specific antigens as a function of treatment.   
 
2. BACKGROUND 
 
 
2.1 
Background: Pembrolizumab 
 
Refer to the Investigator’s Brochures (IB)/approved labeling for detailed background information 
on pembrolizumab. 
 
2.1.1 
 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis. 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors (Thompson, Dong et al. 2007) (Galon, Pagès et al, 2012). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
10 
 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (Sharpe, Freeman et al. 2002).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade (Okazaki, Chikuma et 
al. 2013). The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ 
T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors. 
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor (Sharpe, Freeman et al. 2002).  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion 
in participants with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  Keytruda® (pembrolizumab) has been approved in the United Stated for the 
treatment of unresectable or metastatic melanoma, metastatic non-small cell lung cancer 
(NSCLC) whose tumors express programmed death ligand 1 (PD-L1), and recurrent metastatic 
squamous cell carcinoma of the head and neck,  
 
2.1.2 
 Preclinical and Clinical Trial Data 
 
Refer to the pembrolizumab Investigator’s Brochures for Preclinical and Clinical data. 
 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
11 
 
2.1.3 Previous experience with immune checkpoint blockade (CTLA-4) and anti-
angiogenesis  
 
Human immune responses against cancer can be suppressed through various mechanisms during 
disease progression such that cancers evade immune recognition and anti-tumor effector functions. 
The expression of immune regulatory molecules such as cytotoxic T-lymphocyte associated 
antigen-4 (CTLA-4) and programmed death 1 (PD-1), etc. inhibits the proliferation and function 
of conventional T cells. Immune checkpoint blockade with ipilimumab (CTLA-4 blockade) has 
revealed improved survival in patients with metastatic melanoma (Robert, Thomas et al., Hodi, 
O'Day et al. 2010). Blockade of PD-1 and PD-L1 interactions has also revealed durable clinical 
benefits in patients with a variety of cancers including melanoma, non-small cell lung cancer, and 
renal cell carcinoma (Topalian, Hodi et al. 2012, Hamid, Robert et al. 2013). Currently, efforts are 
needed to better understand treatment modality combinations that could improve efficacy of 
immune checkpoint blockade. This would include clinical benefits in cancers that exhibit limited 
efficacy to checkpoint blockade alone. There is increasing evidence of the role that angiogenic 
factors play in affecting immune regulation as well as immune effector cell trafficking into tumors.  
We have recently demonstrated that soluble VEGF (sVEGF) predicts clinical benefit to 
ipilimumab therapy (Yuan, Zhou et al. 2014).     
 
 
 
 
 
 
 
 
 
 
 
Anti-CTLA-4 blockade 
Ipilimumab is a fully human monoclonal antibody that blocks the costimulatory checkpoint 
molecule CTLA-4. The anti-tumor mechanism of action involves amplification of T cells by 
blocking endogenous CTLA-4 with resultant T cell proliferation and tumor cell killing. Activity 
has been observed when administered as a single agent or in combination with other 
immunotherapies such as vaccines or interleukin-2 (IL-2) as we well as when combined with 
chemotherapy, and in multiple indications including melanoma.  
Figure 1: Baseline VEGF value correlated with patient overall survival.  
Kaplan-Meier curves demonstrating the difference in OS for patients with 
VEGFlow and VEGFhi are statistically significant: 3 mg/kg dose of 
ipilimumab (median OS 14.33 vs 7.44 months, p=0.0367); 10 mg/kg dose 
of ipilimumab (median OS 10.85 vs 6.16 months, p=0.0477); all patients 
(median OS 12.87 vs 6.56 months p=0.006). 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
12 
 
 
CTLA-4 blockade with ipilimumab leads to improved overall survival in patients with advanced 
melanoma as documented in two phase III studies, emphasizing the antitumor activity of immune 
checkpoint blockade. The published response rate is approximately 18%, with a substantial 
number of responses being durable and/or complete. Recent long-term analyses of follow up for 
patients treated with ipilimumab reveal a durable 22% survival rate with an inflection and 
flattening of the survival curves at approximately 3 years (ECCO 2013), demonstrating long-
term benefits for patients. 
 
The question remains what treatment modalities exist to combine with checkpoint blockade to 
improve efficacy.  Anti-angiogenesis has been one modality we have pursued. 
 
Combination of anti-CTLA-4 and anti-VEGF therapy in patients with advanced melanoma 
Our own experience with ipilimumab includes its administration to patients following a 
therapeutic vaccine. In patients in whom pre-existing sites of disease were biopsied following 
treatment, we have observed the consistent presence of an immune mediated vasculopathy 
around the vasculature feeding the tumor deposit associated with extensive tumor necrosis 
(Figure 1) (Hodi, Mihm et al. 2003). 
 
 
 
 
 
 
 
 
 
 
 
In addition to this evidence, VEGF is known to be a potent inhibitor of dendritic cell maturation. 
VEGF inhibition has also been demonstrated to facilitate T cell trafficking across endothelia. As 
a result of these observations, we initiated and completed a phase 1 trial of the combination of 
bevacizumab and ipilimumab in patients with unresectable stage III or IV melanoma. The results 
of the trial provide the first experience of combining anti-angiogenesis with immune checkpoint 
blockade. 
The primary endpoints of the trial were the safety and preliminary activity of the combination of 
the two treatments for patients with advanced melanoma. Patients received ipilimumab every 3 
weeks for four doses then every 12 weeks, and bevacizumab every 3 weeks.  Patients could 
Figure 2: Left: Melanoma tumor deposit post-ipilimumab demonstrating extensive 
hemorrhagic tumor necrosis with rim of viable tumor heavily infiltrated with granulocytes 
and lymphocytes. 
Right: Melanoma tumor deposit post-ipilimumab with severe tumor vasculopathy 
accompanied by perivascular and intramural lymphoid infiltrates associated with luminal 
thrombosis. (Magnification: ×125).

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
14 
 
 
 
 
 
 
 
The highest percentage with disease control was 76.5%, which was reported in Cohort 2 (95% 
exact CI: 50% to 93%). A number of patients had durable responses, with several achieving best 
response after months of therapy.  A patient in Cohort 2 (MTD) experienced approximately 7 
months of stable disease before a partial response and subsequently had a complete response 
beginning approximately 17 months following the initiation of therapy.  Eight patients in Cohorts 
1 and 2 remain alive for months after discontinuation of therapy.  There is significantly shorter 
Figure 4: Activity in treated 
patients by cohort 
according to RECIST 
criteria. Arrows indicate 
alive at time of analysis. 
Crosses indicate death. 
Black bars indicate 
discontinuation of treatment 
other than due to 
progressive disease.  Five 
patients came off trial due 
to toxicity requiring 
systemic steroids.  One 
patient withdrew consent 
after week 12 without dose-
limiting toxicity. PD= 
progressive disease. SD = 
stable disease. PR = partial 
response. CR = complete 
response.
Figure 5: Response kinetics in 
treated patients. Baseline tumor 
measurements are standardized to 
zero. 
A. 
Entire 
treatment 
population (cohorts 1-4).  B.  
Cohort 
2 
patients 
(MTD).  
Horizontal line PD = progressive 
disease representing 20% increase.  
Horizontal line PR represents 30% 
decrease from baseline. 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
18 
 
 
 
Angiopoietin-2 and its relevance to immune checkpoint blockade 
Angiopoietin-2  
Angiopoietin-1 is constitutively expressed in many adult tissues and is required for normal 
vascular homeostasis, whereas Ang-2 is predominantly expressed in tissues undergoing vascular 
remodeling and in hypoxic tumor microenvironments (Nasarre, Thomas et al. 2009). Ang-2 is a 
critical regulator of blood vessel maturation (Augustin, Koh et al. 2009). The molecule, which is 
in normal tissue almost exclusively produced by endothelial cells (EC), functions as a vessel-
destabilizing molecule that facilitates the activities of other endothelial-acting cytokines by 
controlling the Ang-2/Tie-2 signaling pathway (Wong, Haroon et al. 1997; Augustin, Koh et al. 
2009). Several studies have demonstrated that elevated levels of Ang-2 and higher Ang-2/Ang1 
ratios compared to levels in normal tissues are associated with a worse prognosis in a number of 
different tumor types. The expression patterns of Ang-2 in normal tissues versus tumor suggest 
that Ang-2 may be a promising target for cancer therapy. Circulating Ang-2 was identified as a 
biomarker for progression and metastasis in melanoma (Helfrich, Edler et al. 2009) Furthermore, 
Ang-2 was found to be expressed by tumor-associated endothelial cells and melanoma cells; 
siRNA silencing of Ang-2 lead to strongly reduced invasive and migratory capacity of melanoma 
cells. 
 
Angiopoietin-2 in ipilimumab studies 
In our previous experience in early ipilimumab studies, serologic screening of cDNA expression 
libraries identified angiopoietin-2 (Ang-2) as a target of high titer antibodies in treated patients. 
Furthermore, a number of patients who experienced favorable clinical outcomes from these 
studies have developed high titer antibodies to Angiopoietin-2 (Ang-2) as a function of 
treatment. 
 
 
These antibodies in patients have proven to be functional in TIE-2 binding assays as well as tube 
formation assays (TIE-2 receptor signaling in endothelial cells), suggesting that synergy of 
Figure 11: Humoral immune response 
to Ang-2 in treated melanoma patients 
with favorable clinical outcomes. 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
23 
 
Changes in Serum Recognition of TEC and 
Melanoma Cell line as Function of Treatment
Pre  Post
Pre  Post
Pre  Post
K008
Melanoma
cells
Pt 6 TEC
Pt 8 TEC
 
 
 
 
2.2 
Trebananib 
 
Angiopoietin 2 (Ang2) is an autocrine cytokine, and it is expressed in endothelial cells and stored 
in Weibel-Palade bodies for rapid releasing upon stimulation (Reiss, Droste et al. 2007 Imhof, 
Aurrand-Lions et al. 2006). Tie-2, its receptor is predominately expressed on embryonic 
endothelium, and also found in the entire quiescent vasculature in a wide range of adult tissue 
(Dumont, Gradwohl et al. 1993; Wong, Haroon et al. 1997). Ang2 functions as an antagonist of 
Ang1/Tie-2 signaling in angiogenesis (Gale, Thurston et al. 2002; Augustin, Koh et al 2009; 
Maisonpierre, Suri et al 1997).  In varieties of tumors, Ang2 expression by EC is up-regulated 
(Tsutsui, Inoue et al 2006; Sfiligoi, de Luca et al 2003; Currie, Gunningham et al 2002; Detjen, 
Rieke et al. 2010; Helfrich, Edler et al. 2009; Lind, Wikstrom et al 2005).  In tumor 
microenvironment, vessel destabilization and regression by Ang2 is involved in vasculature 
remodeling and facilitates VEGF dependent angiogenesis (Augustin, Koh et al 2009; Holash, 
Maisonpierre et al 1999).  Disruption of Ang2 with blocking antibody and genetic depletion 
indicates important roles in tumor angiogenesis and tumor growth (Brown, Cao et al. 2010; 
Hashizume, Falcon et al. 2010; Mazzieri, Pucci et al. 2011; Oliner, Min et al. 2004; Nasarre, 
Thomas et al. 2009).   
 
Tie-2 is also found to be expressed on a proangiogenic subpopulation of myeloid cells in 
circulation and tumors called Tie-2-expressing monocytes/macrophages (TEM) (De Palma, 
Venneri et al. 2003; De Palma, Venneri et al. 2005; Coffelt, Scholz et al. 2010). Ang2 augments 
the ability of TEM in angiogenesis and facilitates TEM toward an M2-like macrophage 
phenotype (Coffelt, Scholz et al. 2010; Pucci, Venneri et al. 2009).  Furthermore, Ang2 
stimulates the immunno-suppressive properties of TEM via suppression of T cell activation, 
promotion of Treg expansion, and upregulations of IL10 and CCR17 (Coffelt, Scolz et al. 2010).   
Figure 20: Treatment with ipiliumab plus 
bevacizumab resulted in humoral immune 
recognition of targets on tumor associated 
endothelial cells (TEC) isolated from fresh 
post-treatment biopsies as well as targets 
on melanoma cells. 

A Phase Ib study to test the safety and potential synergy of pembrolizumab (anti-PD-1) and AMG386 (angiopoietin-
2 (ANG-2)) in patients with advanced solid tumors 
Version 5.0 – August 12, 2021 
 
27 
 
indicated that higher levels of sPD-L1 are associated with progressive diseases in advanced 
melanoma patients, and expression of PD-L1 is associated with secretion of sPD-L1. Whether 
sPD-L1 secretion occurs and how Ang2 and trebananib affects sPD-L1 secretion in CD14+Tie-2+ 
monocytes are worthy of further investigation.  
 
In summary, Tie-2 pathway plays roles in the regulation of expression of PD-L1, ICOSL, and 
IL10, which are involved in the modulations of T cell and tumor immunity.  Impacts of Ang2 
and its neutralizing trebananib on Tie-2 pathway are worthy of further investigation.   
 
 
2.3 
Rationale 
 
2.3.1 Rationale for the Trial and Selected Participant Population 
 
The combination of CTLA-4 and VEGF blockade appears to be well tolerated in patients with 
advanced melanoma. The clinical efficacy data and correlative studies of the immune response 
suggest that the combination has enhanced antitumor immunostimulatory effects beyond those 
observed with CTLA-4 blockade alone. One potential mechanism is that VEGF blockade promotes 
normalization of tumor blood vessels and permits enhanced egress of tumor specific lymphocytes 
and other immune effectors. Another, non-exclusive mechanism is that VEGF may inhibit some 
aspects of an effective adaptive immune response itself, including endothelial cell activation and 
dendritic cell maturation, and that blockade of VEGF further augments the anti-tumor immune 
response. The emergence of antibodies to Ang-2 after vaccination or CTLA-4 blockade observed 
in our studies suggests that synergy of immune checkpoint blockade may go beyond VEGF and 
include the family of angiogenic factors including Ang-2. There also remains the potential role for 
Ang2 blockade at influencing immune suppressor cells such as myeloid and M2 macrophages. 
These data in conjunction with the increasing evidence for Ang-2 as an important target for cancer 
therapy provide the rationale for the proposed trial of combined blockade.  
 
Given the currently available data and clinical experiences, there are several cancer types that are 
reasonable to target based on this biology and clinical activity when considering combination 
therapies of immune checkpoint blockade and anti-angiogenesis. Pembrolizumab has 
demonstrated significant clinical activity in melanoma patients who have previously been treated 
with ipilimumab or are ipilimumab-naïve (Hamid, Robert et al. 2013, Robert, Ribas et al. 2014). 
Overall response rate is approximately 26-38% with evidence for durable benefit. The anti-PD-1 
antibody nivolumab has also demonstrated significant clinical activity with a response rate of 
approximately 31%, median overall survival of 16.8 months, and median response duration of two 
years. Furthermore with this clinical activity, improved outcomes and understanding of 
combination approaches are needed. In addition, single agent activity of ziv-aflibercept as anti-
angiogenesis in metastatic cutaneous or uveal melanoma included a 7.5% response rate and a 
median overall survival of 16.3 months (Tarhini Frankel, and Margolin, 2011). With the 
ipilimumab and bevacizumab combination clinical experience (Hodi, Lawrence et al. 2014), the 
single agent activity of zivaflibercept in melanoma, as well as known clinical activity for 
pembrolizumab in melanoma, melanoma is one disease to include investigations with this novel 
combination. Clinical activity with immune checkpoint blockade with ipilimumab and PD-1 
agents has also been seen in renal cell carcinoma, and anti-VEGF agents are a mainstay of 

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treatment for this disease (Choueiri 2013, Escudier, Albiges et al. 2013, McDermott and Atkins 
2013, Mooney, Paluri et al. 2014). Currently available are a number of VEGF TKI agents that have 
demonstrated clinical activity but with the development of resistance. Therefore, treatment of renal 
cell carcinoma patients with such combinations should also be considered as improvement of 
patient outcomes is still warranted. Anti-angiogenesis with bevacizumab and Ziv-aflibercept has 
become a mainstay treatment for colorectal cancer in combination with chemotherapy (Damin and 
Lazzaron 2014) (Patel and Sun 2014) (Dietvorst and Eskens 2013). There remains a need for 
improving patient outcomes from these combinatorial approaches. Improved understanding of 
checkpoint blockade as well as combinations is warranted in this disease with unmet need. Finally, 
ipilimumab has demonstrated activity in ovarian cancer (Hodi, Mihm et al. 2003). Bevacizumab 
is an active agent used in combination therapy for ovarian cancer. As part of the mainstay in this 
disease, there remains an unmet need in platinum-resistant ovarian cancer (Jayson, Kohn et al. 
2014, Syrios, Banerjee et al. 2014).  
Accumulating clinical experience with trebananib has demonstrated both activity and a favorable 
safety profile. VEGF and PD-1 blockade has also shown successful combination in pre-clinical 
animal models. Ang-2 and VEGF blockade together has revealed synergy in pre-clinical animal 
models and have successfully been combined in clinical trials.  Ang-2 plays an important role in 
the proangiogenic and immune inhibitory effects of TIE-2 positive monocytes.  The addition of 
Ang-2 inhibition to PD-1 blockade with pembrolizumab may further complement the reversal of 
angiogenic immune suppression and improve immune cell trafficking. We hypothesize to test 
whether the combination of Ang-2 inhibition with PD-1 blockade is tolerable and safe. We next 
seek to determine if the combination augments anti-tumor activity through evidence of clinical 
responses and biomarker responses. 
 
In order to gain greater safety as well as preliminary efficacy data and correlatives to determine 
mechanisms of potential synergy in these patient populations, expanded cohorts will be treated at 
the recommended part 2 (expansion cohort) dose for pembrolizumab plus trebananib.   
 
2.3.2 Rationale for Dose Selection/Regimen/Modification 
 
2.3.2.1 
Rationale Pembrolizumab Dose Selection 
 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated by Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications, regardless of tumor type. As outlined 
below, this dose is justified by: 
 
 Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg Q2W, representing an approximate 5- to 7.5 – fold exposure range (refer to IB, 
Section 5.2.2) 
 Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distribution of 
exposures, supporting suitability of 200 mg Q3W 

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 Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK]  
 
2.3.2.2 
 Rationale Trebananib Dose Selection 
 
The safety, pharmacokinetics, and antitumor activity of Trebananib were evaluated in Phase I 
study in patients with advanced solid tumors. Thirty-two patients received weekly intravenous 
trebananib doses of 0.3, 1, 3, 10, or 30 mg/kg in sequential cohorts. One DLT was reported in the 
30 mg/kg cohort (respiratory arrest), which likely was caused by tumor burden that was possibly 
related to trebananib. The most common toxicities were fatigue and peripheral edema. Proteinuria 
(n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-
related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-
linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum 
trebananib levels appeared to reach steady-state after four weekly doses, and there was minimal 
accumulation. No anti-trebananib neutralizing antibodies were detected (Herbst, Hong et al. 2009). 
The safety of trebananib was also evaluated in a Phase I study in the Japanese population using 
dose escalation of 3, 10, or 30 mg/kg. Trebananib was well tolerated at all dose levels and no DLT 
was observed (Doi, Ohtsu et al. 2012).  Trebananib has been evaluated as monotherapy and in 
combination with chemotherapy or other biologic agents across tumor types, including mixed solid 
tumors, ovarian, breast, renal, gastric, hepatic, and colorectal cancers. As of the study-specific data 
cutoff dates, 3611 participants have been enrolled into 20 studies in the trebananib clinical 
program, of whom 3561 participants have received ≥ 1 dose of trebananib or trebananib placebo, 
at doses ranging from 0.3 mg/kg to 30 mg/kg intravenously (IV) once weekly (QW). No maximum 
tolerated dose for trebananib monotherapy has been identified at doses up to 30 mg/kg IV QW. 
Most of early phase 1b/2 studies (in combination with other agents) were conducted with 3 and 10 
mg/kg every week (QW) doses. Later, based on exposure response modeling the 15 mg/kg QW 
dose was elected in all 3 of the large Phase 3 trials and this dose was explored further in a few 
Phase 1b/2. Few small studies using 30 mg/kg QW in combination with chemotherapy or other 
agents are currently ongoing and there is no controlled studies comparing 15 to 30 mg/kg.     
A summary of anticipated overlapping toxicities with pembrolizumab includes: 
 Diarrhea 
 Fatigue 
 Nausea and vomiting 
 Shortness of breath 
 Skin itching 
 Rash 
 Cough 
 Joint pain 
 Fever 
 Swelling 

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 Weakness 
 Back pain 
 Abdominal pain 
 Anemia 
 Inflammation of the bowel 
 
2.3.3 Rationale for Endpoints 
 
2.3.3.1 
Efficacy Endpoints 
 
The primary endpoint of this study is to determine the safety, tolerability and recommended dosing 
for the combination of pembrolizumab plus trebananib. Our secondary objective are to obtain in 
preliminary fashion the efficacy of the combination including PFS at 6 months, the rate of 1-year 
overall (OS), the response rate (RR) and time to progression in diseases where anti-angiogenesis 
had shown to be effective. Chest, abdomen, and pelvic CT scan will be obtained every twelve 
weeks for determination of therapeutic efficacy. Standard solid tumor response criteria (RECIST) 
will be obtained. To further explore the clinical observations in some patients receiving 
ipilimumab of delayed responses and disease burden increasing before stable disease or response 
attained, we will incorporate proposed immune response criteria to assess for clinical activity. 
These immune response criteria (irRC) (Hodi, Hoos et al. 2008) (Wolchok et al., 2009) will be 
captured and compared to standard response criteria for solid tumors.   
 
2.4 
Correlative Studies Background 
 
Antigen-specific T cell responses are controlled by co-stimulatory and co-inhibitory molecules 
positively and negatively. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and 
programmed cell death 1 (PD-1, CD279) are among the key co-inhibitory molecules, broadly 
categorized as “checkpoint molecules” (Pardoll DM, 2012). CD279 is up-regulated on activated T 
lymphocytes and mediate immunosuppression when binding to its ligands B7-H1 (CD274) and 
B7-DC (CD273).  Blockade of CD279 or CD274 induced durable objective response in patients 
with advanced melanoma, renal cell carcinoma and non-small cell lung cancers in clinical trials 
(Topalian S, 2012; Brahmer J, 2012; Hamid O, 2013). Moreover, immunohistochemical staining 
performed on pretreatment tumor tissues from patients with anti-CD279 treatment showed that 
none of 17 patients with CD274 negative tumors had an objective response whereas 36% (9/25) 
patients with CD274 positive tumors had an objective response (P=0.006). This striking difference 
suggests that CD274 expression on tumor specimen might be a useful biomarker to predict 
response to anti- CD279 treatment.  
Anti-vascular endothelial growth factor pathway therapies preferentially target immature tumor 
blood vessels and leave behind normalized and resistant blood vessels. Angiopoietin-2 
(ANGPT2)/TIE pathway is largely confined to vasculature. It has two receptors TIE1 and TIE2 as 
well as three ligands, angiopoietin-1, angiopoietin-2 (ANGPT2) and angiopoietin-4.  ANGPT2 
plays an important role in vascular remodeling and angiogenesis. It acts as context-specific 
antagonist of angiopoietin-1/TIE2 signaling, destabilizes the quiescent blood vessels as a 
prerequisite to sprouting angiogenesis in the presence of proangiogenic stimulation or vascular 

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regression in the absence of such stimuli.  Therapeutics targeting the ANGPT2/TIE pathways 
including selective anti-ANGPT2 antibodies is in development (Gerald D, 2013; Karlan BY, 2012; 
Hashizume H, 2010). Serum ANGPT2 is found to be a biomarker for tumor progression and 
survival in various malignancies (Helfrich I, 2009).    
We further hypothesize that not only CD274 but also CD279 and CD273 protein expression in 
tumor tissues might be associated with favorable clinical response, and might be served as 
biomarkers for patient selection for CD279 blockade in clinical treatment.  
We also hypothesize that ANGPT2 protein expression in tumor tissue might be a biomarker to 
identify a group of patients who might have objective responses on anti-ANGPT2 or/with anti-
vascular endothelial growth factor therapies. 
 
3. PARTICIPANT SELECTION 
 
Participants must meet all eligibility criteria below prior to registration. See Section 4 for further 
information regarding registration procedures and Section 9 for study calendar and further 
details.  
 
All assessments are to occur within 28 days of registration except where noted otherwise. The 
participant must be thoroughly informed about all aspects of the study, including the study visit 
schedule and required evaluations and all regulatory requirements for informed consent. The 
written informed consent must be obtained from the participant prior to enrollment. 
 
Following registration, any additional laboratory assessments obtained prior to start of treatment 
will not be used to re-confirm eligibility. 
 
 
3.1 
Eligibility Criteria  
 
In order to be eligible for participation in this trial, the participant must meet the following 
criteria on screening examination: 

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3.1.1 Be willing and able to provide written informed consent for the trial. 
3.1.2 Be  18 years of age on day of signing informed consent. 
3.1.3 Have measurable disease based on RECIST 1.1.   
3.1.4 In dose escalation (Phase I), patients must have histologically or cytologically confirmed 
metastatic disease from any solid tumor that is incurable and fulfills one of the following 
criteria:  
a) Has demonstrated progression of disease following at least one line of effective 
systemic therapy. Prior treatment with anti-CTLA-4 antibody (including 
ipilimumab) is allowable  
OR 
b) For which effective therapy does not exist 
3.1.5 In dose expansion (part 2), patients must have histologically or cytologically confirmed 
unresectable or metastatic melanoma, renal cell carcinoma, ovarian cancer, or colorectal 
cancer. 
3.1.6 Renal cell patients must have had at least one prior VEGF TKI. 
3.1.7 Ovarian cancer patients must be resistant to platinum therapy (i.e. within 6 months of last 
platinum therapy).  
3.1.8 Patients with colorectal cancer should have progressed on at least one fluorouracil plus 
irinotecan or oxaliplatin containing regimen. 
3.1.9 Patients with melanoma should have unresectable or metastatic disease. Melanoma patients 
with BRAF V600E or V600K mutation-positive melanoma who have previously received 
a BRAF inhibitor with or without a MEK inhibitor) are eligible.  
3.1.10 In the dose expansion cohort patients should be willing to provide tissue from a newly 
obtained core or excisional biopsy of a tumor lesion (pre-treatment) and an on-treatment 
biopsy. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to 
initiation of treatment on Day 1.  Patients for whom newly-obtained samples cannot be 
provided (e.g., inaccessible, participant safety concern, or unwilling to undergo biopsy) 
may submit an archived specimen only upon agreement from the Sponsor. An on-treatment 
biopsy will be collected approximately halfway through the induction period, about 6 
weeks from the start of study treatment (sometime between Cycle 2 Day 8– Cycle 3 Day 
1).  
3.1.11 Have a performance status of 0 or 1 on the ECOG Performance Scale (see Appendix A) up 
to 28 days before treatment initiation 

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3.1.12 Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed up to 28 days before treatment initiation.   
Table 1.  Adequate Organ Function Laboratory Values 
 
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC) ≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment)
Renal 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for participant with creatinine levels 
> 1.5 X institutional ULN 
Hepatic 
Serum total bilirubin
≤ 1.5 X ULN OR
 
Direct bilirubin ≤ ULN for participants with total 
bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for participants with liver metastases
Albumin
>2.5 mg/dL
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
 
 
3.1.13 Negative protein on screening urinalysis 
 
3.1.14 Female participant of childbearing potential should have a negative serum pregnancy test 
performed during the screening period.  
 
Female participants of childbearing potential (Section 5.11.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.11.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication. Should a 
woman become pregnant or suspect she is pregnant while she is participating in this 
study, she should inform her treating physician immediately. 

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 Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant. 
 
3.1.15 Male participants of reproductive potential (Section 5.11.2) must agree to use an adequate 
method of contraception as outlined in Section 5.11.2- Contraception, starting with the first dose 
of study therapy through 120 days after the last dose of study therapy. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
 
3.2 
Exclusion Criteria 
 
The participant must be excluded from participating in the trial if the participant: 
 

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3.2.1 Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
3.2.2 Has a diagnosis of immunodeficiency including participants infected with Human 
Immunodeficiency Virus (HIV). 
3.2.3 Is receiving systemic steroid therapy or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment. 
3.2.4 Has a known history of active TB   (Bacillus Tuberculosis). 
3.2.5 Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
3.2.6 Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent.  
Note:  Participants with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study.  
Note:  If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
3.2.7 Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
3.2.8 Lesions suspected to be at higher-risk for bleeding such as bowel involvement with tumor 
that invades into the bowel wall or involves the intraluminal component of bowel by 
imaging or direct visualization or central pulmonary lesions. 
3.2.9 Ulcerated skin lesions 
3.2.10 Poorly-controlled hypertension as defined BP > 150/100 mmHg, or SBP > 180 mmHg 
when DBP < 90 mmHg, on at least 2 repeated determinations on separate days within 3 
months prior to study enrollment. 
3.2.11 History within 6 months prior to treatment of myocardial infarction, severe/unstable angina 
pectoris, CABG, NYHA class III or IV CHF, stroke or TIA. 
3.2.12 History within 3 months prior to treatment of  Grade 3-4 GI bleeding/hemorrhage, 
treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or 
inflammatory bowel disease, diverticulitis, pulmonary embolus, or other uncontrolled 
thromboembolic event. 

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3.2.13 Patients who are less than 4 weeks post-op after major surgery. 
3.2.14 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to pembrolizumab and trebananib including history of allergic reactions to 
bacterially produced proteins. 
3.2.15 Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants 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 trial treatment.  This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.   
3.2.16 Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
3.2.17 Treatment within 30 days prior to enrollment/randomization with strong immune 
modulators including but not limited to systemic cyclosporine, tacrolimus, sirolimus, 
mycophenolate mofetil, methotrexate, azathioprine, rapamycin, thalidomide, and 
lenalidomide. 
3.2.18 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
interstitial lung disease or active, non-infectious pneumonitis, nephritis,  pancreatitis, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
3.2.19 Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids 
or current pneumonitis/interstitial lung disease.. 
3.2.20 Has an active infection requiring systemic therapy. 
3.2.21 Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the participant’s participation for the 
full duration of the trial, or is not in the best interest of the participant to participate, in the 
opinion of the treating investigator.   
3.2.22 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
3.2.23 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 

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3.2.24 Patient with ovarian cancer and  colorectal cancer who have received prior therapy with an 
anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody. Melanoma and renal cell carcinoma 
patients who received prior anti-PD-1 or anti-PD-L1 or CTLA-4 antibodies are allowed to 
participate.  
3.2.25 Has received trebananib or another angiopoietin-2 directed therapy (prior treatment with 
bevacizumab is not an exclusion criteria) 
3.2.26 Has active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
3.2.27 Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose 
of study drug. Administration of killedvaccines is allowed. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Participant Research Titled Centralized 
Participant Registration (SOP #: REGIST-101A) or Decentralized Participant Registration (SOP 
#: REGIST-101B) must be followed.   
 

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5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
This is a prospective trial which will accrue participants with solid tumors to evaluate the safety, 
clinical, and immunological effect of the combination of pembrolizumab and trebananib. The 
treatment will include an induction phase of pembrolizumab and trebananib for 4 cycles (12 wks) 
followed by pembrolizumab alone for up to 2 years. This trial will be conducted in 2 parts: 
Part I will use a standard 3+3 dose escalation design in all solid tumors (refer to Table 2. Dose 
escalation will begin in dose cohort +1 (refer to Table 3). If two or more patients in dose cohort 
+1 experience a DLT, the next cohort of patients will be enrolled into dose cohort -1.  Should 
dose cohort -1 prove too toxic (i.e. two or more patients experience a DLT), enrollment to the 
study will stop.  If the toxicity profile of dose cohort +1 is acceptable per the escalation decision 
rules in Table 2, the next cohort will be enrolled into dose cohort +2.  Should dose cohort +2 
have acceptable toxicity per the escalation decision rules in Table 2, that will be the RP2D; 
otherwise, dose cohort +1 will be the RP2D. 
 
Table 2. Dose Escalation Schema 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
 
Table 3.  Part I Dose Escalation Schedule  

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**** First dose of trebananib should be administered over 60 minutes.
 
5.2.1 Dose Selection/Modification   
 
5.2.1.1 
Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 2.3.2 
 
Details on the preparation and administration of pembrolizumab and trebananib are provided in 
the pharmacy manual.  
 
5.3 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Dose for weight-based drugs should be 
flagged for recalculation at the start of each cycle should the weight of a participant change by 
more than 5% from the previous cycle’s Day 1 weight. No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient's malignancy.  
 
5.3.1 Timing of Dose Administration: Pembrolizumab 
 
Pembrolizumab should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 9).  Pembrolizumab may be 
administered with trebananib up to 2 days before or after the scheduled Day 1 of each cycle due 
to administrative reasons. Pembrolizumab will be administered before trebananib.  
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
 The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
5.3.2 Timing of Dose Administration: Trebananib  
 
Trebananib should be administered on Day 1, 8, and 15 of each 21-day cycle after all 
procedures/assessments have been completed. Trebananib may be administered with 
pembrolizumab up to 2 days before or after the scheduled Day of each cycle due to administrative 
reasons (±2 days).  
 
The first dose of trebananib will be administered by IV infusion over a 60-minute period. If the 
initial dose administration is well tolerated, future administrations may be given over 
approximately 30 minutes (treatment cycle intervals may be increased due to toxicity a described 
in section 5). A window of -5 to +10 minutes is permitted (i.e. infusion time is 30 minutes: -5 
min/+10 min). Trebananib will be administered within 2 hours after Pembrolizumab.  

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The Investigational Product Instruction Manual (IPIM) contains specific instructions for the 
preparation of the trebananib infusion fluid and administration of infusion solution. 
 
5.3.3 Dose Modifications 
 
5.3.3.1 
Pembrolizumab Dose Modification and Toxicity Management for Immune-
Related AEs Associated with Pembrolizumab and Combination Therapy 
 
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic etiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab/combination treatment are 
provided in Table 5..  See Section 5.9 for supportive care guidelines, including use of 
corticosteroids. 
 
Attribution of Toxicity: 
 
When study interventions are administered in combination, attribution of an adverse event to a 
single component is liely to be difficult. Therefore, while the investigator may attribute a toxicity 
event [to the combination, to [trebananib alone] or to pembrolizumab alone], for adverse events 
listed in Table 5, both interventions must be held according to the criteria in Table 5 Dose 
Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Associated with Pembrolizumab. 
 
Holding Study Interventions: 
 
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to the recommended dose modifications. 
 
Restarting Study Interventions: 
 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 5. 
 
 If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions 
 If the toxicities do not resolve and conditions are aligned with what is defined in Table 5, 
the combination of trebananib and pembrolizumab may be restarted at the discretion of the 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
** In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further trial treatment administration.
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov. 
 
 
Other allowed dose interruption for pembrolizumab 
 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events and/or unforeseen circumstances not related to study intervention. 
However, intervention is to be restarted within 3 weeks of the originally scheduled dose and within 
42 days of the previously administered dose, unless otherwise discussed with the Sponsor. The 
reason for study intervention interruption should be documented in the patient's study record. 
 
If pembrolizumab is held or treatment delayed, trebananib should also be delayed such that the 
two drugs are administered on the same day. If pembrolizumab is to be permanently 
discontinued, the patients may continue trebananib treatment alone.   
 
5.3.3.2 
Trebananib Dose Modification and Toxicity Management 
 
Criteria for dose modification as well as specific toxicity management are described below: 
 
For infusion reaction and delayed infusion related reactions: Any potential infusion reaction 
should be classified based upon severity and time of onset relative to the infusion, and recorded 
in the case history (and AE eCRF) as an infusion reaction in addition to the underlying symptom.  
 
For infusion reactions occurring within 24 hours of infusion of trebananib and deemed by the 
investigator to be related to trebananib infusion:  

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 Mild (grade 1) or moderate (grade 2) – treat per appropriate medical guidelines. 
Trebananib dosing may resume; however all subsequent doses of trebananib should be 
administered no faster than over 60 minutes.  
 Severe (grade 3) or life-threatening (grade 4) –permanently discontinue trebananib 
 
For infusion – related reactions occurring more than 24 hours after the infusion of trebananib, 
regardless of whether the reaction is deemed related or not –related to trebananib: 
 All grades – treat per appropriate medical guidelines. Contact the Priniciple Investigator 
prior to any additional administration of trebananib. 
 
Hemorrhage: Participants who develop any new grade of hemorrhage in the central nervous 
system will permanently discontinue trebananib. 
 
Participants who develop grade 3 or 4 hemorrhage in any other organ system (pulmonary, GI, 
etc.) will permanently discontinue trebananib. 
 
Thromboembolic Events: For grade 1 or 2 venous thromboembolic event, no dose modification 
is required. For grade 3 venous thromboembolic event, or asymptomatic grade 4 venous 
thromboembolic event (asymptomatic pulmonary embolus), hold trebananib. If the planned 
duration of the full‐dose anticoagulant is ≤ 2 weeks, trebananib should be held until the full‐dose 
anticoagulation period is over. If the planned duration of full‐dose anticoagulation is > 2 weeks, 
trebananib may be resumed during the period of full dose anticoagulation if the following 
criterion is met: 
 The participant must be therapeutically anti‐coagulated with an approved anticoagulant 
agent according to standard prescribing guidelines. 
 
Participants, while on anticoagulation, who develop a second thromboembolic event of grade 2 
or higher, should permanently discontinue trebananib. 
 
For symptomatic grade 4 venous thrombosis, permanently discontinue trebananib. 
 
For any grade of arterial thromboembolic event, trebananib will be permanently discontinued. 
 
Edema/lymphedema: A higher incidence of peripheral edema was observed in the trebananib 
arms vs. the placebo arm in the 20060342 study. To provide a common framework for reporting 
edema (including lymphedema) investigators should report new edema or edema that 
significantly worsens from pre‐study baseline, and manage their participants as defined in this 
section. 
 
All adverse events of peripheral edema must be reported and graded as found in this section and 
NOT per CTCAE v4.0. 
 
Edema of a visceral organ or body cavity, such as pulmonary congestion, ascites, or pleural 
effusion, should NOT be reported as per this section but per CTCAE v4.0. 
 

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Investigators should attempt to ascertain the etiology of edema, which may include, but is not 
limited to, thromboembolism, chronic corticosteroid dosing, tumor obstruction of lymphatic or 
blood vessels, congestive heart failure, iatrogenic fluid overload, renal insufficiency, nephrotic 
syndrome or other significant hypoalbuminemic states. 
 
Edema/lymphedema should be classified as: 
 LOCALIZED (confined to a single body area, e.g. lower extremities only) or 
 GENERALIZED (contiguous extension to more than a single body area). 
Additionally, both localized and generalized edema/lymphedema should be graded as follows: 
 Grade 1 (MILD): defined as trace thickening or faint discoloration of the affected area. 
 Grade 2 (MODERATE): defined as moderate thickening or marked discoloration; 
leathery skin texture; papillary formation. 
 Grade 3 (SEVERE): defined as severe symptoms that may involve skin blistering or skin 
breakdown; limitations of activities of daily living (ADL). 
The management of edema / lymphedema should be as follows based upon the above grading: 
 Grades 1 or 2 – Continue trebananib dosing per protocol and treat edema / lymphedema 
per appropriate medical and institutional guidelines 
 Grade 3 or 4 – Discontinue trebananib permanently. Treat edema /lymphedema per 
appropriate medical and institutional guidelines 
 
Hypertension: Hypertension (HTN) should be managed per institutional standards and 
appropriate medical guidelines.  trebananib should be held for systolic BP > 200 mmHg or 
diastolic BP > 110 mmHg, or symptomatic hypertension.  trebananib may be resumed at the pre‐
hold dose upon resolution of symptomatic HTN, systolic BP ≤ 140 mmHg and diastolic BP ≤ 90 
mmHg, or returned to participant’s baseline blood pressure. If the participant’s BP is elevated 
upon first reading, measurements should be confirmed with a repeat measurement. 
 
For any grade of hypertensive crisis or hypertensive encephalopathy, permanently discontinue 
trebananib.  
 
Hypokalemia: Participants should have their serum potassium checked as outlined in the Section 
9 and managed per institutional guidelines. If hypokalemia is present, replacement should be 
managed with either oral and/or parenteral replacement, according to institutional practice and to 
the degree of hypokalemia present. It is recommended that the participant’s serum potassium 
level should be maintained within the normal range, as much as possible, during study treatment. 
Isolated hypokalemia without clinical sequelae should not be reported as an adverse event. 
 
Pleural Effusion and Ascites: Pleural effusion and ascites should be graded according to CTCAE 
v4.0. However, since trebananib is known to cause or worsen pre‐existing pleural effusions and 
ascites, these adverse events should be managed as noted below: 
Life‐threatening pleural effusions or ascites: 
 Institute emergency measures per institutional guidelines 
 Permanently discontinue trebananib 
For all non‐life‐threatening pleural effusion or ascites: 
 Treat per institutional guidelines which may include, 

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o non‐investigational diuretics, 
o thoracentesis, chest tube drainage or paracentesis 
o pleurodesis 
 Investigators should document each paracentesis and /or thoracentesis that occurs while a 
participant is on study. 
 
Additional toxicities to permanently discontinue trebananib for:  
 Gastrointestinal perforation 
 Compromised wound healing 
 Fistula formation 
 Nephrotic syndrome or thrombotic microangiopathy (TMA) 
 Reversible posterior leukoencephalopathy syndrome (RPLS) 
 Ascites or pleural effusion requiring therapeutic invention 
 
Trebananib should be temporarily suspended at least 4 weeks prior to an elective surgery. 
Trebananib should not be resumed until 4 weeks after major surgery, or 2 weeks after minor 
surgery, and until wounds are healed and drainage tubes removed. 
 
Any grade 1 or 2 toxicities other than those listed above considered to be related to trebananib or 
the combination of trebananib and pembrolizumab should be managed according to standard 
medical practice. 
 
When a participant experiences a grade-3 or 4 toxicity other than those listed above considered to 
be related to trebananib or the combination of trebananib and pembrolizumab, trebananib should 
be held until the toxicity resolves to ≤ grade 1 or the patient’s baseline. When resumed trebananib 
will be dose reduced by one dose level, however, patients at dose level -1 requiring a reduction 
will discontinue trebananib. 
 
If more than three doses of trebananib need to be held then trebananib will be discontinued.  
 
If a toxicity is assessed as related to trebananib and not pembrolizumab, pembrolizumab may be 
continued when the toxicity is improved to grade 1 or resolved. If trebananib is to be 
permanently discontinued, the patient may continue treatment with pembrolizumab alone. If the 
patient continues pembrolizumab alone due to a toxicity related to trebananib, then they are 
permitted to skip any Day 8 and Day 15 visits and assessments that coincide with the 
administration of trebananib. 
 
5.4 
Criteria to Resume Treatment 
 
For non-autoimmune or inflammatory events, patients may resume treatment with study drug 
when the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following 
exceptions: 
 Patients may resume treatment in the presence of Grade 2 fatigue.  
 Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 

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the presence of Grade 2 AST/ALT OR total bilirubin. 
 Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must 
have resolved to baseline before treatment is resumed. 
 Drug-related endocrinopathies (not including drug-related adrenal insufficiency or 
hypophysitis) adequately controlled with only physiologic hormone replacement may 
resume treatment after replacement correction and clinically stable regimen. 
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than the 
next scheduled time point per protocol.  However, if the treatment is delayed past the next 
scheduled time point per protocol, the treatment should resume at the earliest convenient point 
that is within the 12 week delay period.  
 
If treatment is delayed >12 weeks, the patient must be permanently discontinued from study 
therapy, except as specified in Section 5.12 (Duration of Therapy). 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT)  
 
Dose –limiting toxicities (DLTs) will be assessed during the first 3 weeks of treatment so that 
labs and other evaluations taken at the end of the first cycle (start of the second cycle) are 
included in the assessment period. A DLT is defined as an adverse event that is (a) related to 
pembrolizumab and/or trebananib with an attribution of possible, probable, or definite, and (b) 
occurs during and/or begins during the first 3 weeks of the study treatment and (c) meets any of 
the following criteria:  
 
Hematological toxicities 
 
A Grade 4 hematological toxicity unrelated to an underlying medical condition 
 
Arterial thromboembolic event 
 
Non-hematological toxicities: 
 
A non-hematological toxicity of grade 3 unrelated to an underlying medical condition 
 
Eye pain of grade 2 or higher. 
 
Urine protein: creatinine > 3.5 or >2g protein on 24hour urine collection 
 
Two delays of treatment (not due to scheduling non-compliance) each lasting more than 
10 days within 4 cycles of drug. 
 
Exclusions to Dose limiting toxicities: 
 
 
Grade 3 electrolyte toxicities that can be corrected to Grade 1 or less within 24 hours will 
not be considered dose limiting. 
 
Grade 3 hypertension that can be controlled with oral medications and does not require 
treatment delay for > 7 days will not be considered a DLT. 
 
Grade 3 diarrhea that can be corrected to Grade 1 or less within 48 hours after anti-diarrhea 
medication will not be considered dose limiting. 
 
Grade 3 nausea and vomiting that can be corrected to Grade 1 or less within 48 hours after 
anti-emetic therapy will not be considered a DLT.  

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 
Grade 3 rise in creatinine that can be corrected to Grade 2 or less after 2 liters of intravenous 
fluids within 24 hours will not be considered dose limiting. 
 
Grade 3 elevation in AST/ALT if AST/ALT levels were <1.5 times the baseline level will 
not be considered a DLT.  
 
Grade 3 elevation on ALP (Alkaline phosphatase) will not be considered a DLT. 
 
Grade 3 lymphopenia will not be considered a DLT. 
 
Grade 3 rash that returns to ≤ grade 2 after 1 week of symptomatic treatment will not be 
considered a dose limiting toxicity. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 5.3.3. 
 
Dose escalation will proceed within each cohort according to the following schema.  Dose-
limiting toxicity (DLT) is defined above.  
 
5.6 
Definition of Maximum Tolerated Dose  
 
The MTD will be based on the assessment of DLTs as defined in section 5.5 and will not exceed 
the 30mg/kg trebananib weekly dose. The MTD will be defined as the dose at which fewer than 
one-third of participants experience a DLT to pembrolizumab and trebananib.  
 
5.7 
Trial Blinding/Masking 
 
This is an open-label trial; therefore, the Sponsor, investigators, and participant will know the 
treatment administered. 
 
5.8 
Stratification 
 
No stratification based on age, gender or other characteristic will be used in this trial. 
 
5.9 
General Concomitant Medication and Supportive Care Guidelines 
 
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 DFCI Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the participant's primary physician.  
 
5.9.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 

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fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 9.2.13. 
5.9.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion =may be allowed at the 
investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Participants should not receive strong immune modulators including but not limited to 
systemic cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, 
azathioprine, rapamycin, thalidomide, lenalidomide, and targeted immune modulators such as 
abatacept (CTLA4Ig), adalimumab, alefacept, anakinra, belatacept (LEA29Y), efalizumab, 
etanercept, infliximab, or rituximab. 
 
Participants 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.  
Participants may receive other medications that the investigator deems to be medically 
necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 

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5.10 Pembrolizumab Rescue Medications & Supportive Care 
5.10.1 Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outline along with the dose modification guidelines in 
Section 5.3.3 [Table 5]. 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). Refer to Table 5 in Section 5.3.3 for 
dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 
5.11 Diet/Activity/Other Considerations 
5.11.1 Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
5.11.2 Contraception 
 
Pembrolizumab and trebananib may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab or trebananib has transient adverse effects on the composition of 
sperm.   
 
For this trial, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
 
Female participants will be considered of non-reproductive potential if they are either:  
 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 

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amenorrhea, a single FSH measurement is insufficient.);  
OR  
 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
 
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male participants of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
 
(1) practice abstinence† from heterosexual activity;  
 
OR  
 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
 intrauterine device (IUD) 
 vasectomy of a female participant’s male partner  
 contraceptive rod implanted into the skin 
 Combination method (requires use of two of the following): 
 diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
 cervical cap with spermicide (nulliparous women only)   
 contraceptive sponge (nulliparous women only)  
 male condom or female condom (cannot be used together) 
 hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the participant’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, 
etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for participants 
participating at sites in this country/region. 
 
Participants 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 participants of childbearing potential must adhere to the contraception requirement 

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(described above) from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 120 days after the last 
dose of trial therapy.  If there is any question that a participant of childbearing potential will not 
reliably comply with the requirements for contraception, that participant should not be entered 
into the study. 
 
5.11.3 Use in Pregnancy 
 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab and 
trebananib, the participant will immediately be removed from the study.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor, Merck, 
and Amgen. This should be reported without delay within 24 hours to the Sponsor and within 2 
working days to Merck and Amgen if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male participant 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor, Merck, and Amgen and followed as described above and 
in Section 6.2. 
5.11.4 Use in Nursing Women 
 
It is unknown whether pembrolizumab or trebananib 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, participants who are breast-feeding are not eligible for enrollment. 
 
5.12 
Duration of Therapy and Criteria for Taking a Participant Off Protocol 
Therapy/Participant Withdrawal 
 
Discontinuation of study intervention does not represent withdrawal from the study. 
 
As certain data on clinical events beyond study intervention discontinuation may be important to 
the study, they must be collected through the participant’s last scheduled follow-up, even if the 
participant has discontinued study intervention. Therefore, all participants who discontinue study 
intervention prior to completion of the protocol-specified treatment period will still continue to 
be monitored in this study and participant in the study visits and procedures unless the 
participant has withdrawn from the study. 
 
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect occur. 
In addition, a participant may be discontinued from study intervention by the investigator or the 
Sponsor if the study intervention is inappropriate, a study plan is violated, or for administrative 
and/or other reasons. 
 

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Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
two years with pembrolizumab and three months with trebananib or until one of the following 
criteria applies: 
 
 Disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 
11.1.6. 
Note: A participant may be granted an exception to continue on treatment 
despite radiographic disease progression if clinically stable, please see Section 
11.1.6. 
 Intercurrent illness that prevents further administration of treatment. 
 Participant or their legal representative (such as a parent or legal guardian) 
decides to withdraw from the study. 
 Investigator decides to withdraw the participant 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 The participant has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The participant is lost to follow up. 
 The participant completes 24 months of uninterrupted treatment with 
pembrolizumab or 35 administrations of study pembrolizumab, whichever is 
later 
 Administrative reasons 
 Unacceptable adverse event(s), including: 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that 
does not respond to topical therapy and does not improve to Grade 1 
severity within the re-treatment period OR requires systemic treatment 
 Grade 3 drug-related autoimmune or inflammatory event including 
uveitis, pneumonitis, diarrhea, colitis, neurologic adverse events, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. 
 Any Grade 3 or 4 drug-related laboratory imbalance or electrolyte 
abnormality, not associated with underlying organ pathology and that 
do not require treatment except for electrolyte replacements do not 
require treatment discontinuation, with the following exceptions with 
approval of the Principal Investigator: 
 Hypophysitis or pan-hypopituitarism any grade should discontinue 
treatment. 
 Grade 4 amylase or lipase abnormalities that are not associated with 
DM, associated liver or gall bladder inflammation clinical 
manifestations of pancreatitis may stay on study. 
 Any drug-related liver function test (LFT) abnormality that meets the 
following criteria requires discontinuation: Grade 4 AST or ALT. 

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 Grade 3 drug-related thrombocytopenia >7 days or associated with 
bleeding requires discontinuation. 
 For patients with skin-only toxicity, when symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Discontinue pembrolizumab if unable to reduce 
corticosteroid dose for irAEs to ≤10 mg. Pembrolizumab treatment 
may be restarted and the dose modified as specified in the protocol. 
 Patients with endocrinopathy (e.g. thyroiditis, hypophysitis) and no 
other autoimmune/inflammatory event may be restarted after a short 
course of steroids and/or on a stable replacement regimen. 
 Any dosing interruption lasting >12 weeks with the following exceptions: 
 Dosing interruptions >12 weeks that occur for non-drug-related 
reasons may be allowed if approved by the Principal Investigator.  
Prior to re-initiating treatment in a participant with a dosing 
interruption lasting >12 weeks, the Principal Investigator must be 
consulted. 
 Tumor assessments should continue as per protocol even if dosing is 
interrupted. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, F. Stephen Hodi, MD by phone (617-632-5053) or by pager (44131).  
 
 
5.13 
End of Treatment Evaluation and Follow-Up 
 
The End of Treatment and Follow-up visit procedures are listed in Section 9 (Protocol Flow 
Chart) and Section 11 (Visit Requirements). After the end of treatment, each participant will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 6).   
 
Participants who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up. 
 

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5.14 
Long-Term Follow-Up and Study Completion 
 
Patients will be followed every 12 weeks after discontinuing study treatment.  
 
Patients removed from study for unacceptable adverse event(s) will be followed until 
progression.  
 
All patients will be followed for at least a year from the time of initiation of treatment or until 
death, whichever occurs first. 
 
After documented disease progression each participant will be followed by telephone or medical 
record review for overall survival until death, withdrawal of consent, or the end of the study as 
detailed below. 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up 
 Withdrawal of consent 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A ODQ Off Study Form will be filled out when a participant comes off study. This form can be 
found on the ODQ website or obtained from the ODQ registration staff. 
 
5.15 Discontinuation of Study Therapy after Stable Disease, PR, or CR 
Participants who discontinue treatment may be eligible for up to one year of additional treatment 
with pembrolizumab when they experience radiographic recurrence of disease via the Second 
Course Phase at the discretion of the investigator if no cancer treatment was administered since 
the last dose of pembrolizumab, the participant meets the safety parameters listed in the 
Inclusion/Exclusion criteria, and the trial is open. Participants will resume treatment at the same 
dose and schedule of time of initial discontinuation. 
 
 
5.16 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
 
1. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to participants 
2. Plans to modify the development of the study drug 
3. If for any reason Merck or Amgen makes a decision to no longer supply study drug. 

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5.17 
Participant Replacement Strategy 
 
Additional participants may be enrolled to ensure that the required number of evaluable 
participants in each cohort is achieved. A participant that discontinues the trial for progressive 
disease or a drug-related AE will not be replaced and will be counted in the evaluable population 
of participants for the respective cohort.  
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
 
Merck and Amgen products includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo or 
active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck and Amgen for human use. 
 
Adverse events may occur during the course of the use of Merck or Amgen product in clinical 
trials, or as prescribed in clinical practice, from overdose (whether accidental or intentional), 
from abuse and from withdrawal. 
 
Progression of the cancer under study is not considered an adverse event.  
 
All adverse events that occur after the consent form is signed but before presenting for cycle 1 
day 1 must be reported by the investigator ONLY if they cause the participant to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of cycle 1 day 1 through 30 days following cessation of treatment, all adverse 
events must be reported by the investigator. Such events will be recorded at each examination 
on the Adverse Event case report forms/worksheets.  The reporting timeframe for adverse 
events meeting any serious criteria is described in section 6.3 The investigator will make every 
attempt to follow all participants with non-serious adverse events for outcome. 

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Adverse events will not be collected for participants during the pre-screening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention.   
 
6.1 
Definition of an Overdose for Pembrolizumab and Reporting of Overdose to the 
Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the participant should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the IND holder and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
 
6.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck and Amgen 
 
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 participant 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the participant to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 

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Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220) and Amgen Global 
Safety (Attn: Amgen Global Safety - FAX is #:1-888-814-8653). 
 
6.3 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
 
6.3.1 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck or 
Amgen products that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another important medical event  
 Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor, Merck and Amgen 
in the same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck and Amgen for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
For the time period beginning when the consent form is signed until the participant presents for 
cycle 1 day 1, any serious adverse event that occurs to any participant must be reported within 24 
hours to the IND holder and within 2 working days to Merck Global Safety and Amgen ONLY if 
it causes the participant to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
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 participant from the 
time  the participant presents for Cycle 1 Day 1 through 90 days following cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or not 
related to Merck or Amgen product, must be reported within 24 hours to the Sponsor and within 
2 working days to Merck Global Safety and Amgen. Additionally, any serious adverse event, 
considered by an investigator who is a qualified physician to be related to Merck product that is 
brought to the attention of the investigator at any time following consent through the end of the 
specified safety follow-up period specified in the paragraph above, or at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the IND 
holder and to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
 
 

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A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; 
 and Amgen (Attn: Global Safety - 
 at the time of submission to FDA. 
 
6.3.2 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
6.3.3 Expedited Reporting to the Food and Drug Administration (FDA) 
 
The IND holder will be responsible for all communications with the FDA. The Overall PI will 
report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the 
FDA’s criteria for expedited reporting following the reporting requirements and timelines set by 
the FDA. 
 
6.3.4 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
6.3.5 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
6.3.6 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
 
Efficacy endpoints as outlined in this section will not be reported to Merck or Amgen as 
described in Section 6.3.1- Immediate Reporting of Adverse Events to the IND holder and to 
Merck and Amgen, unless there is evidence suggesting a causal relationship between the drug 
and the event. Any such event will be submitted to the IND holder within 24 hours and to Merck 
Global Safety and Amgen Global Safety within 2 working days either by electronic or paper 
media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The IND holder will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety and Amgen 

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Global Safety as a SAE within 2 working days of determination that the event is not progression 
of the cancer under study 
Hospitalization related to convenience (e.g., transportation issues etc.) will not be considered a 
SAE. 
 
6.3.7 Events of Clinical Interest for Pembrolizumab 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the IND holder and within 2 working days to 
Merck Global Safety. 
 
 
For the time period beginning when the consent form is signed until the participant presents for 
cycle 1 day 1, any ECI, or follow up to an ECI, that occurs to any participant must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety ONLY if it 
causes the participant to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning when the participant presents for cycle 1 day 1 through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to Merck product, must be reported within 24 hours to the Sponsor and within 24 
hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
 
1.  An overdose of Merck product., as defined in Section 6.1 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms 
or abnormal laboratory results.  
 
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.  
 
6.4 
Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 

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recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
as defined in Section 6.3.1. In addition, attribution of AEs must be classified based on the following 
definitions: 
 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment.

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Table 15.  Adverse Events Evaluation 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization 
indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This 
does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing 
condition that has not worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a 
Merck product and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis); or
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the IND holder within 24 hours and to 
Merck within 2 working days to meet certain local requirements); or
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be 
reported within 24 hours to the Sponsor and to Merck within 2 working days.
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious 
adverse event when, based upon appropriate medical judgment, the event may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause Merck product to be discontinued?
Relationship 
to Merck 
Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE):
 
Exposure 
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
 
Time 
Course
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved 
despite continuation of the IND holder’s product; or (3) the trial is a single-dose drug trial); or (4) IND holder’s product(s) is/are 
only used one time.)
 
Rechallenge 
Was the participant re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose 
drug trial); or (3) IND holder’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY 
HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE IND HOLDER AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product 
relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck 
product is reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product 
is not reasonable OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant 
with overdose without an associated AE.) 
 
Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, physical examinations and clinical laboratory tests. The incidence of AEs will be 
tabulated and reviewed for potential significance and clinical importance. The reporting period 
for safety data will be from the date of first on-study dose to 70 days after the last dose is 
received. Additionally, from the time of consent forward, any occurrence of a serious adverse 
event (SAE) must be reported to the IND holder. The DSMC at DFCI will have oversight of this 
study. 
 
6.5 
Sponsor Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
7. PHARMACEUTICAL INFORMATION 
 
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. 
 
 
7.1 
Product Descriptions 
 

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7.1.1 Description 
 
7.1.1.1 
Pembrolizumab Description 
 
Pembrolizumab is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a stabilizing 
S228P sequence alteration in the fragment crystallizable (Fc) region.  Pembrolizumab binds to 
human PD-1 and blocks the interaction between PD-1 and its ligands. The theoretical molecular 
weight of the polypeptide is 146,288 Da and its theoretical pI is 7.5.  Additional information on 
pembrolizumab nomenclature is detailed in the following table: 
 
Code Name
MK-3475 (Anti–PD-1)
Other Code Name
MK3, 02P106, ORG 307448-0, SCH 900475 (Anti–PD-1)
Chemical Name
Humanized X PD-1-mAb (H409A11) IgG4
CAS Number
1374853-91-4
CAS Name 
Anti-(human protein PDCD1 (programmed cell death 1)) immunoglobulin G4 (human-
Mus musculus monoclonal heavy chain) disulfide with human-Mus musculus monoclonal 
light chain, dimer
Trade Name
KEYTRUDA®
 
7.1.1.2 
Trebananib Description 
 
Trebananib is a novel Fc fusion protein directed against Ang1 and Ang2, expressed 
recombinantly in Escherichia coli (E coli). The molecule is a non-glycosylated homodimer 
engineered by fusing an immunoglobulin G1 (IgG1) Fc domain to 4 copies of an anti-Ang1 / 
anti-Ang2 peptide. Each monomeric unit contains 10 cysteine residues that are involved in 4 
intrachain disulfide bonds and 2 interchain disulfide bonds. Trebananib contains 287 amino 
acids. The molecular weight is approximately 63.5 kDa. 
 
7.1.2 Form 
 
7.1.2.1 
Pembrolizumab Form 
 
Two drug product (DP) dosage forms are available for pembrolizumab: a white to off-white 
lyophilized powder, 50 mg/vial, and a liquid, 100 mg/vial, both in Type I glass vials intended 
for single use only. The drug products are manufactured using facilities and practices under 
Good Manufacturing Practice (GMP) requirements. 
 
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial is a lyophilized powder that 
is reconstituted with sterile water for injection prior to use. It is manufactured using 
either the fully formulated DS or the partially formulated DS. The fully formulated DS 
uses L-histidine as a buffering agent, polysorbate 80 as surfactant, and sucrose as 
stabilizer/tonicity modifier. Pembrolizumab DP using the partially formulated DS is 
formulated with L-histidine as a buffering agent, polysorbate 80 as a surfactant, and 
sucrose as a stabilizer/tonicity modifier, and may contain hydrochloric acid and/or 
sodium hydroxide for pH adjustment (if necessary). 
 

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Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP (manufactured using the 
fully formulated DS with L-histidine as a buffering agent, polysorbate 80 as a surfactant, 
and sucrose as a stabilizer/tonicity modifier). 
 
Pembrolizumab will be provided by Merck as summarized in the following table:  
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
7.1.2.2 
Trebananib Form 
 
Trebananib is provided as a sterile, preservative-free, lyophilized powder for reconstitution with 
sterile water for injection (sWFI) and dilution in normal saline (0.9% sodium chloride) for IV 
administration. Each sterile vial contains specified amount of deliverable drug product, that when 
reconstituted with a specified volume of sWFI contains an isotonic formulation of 30 mg/mL 
trebananib formulated with 10 mM histidine, 4% (weight/volume [w/v]) mannitol, 2% (w/v) 
sucrose, 10 mM arginine hydrochloride, and 0.01% (w/v) polysorbate 20 to a pH of 7.1. Each 
vial is for single use only. Lyophilized vials are manufactured in 4 presentations based on the 
deliverable drug product. The vial presentations, vial sizes, deliverable amount, and 
reconstitution volume are provided in the table below. 
 
 
7.1.3 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
7.1.4 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 
 
7.1.5 Storage, Handling, and Preparation Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of trial medication must be recorded by an 
authorized person at the trial site. Clinical supplies may not be used for any purpose other than 

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that stated in the protocol. 
 
7.1.6 Administration 
 
7.1.6.1 
Pembrolizumab Administration 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
7.1.6.2 
Trebananib  
 
Trebananib should be administered on Day 1, 8, and 15 of each 21-day cycle after all 
procedures/assessments have been completed. Trebananib may be administered up to 2 days before 
or after the scheduled Day of each cycle due to administrative reasons (±2 days).  
 
The first dose of trebananib will be administered by IV infusion over a 60-minute period. If the 
initial dose administration is well tolerated, future administrations may be given over 
approximately 30 minutes (treatment cycle intervals may be increased due to toxicity a described 
in section 5). Trebananib will be administered immediately after Pembrolizumab.  
 
7.1.7 Ordering 
 
Investigative sites will order and acquire Pembrolizumab directly from Merck. Pembrolizumab 
will be supplied from an investigational supply. 
 
Investigative sites will order and acquire trebananib directly from Amgen, Inc. Trebananib will 
be supplied from an investigational supply. 
 
7.1.8 Accountability 
 
The investigator, or a responsible party designated by the investigator, is responsible for keeping 
accurate records of the clinical supplies received from Merck and Amgen, the amount dispensed 
to and returned by the participants and the amount remaining at the conclusion of the trial agent 
using the NCI Drug Accountability Record Form (DARF) or another comparable drug 
accountability form.   
 
7.1.9 Destruction and Return 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 

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8. ADMINISTRATIVE AND REGULATORY DETAILS 
 
8.1 
Confidentiality 
 
8.1.1 Confidentiality of Data 
 
The investigator affirms to the Sponsor that information furnished to the investigator by the 
Sponsor will be maintained in confidence, and such information will be divulged to the 
institutional review board, ethics review committee (IRB/ERC) or similar or expert committee; 
affiliated institution and employees, only under an appropriate understanding of confidentiality 
with such board or committee, affiliated institution and employees. Data generated by this trial 
will be considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol. 
 
8.1.2 Confidentiality of Participant Records 
 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the participant 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor. By signing this protocol, 
the investigator agrees to treat all participant data used and disclosed in connection with this trial 
in accordance with all applicable privacy laws, rules and regulations. 
 
8.1.3 Confidentiality of Investigator Information 
 
Information with respect to the investigator, and all sub-investigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory submissions, 
and as required by law. This information may include: 
 name, address, telephone number and e-mail address; 
 hospital or clinic address and telephone number; 
 curriculum vitae or other summary of qualifications and credentials; and 
 other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. Additionally, 
the investigator’s name and business contact information may be included when reporting certain 
serious adverse events to regulatory authorities or to other investigators. By signing this protocol, 
the investigator expressly consents to these uses and disclosures. In order to facilitate contact 
between investigators, the Sponsor may share an investigator’s name and contact information 
with other participating investigators upon request. 
 

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8.1.4 Confidentiality of IRB/IEC Information 
 
The Sponsor is required to record the name and address of each IRB/IEC member that reviews 
and approves this trial. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names and 
qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies. 
 
8.2 
Compliance 
 
8.2.1 Compliance with Financial Disclosure Requirements 
 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Pa rt 54). It is the Sponsor's 
responsibility to determine, based on these regulations, whether a request for Financial 
Disclosure information is required. It is the investigator's/sub-investigator's responsibility to 
comply with any such request. The investigator/sub-investigator(s) agree, if requested by the 
Sponsor in accordance with 21 CFR Part 54, to provide his/her financial interests in and/or 
arrangements with the Sponsor to allow for the submission of complete and accurate certification 
and disclosure statements. 
 
The investigator/sub-investigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by the 
Sponsor or through a secure password-protected electronic portal provided by the Sponsor. The 
investigator/sub-investigator(s) also consent to the transmission of this information to the 
Sponsor in the United States for these purposes. This may involve the transmission of 
information to countries that do not have laws protecting personal data. 
 
8.2.2 Compliance with Law, Audit, and Debarment 
 
The investigator agrees to conduct the trial in an efficient and diligent manner and in 
conformance with this protocol; generally accepted standards of Good Clinical Practice (e.g., 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of good clinical practice); and all applicable federal, state and local 
laws, rules and regulations relating to the conduct of the clinical trial. The investigator also 
agrees to allow monitoring, audits, IRB/ERC review and regulatory authority inspection of trial-
related documents and procedures and provide for direct access to all trial-related source data 
and documents. The investigator agrees not to seek reimbursement from participants, their 
insurance providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor. The investigator shall prepare and maintain 
complete and accurate trial documentation in compliance with Good Clinical Practice standards 
and applicable federal, state and local laws, rules and regulations; and, for each participant 
participating in the trial, provide all data, and, upon completion or termination of the clinical 
trial, submit any other reports to the Sponsor as required by this protocol or as otherwise required 
pursuant to any agreement with the Sponsor. 
 

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Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon 
request and also shall be made available at the trial site upon request for inspection, copying, 
review and audit at reasonable times by representatives of the Sponsor or any regulatory 
authorities. The investigator agrees to promptly take any reasonable steps that are requested by 
the Sponsor as a result of an audit to cure deficiencies in the trial documentation and 
worksheets/case report forms. The investigator must maintain copies of all documentation and 
records relating to the conduct of the trial in compliance with all applicable legal and regulatory 
requirements. This documentation includes, but is not limited to, the protocol, worksheets/case 
report forms, advertising for participant participation, adverse event reports, participant source 
data, correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or quality 
control procedures and laboratory director curriculum vitae. By signing this protocol, the 
investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. Because the 
clinical development and marketing application process is variable, it is anticipated that the 
retention period can be up to 15 years or longer after protocol database lock. The Sponsor will 
determine the minimum retention period and notify the investigator when documents may be 
destroyed. The Sponsor will determine the minimum retention period and upon request, will 
provide guidance to the investigator when documents no longer need to be retained. The sponsor 
also recognizes that documents may need to be retained for a longer period if required by local 
regulatory requirements. All trial documents shall be made available if required by relevant 
regulatory authorities. The investigator must consult with and obtain written approval by the 
Sponsor prior to destroying trial and/or participant files. ICH Good Clinical Practice guidelines 
recommend that the investigator inform the participant’s primary physician about the 
participant’s participation in the trial if the participant has a primary physician and if the 
participant agrees to the primary physician being informed. The investigator will promptly 
inform the Sponsor of any regulatory authority inspection conducted for this trial. Persons 
debarred from conducting or working on clinical trials by any court or regulatory authority will 
not be allowed to conduct or work on this Sponsor’s trials. The investigator will immediately 
disclose in writing to the Sponsor if any person who is involved in conducting the trial is 
debarred or if any proceeding for debarment is pending or, to the best of the investigator’s 
knowledge, threatened. In the event the Sponsor prematurely terminates a particular trial site, the 
Sponsor will promptly notify that trial site’s IRB/IEC.   
 
8.2.3 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are participant to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow participants to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     

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8.3 
Quality Management System 
 
By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining 
a quality management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that trials are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of Good Clinical 
Practice, and all applicable federal, state, and local laws, rules and regulations relating to the 
conduct of the clinical trial. 
 
8.4 
Data Management 
 
The investigator or qualified designee is responsible for recording and verifying the accuracy of 
participant data. By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature. By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate. 
Detailed information regarding Data Management procedures for this protocol will be provided 
separately. 
 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 28 days prior to start of registration except 
where noted otherwise.  In the event that the participant’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 2 days of the protocol-specified date, unless 
otherwise noted. 
Screening and Induction 
Trial Period: 
Induction  
Treatment Cycle/Title: 
Screening 
Visit 
Cycle 1 J 
Cycles 2, 3, and 4 J 
Scheduling Window (Days): 
-28 to -1 
1± 
2
8± 
2
15± 
2
1± 
2
8± 
2
15± 2 
Informed Consent 
x 
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
x 
  
  
  
  
  
  
Demographics and Medical History 
x 
  
  
  
  
  
  
Prior and Concomitant Medication Review 
x 
x 
x 
x 
x 
x 
x 
Pembrolizumab Administration 
  
x 
  
  
x 
  
  
Trebananib Administration (induction 
phase only for 12 weeks)I 
  
x 
x 
x 
x 
x 
x 

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Review Adverse Events 
  
x 
x 
x 
x 
x 
x 
Physical Examination 
x 
x 
x 
x 
x 
x 
x 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
Single EKG 
x 
  
  
  
  
  
  
HIV, Hepatitis C Antibody, Hepatitis B 
Surface Antigen 
x 
  
  
  
  
  
  
Pregnancy Test –  Serum -HCGA 
x 
x 
x 
x 
x 
x 
x 
PT/INR and aPTT 
x 
x 
x 
x 
x 
x 
x 
CBC with Differential 
x 
x 
x 
x 
x 
x 
x 
Comprehensive Serum Chemistry Panel, 
lipase and amylase 
x 
x 
x 
x 
x 
x 
x 
Tumor markers: CEA and CA125H 
 
x 
 
 
x 
 
 
Urinalysis B 
x 
x 
  
  
x 
  
  
T3, FT4 and TSH 
x 
x 
x 
x 
x 
x 
x 
Chest, Abdomen and Pelvic CT scanC 
XE 
  
  
  
x 
Brain MRID 
XE 
  
  
  
x 
Archival or Newly Obtained Tissue 
CollectionF 
x 
X  
Correlative Studies Blood CollectionG 
  
x 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
 
 
Post-Induction 
Trial Period: 
Post Induction 
Treatment Cycle/Title: 
Cycles 5 and beyond for up to 2 years total  
Scheduling Window (Days): 
Day 1 (± 2) 
Prior and Concomitant Medication 
Review 
x 
Pembrolizumab Administration 
x 
Review Adverse Events 
x 
Physical Examination 
x 
Vital Signs and Weight 
x 

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A For women of child-bearing potential, a negative serum -HCG pregnancy test must be performed during screening. A 
urine pregnancy test should be performed within 24 hours of starting treatment. A urine pregnancy test may be performed 
at all other timepoints. If a urine pregnancy test result is positive, a serum pregnancy test must be completed and resulted 
as negative for a participant to receive treatment.  
B Proteinuria will be monitored by urine protein: creatinine ratio at least every six weeks.  If appropriate, 24-hour urine 
collection for protein may be obtained. 
C CT scan of the chest, abdomen, and pelvis will be performed every 12 weeks (± 7 days) 
D Brain MRI to be performed only on melanoma and RCC patients. Brain MRI should be performed during screening. 
Repeat brain MRI should be performed if there are any neurological symptoms or findings. Brain MRI with and without 
contrast is preferred. If a patient is not able to obtain an MRI, CT imaging with contrast is acceptable. If a patient is not 
able to receive IV contrast, CT head without contrast is acceptable.  
E Imaging for baseline tumor assessment is to be performed within 28 days prior to the start of study registration.  
FBiopsy of site(s) of pre-existing disease will be performed up to 6 weeks (42 days) prior to initiation of treatment on 
Day 1. On-treatment biopsies should be performed approximately midway through the Induction period, approximately 
6 weeks from the start of study treatment (sometime between Cycle 2 Day 8 – Cycle 3 Day 1). If for any reason removal 
of tissue requires a greater procedure, the biopsy must be done >28 days from the last planned dose trebananib  
G Serial blood/serum samples to be collected prior to the administration of pembrolizumab at the following time points: 
Cycle 1 Days 1, 8, and 15; Prior to Day 1 of every odd cycle (Cycle 3, Cycle 5, Cycle 7, etc.); End of treatment visit.  
HTumor markers: CEA to be done on participants with colorectal cancer on day 1 of every cycle. CA125 to be done on 
participants with ovarian cancer on day 1 of every cycle. 
IIf trebananib is discontinued due to an AE, participants may omit any Day 8 and Day 15 visits/assessments going forward.
 
Comprehensive 
Serum Chemistry 
Panel, lipase and 
amylase
x 
x 
  
  
Urinalysis B 
  
x 
  
  
T3, FT4 and TSH 
  
x 
  
  
Chest, Abdomen and 
Pelvic CT scanC
x 
  
x 
  
Brain MRID 
x 
  
x 
  
Archival or Newly 
Obtained Tissue 
CollectionG
x 
  
  
  
Correlative Studies 
Blood CollectionG
x 
  
  
  

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10. TRIAL PROCEDURES AND ASSESSMENTS 
 
The Study Calendar (Section 9) summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail below. It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for reasons 
related to participant safety. In some cases, such evaluation/testing may be potentially sensitive 
in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
informed consent be obtained from the participant.  In these cases, such evaluations/testing will 
be performed in accordance with those regulations. 
 
10.1 
Administrative Procedures 
 
10.1.1 Informed Consent 
 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
10.1.2 General Informed Consent 
 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available that 
may be relevant to the participant’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent form 
or addendum to the original consent form that captures the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
10.1.3 Inclusion/Exclusion Criteria 
 

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All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the participant qualifies for the trial.  
10.1.4 Medical History 
 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for which 
the participant has enrolled in this study will be recorded separately and not listed as medical 
history.   
 
10.2 
Prior and Concomitant Medications Review 
 
10.2.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the participant within 28 
days before starting the trial.  Treatment for the disease for which the participant has enrolled in 
this study will be recorded separately and not listed as a prior medication.  
 
10.2.2 Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 6. 
 
10.3 
Disease Details and Treatments 
 
10.3.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
 
10.3.1.1 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
10.3.1.2 
Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the participant will move 
into survival follow-up.  

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10.3.1.3 
Assignment of Screening Number 
All consented participants will be given a unique screening number that will be used to identify 
the participant for all procedures that occur prior to randomization or treatment allocation. 
Screening numbers will be assigned and maintained by the clinical research coordinator at the 
lead site. Each participant will be assigned only one screening number. Screening numbers must 
not be re-used for different participants. Any participant who is screened multiple times will 
retain the original screening number assigned at the initial screening visit.  
 
10.3.1.4 
Trial Compliance (Medications) 
Interruptions from the protocol specified treatment plan for 12 weeks between doses due to 
toxicity require consultation between the investigator and the Sponsor and written documentation 
of the collaborative decision on participant management. Administration of trial medications will 
be witnessed by the investigator and/or trial staff. The total volume of trial treatments infused 
will be compared to the total volume prepared to determine compliance with each dose 
administered. The instructions for preparing and administering pembrolizumab and trebananib 
are provided in the Investigational Product Instruction Manual.  
 
10.3.2 Clinical Procedures/Assessments 
 
10.3.2.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0.  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to section 6 for detailed information regarding the assessment and recording of AEs.   
10.3.2.2 
Physical Exam 
The investigator or qualified designee will perform a physical exam during the screening period. 
Clinically significant abnormal findings should be recorded as medical history.  A physical exam 
should be performed during screening, prior to the administration of each dose of trial treatment 
and as specified in the Trial Flow Chart (Section 9).  
10.3.2.3 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 9).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
10.3.2.4 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart.  Please refer to Appendix A. 
 

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10.3.2.5 
Laboratory Tests for Hematology, Chemistry, Urinalysis, and other laboratory 
tests 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 14 
 
Pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing with the 
exception of the urine pregnancy test for women of child bearing potential (which must be 
performed within 24 hours prior to dosing).  Results must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment.  
 
Table 14.  Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG) 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test  
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
Creatinine 
  
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
 CEA for colorectal participants 
 
Potassium   
 
 CA125 for ovarian participants 
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Lipase 
 
 
 
Amylase 
 
 

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10.4 
Other Procedures 
 
10.4.1 Screening 
 
The informed consent form must be signed prior to completing any protocol-specified procedure. 
Within 28 days prior to registration (except where noted below), potential participants will be 
evaluated to determine if they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor. After providing consent, 
participants will be assigned a screening number. Results of a test performed prior to the 
participant signing consent as part of routine clinical management are acceptable in lieu of a 
screening test if performed within the specified time frame. Exceptions to the 28-day screening 
window include the following assessments/tests: 
 
 For women of reproductive potential, a urine pregnancy test will be performed within 24 
hours prior to the first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the local 
study site laboratory). 
 
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu of a 
repeat screening test if performed within the specified time frame and the inclusion/exclusion 
criteria is met. 
 
10.4.2 Withdrawal/Discontinuation 
 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 6 – Adverse Events: List and 
Reporting Requirements. Participants who a) attain a CR or b) complete 24 months of treatment 
with pembrolizumab may discontinue treatment with the option of restarting treatment if they 
meet the criteria specified in Section 10.5.4.  After discontinuing treatment following assessment 
of CR, these participants should return to the site for a Safety Follow-up Visit (described in 
Section 10.5.1) and then proceed to the Follow-Up Period of the study (described in Section 
10.5.2). 
 
10.5 
Post Treatment Visits 
 
10.5.1 Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Participants 
will be followed until the beginning of a new anti-neoplastic therapy.  SAEs that occur within 90 
days of the end of treatment or before initiation of a new anti-cancer treatment should also be 

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followed and recorded.  Participants who are eligible for retreatment with pembrolizumab (as 
described in Section 10.5.4) may have up to two safety follow-up visits, one after the Treatment 
Period and one after the Second Course Phase. 
 
10.5.2 Follow-Up Visits 
 
Participants who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (84± 7 days) by 
radiologic imaging to monitor disease status for at least 1 year. Every effort should be made to 
collect information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the participant begins retreatment with pembrolizumab 
as detailed in Section 10.5.4. Information regarding post-study anti-neoplastic treatment will be 
collected if new treatment is initiated. 
 
Participants who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 11.3.4 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression. Details are provided in Section 9 – Trial Flow Chart for 
Retreatment.    
 
10.5.3 Survival Follow-Up 
 
Once a participant experiences confirmed disease progression or starts a new anti-cancer therapy, 
the participant moves into the survival follow-up phase and should be contacted by telephone every 
12 weeks (84± 7 days) to assess for survival status until death, withdrawal of consent, or the end 
of the study, whichever occurs first.  
 
10.5.4 Second Course Phase (Retreatment Period) 
 
Participants who stop pembrolizumab and trebananib with SD or better may be eligible for up to 
an additional 17 cycles (approximately 1 year) of additional pembrolizumab treatment if they 
progress after stopping study treatment from the initial treatment phase. This retreatment is 
termed the Second Course Phase of this study and is only available if the study remains open and 
the participant meets the following conditions: 
 
Either  
o Stopped initial treatment with pembrolizumab and trebananib after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and 
 Was treated with at least 8 cycles of study treatment before discontinuing therapy 
and 
 Received at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared 

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OR 
 
o Had SD, PR or CR and stopped pembrolizumab and trebananib treatment after 
completion of 35 administrations (approximately 2 years) of study therapy for reasons 
other than disease progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression by 
RECIST 1.1 after stopping their initial treatment with pembrolizumab and trebananib and 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab and 
trebananib 
 Meets all of the safety parameters listed in the inclusion criteria and none of the safety 
parameters listed in the exclusion criteria 
 The study is ongoing 
Participants who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab. Treatment with pembrolizumab will be administered for up to 
one additional year. 
 
An objective response or disease progression that occurs during the Second Course Phase for a 
participant will not be counted as an event for the primary analysis of either endpoint in this 
study. 
 
Participants who have experienced an initial disease progression by RECIST 1.1 and have an 
iSD, iPR, or iCR per iRECIST after completion of 35 administrations of study intervention for 
reasons other than disease progression or intolerability may be considered for Second Course 
Phase after consultation with the Sponsor. 
 
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated every 12 weeks (± 7 days).  In addition to a baseline scan, 
confirmatory scans will also be obtained 4-6 weeks following initial documentation of an 
objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 

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[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  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 or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
 
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. 
 
Non-measurable disease.  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, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
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 

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lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
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 
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.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 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.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 

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thickness greater than 5 mm, the minimum size of 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 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. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 

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11.1.4 Response Criteria 
 
 
11.1.4.1 
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. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
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.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
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 review panel (or Principal 
Investigator). 
 

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this category when no lesions can be measured is not advised
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 
11.1.6 Treatment Beyond Progression  
 
Immunotherapeutic agents such as Pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions. 
 
If radiologic imaging shows progressive disease (PD), tumor assessment may be repeated by the 
site approximately 4 weeks later in order to confirm continued PD with the option of continuing 
treatment per below while awaiting radiologic confirmation of progression. If repeat imaging 
shows a reduction or stabilization in the tumor burden compared to the initial scan demonstrating 
PD, treatment may be continued as per treatment calendar.  If repeat imaging confirms continued 
PD, patients will be discontinued from study therapy. If reimaging is no worse than the prior 
scan 4 weeks prior, patients may continue therapy and be reimaged in another 8 weeks. If 
evidence for continued, increasing progression with subsequent imaging, the patient will be 
discontinued. In determining whether or not the tumor burden has increased or decreased, 
investigators should consider all target lesions as well as non-target lesions. The decision to 
continue study treatment after the first evidence of disease progression determined by radiologic 
imaging is at the Investigator’s discretion based on the clinical status of the patient as described 
in the table below.   
Patients may receive study treatment while waiting for confirmation of continued PD if they are 
clinically stable as defined by the following criteria: 

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 Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
 No decline in ECOG performance status 
 Absence of rapid progression of disease 
 Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
Table 7. Treatment Beyond Progression  
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at approximately 
4 weeks to 
confirm PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan
Repeat imaging 
at approximately 
4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan 
confirms PD
No additional 
imaging required
Discontinue 
treatment
No additional 
imaging required
N/A 
Repeat scan 
shows SD, PR, 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 12 weeks 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 12 weeks 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion
Tumor imaging will be assessed every 12 weeks (84 ±7 days).
 
11.1.7 Progression-Free Survival 
 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 

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11.2 
Antitumor Effect 
 
11.2.1 Anti-Tumor Effect Using irRECIST  
Definition of Tumor Response Using Immune-Related Response Criteria (irRC) 
The sum of the longest diameter of lesions (SPD) 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 irRC criteria accounts 
for the size and growth kinetics of both old and new lesions as they appear. 
 
Definition of Target Lesions Response Using irRC 
irComplete Response (irCR): Complete disappearance of all target lesions. This category 
encompasses exactly the same participants 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 two largest perpendicular diameters of all target and all new measurable lesions 
(i.e., 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 SPD of all target lesions and any new lesions) when compared to SPD at nadir. 
Definition of Non-Target Lesions Response Using irRC 
irComplete Response (irCR): Complete disappearance of all non-target lesions. This category 
encompasses exactly the same participants as “CR” by the mWHO criteria. 
irPartial Response (irPR) or irStable Disease (irSD): non-target 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-target 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 target 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 
participant from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions 
(target and non-target 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 target lesions is measured and captured as the SPD baseline. At 

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each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all 
target 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).  
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: 
At least 25% increase in the SPD of all target lesions over baseline SPD calculated for the target 
lesions. 
At least a 25% increase in the SPD of all target lesions and new measurable lesions (irSPD) over 
the baseline SPD calculated for the target lesions. (Hodi, Hoos et al. 2008) (Wolchok et al., 
2009) 
 
Table 10. Immune-Related Response Criteria Definitions 
Target 
Lesion 
Definition 
Non-
Target 
Lesion 
Definition 
New 
Measurable
Lesions 
New 
Unmeasurable
Lesions 
Percent change in 
tumor burden 
(including 
measurable new 
lesions when 
present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
–100%  
irCR 
Partial 
Response 
Any 
Any 
Any 
> –50% 
irPR 
<–50% to <+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<–50% to <+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
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 participant in the study. For 
the assessment of irBOR, all available assessments per participant 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. 
 

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12. TUMOR TISSUE COLLECTION AND CORRELATIVE STUDIES BLOOD SAMPLING 
 
Correlative sciences will include fresh biopsies of pre-existing sites of disease and following 
treatment to assess histologically for vasculopathy, immune infiltration, and tumor necrosis; stain 
pathologic specimens for VEGF/VEGFR expression, phosphoTie2; monitor circulating levels of 
and development of anti-trebananib antibodies as a function of treatment.  Baseline and on-
treatment values of a number of inflammatory and angiogenic cytokines will be monitored. Pilot 
studies will include the investigation of immune responses to other angiogenic molecules as a 
function of treatment. Flow cytometry of PBMC will be monitored for changes in levels of naïve 
and memory CD4, CD8 and other lymphocyte populations. Cellular and humoral immune 
responses to established antigens as a function of treatment will be performed.  These will 
include melanosomal differentiation antigens as well as novel tumor associated antigen targets, 
Muc-1, CEA, CA-125, and NY-Eso-1 as examples.   
 
12.1 
Fresh tumor biopsies: 
 
Biopsies of fresh tumor will be obtained prior to treatment initiation on day 1 and approximately 
halfway through the induction period (between cycle 2 day 8 and cycle 3 day 1). Dedicated funds 
are currently available at our institution for obtaining post-treatment biopsies in patients 
receiving immune based therapies.  
 
Formalin fixed-paraffin embedded (FFPE) tumor slices will be prepared and H&E stained for 
assessment of TIL in pre- and post-treatment tumor samples. To identify different immune cell 
populations (effector/memory/ CD8 cells, T regulatory cells, dendritic cells, tumor associated 
macrophages, NK cells, TEM) immunohistochemical staining will be performed on FFPE tumor 
slices using the following antibodies:  
 
CD3, CD4, CD8, CD25, FoxP3, Indoleamine 2,3 deoxygenase-1 (IDO), CD11c, 
CD83, CD86, CD56, CD14, CD16, PD-L1, and Tie-2. 
 
We have recently developed immunohistochemical staining on paraffin embedded tissues for 
PD-L1, PD-L2, TIM-3 and LAG-3 through our Center for Immuno-oncology Pathology Core 
  PD-L1 IHC has recently 
been established in a CLIA approved laboratory and we are working to finalize the remaining 
assays for CLIA laboratory conduct. We may also send tissue out to an outside laboratory for 
PD-L1 testing. 
 
 
 
 
 
   
 
1.  Chen BJ et al., Clin Cancer Res. 2013 Jul 1;19(13):3462-73, PMID:23674495 

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2.  Shi M et al., Am J Surg Pathol. 2014, Jul 14, PMID: 25025450. 
 
   
 
Figure 25. Control Hodgkin lymphoma stained for PDL1 (left) and mediastinal large B-cell 
lymphoma stained for PDL2 (right). 
 
As part of the validation of the assays in a CLIA-certified laboratory, identical cases were stained 
multiple times and under a variety of staining conditions and the results reviewed by two 
certified pathologists.  A positive control sample (classical Hodgkin lymphoma for PD-L1 
expression; primary mediastinal large B-cell lymphoma for PD-L2 expression) and negative 
control sample (benign lymph node) is stained with each experimental tissue biopsy sample. The 
controls are reviewed by a certified pathologist at the time of review of the experimental sample.    
 
An IHC assay for PD-1 (CD279, clone NAT105, Cell Marque Inc.) expression has been in 
standard surgical pathology diagnostic practice for several years and used to confirm the 
diagnosis of angioimmunoblastic T-cell lymphoma (AITL). 
 
3.  Yu H et al., Am J Clin Pathol. 2009, Jan;131(1):33-41. PMID:19095563. 
  
 
Figure 26. Control tonsil tissue stained for PD1. 
 
PD-1 IHC is performed routinely in the CLIA-certified laboratory and interpreted by a certified 
pathologist with an appropriate control (reactive lymph node, intra-follicular T-cells are positive 
for PD-1) as described above. 
Manuscript #1 above describes a semi-quantitative scoring method, which is in accordance with 
typical biomarker scoring in anatomic and surgical pathology. Briefly, staining is scored 
according to intensity (0= no staining, 1= weak staining, 2= moderate staining, 3= strong 
staining), staining pattern (M= predominantly cell membrane; C= predominantly cell cytoplasm), 
and the percentage of cells showing positive staining (0-100%). The semi-quantitative scoring is 
performed for: 1) the neoplastic tumor cells and 2) the non-neoplastic infiltrating immune cells.  
In the research setting, all cases are reviewed by two pathologists and any discordant results 
resolved by consensus review. Significantly discordant scoring results have been rare during case 
evaluations (Chen BJ et al., 2013). 

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Figure 27. Semi-quantitative assessment of malignant and non-malignant cell expression of 
PDL1 in Hodgkin lymphoma, from Chen BJ et al. 
Digital, quantitative scoring of stained tissue is performed using the Aperio slide scanning and 
analysis platform. Quantitative assessment of positive staining uses the commercially provided 
algorithm for cell identification and positive pixels counting within a pre-defined DAB (brown, 
chromogenic) channel. We have shown that this method of analysis shows good correlation with 
pathologists' scoring: 
 
4.  Mino-Kenudson M et al., Clin Cancer Res. 2010 Mar 1;16(5):1561-71. PMID:20179225. 
 
 
Figure 28. Aperio-base quantitative assessment of ALK protein expression in lung cancers, from 
Mino-Kenudson et al. 
 
We have also used this method to score PD-L1 expression in tumor cells: 
 
5.  Green MR et al., Blood. 2010 Oct 28;116(17):3268-77. PMID: 20628145. 
 
The correlation between quantitative IHC as determined by Aperio analysis, and semi-
quantitative scoring, as determined by visual interpretation, will be determined as part of this 
study.   
 
The scoring for markers (such as the PD-Ligands) that stain macrophages, dendritic cells, and 
other cells of heterogeneous morphology will be semi-quantitative and performed by a 
pathologist using a modified H-score to capture 1) the percentage of neoplastic cells positive for 
biomarker expression, intensity of expression, and membrane or cytoplasmic expression, and 2) 
the percentage of non-neoplastic cells (macrophages, dendritic cells, endothelial cells) positive 
for biomarker expression, intensity of expression, and membrane or cytoplasmic expression.   
 
Scoring for PD-1 and other markers that stain lymphoid cells (CD3, CD4, CD8, CD25, FOXP3, 

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IDO, CD16, CD56, LAG-3, TIM-3) will primarily be performed by automated analysis using the 
Aperio system.   
 
Aperio scoring for PD-1+ (and other lymphoid markers) lymphocytes will be accomplished 
using a standard Aperio algorithm, developed for quantifying nuclear stains, but that we have 
found is applicable to quantifying membrane staining of cells with a very high N:C ratio- such as 
lymphocytes (Nuclear algorithm). The output is number of positive-staining cells per unit area 
(microns2).  
 
The data derived from the analyses above will be used as individual data points compared to 
other clinical (response to treatment) and pathological (histomorphological) data in the study.  A 
goal will be to determine whether individual data points (i.e. number of PD-1+ T-cells/ unit area) 
are of prognostic value, or if combined data using two or more data (an "immuno-score") 
provides prognostic data. These investigations are exploratory and will be performed in 
conjunction with the biostatisticians associated with this study. 
 
For image analysis:  
 
1.  IHC stained slides will be digitally scanned using the Aperio ScanScope XT (
 
 
 
 
 
  
 
 
 
   
 
3. Quantitative analysis is performed using analytical software associated with ImageScope, 
specifically Aperio Color Deconvolution V.9 (for PD-Ligands) and nuclear algorithm (for PD-1+ 
lymphocytes) and the results given as the percentage of positive pixels per unit area (for PD-
Ligands) or number of positive cells per unit area (for PD-1+ lymphocytes).  Intensity of staining 
is also captured automatically using the above algorithms and assigned a score (0, 1, 2, or 3) 
based upon the average optical density of the region or cells.  All results are exported into an 
excel spreadsheet. 
 
4.  Individual scoring data will be compared to clinical parameters to determine if there is an 
association with outcome. Scores using a combination of biomarker data will also be considered. 
 
Below, we provide a schematic of the workflow for the tissue-based biomarker analysis: 
 
 

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CD14 
3 
ab49755 
Abcam 
Mouse 
1/100 
Yes 
CD16 
3 
ab183354 
Abcam 
Rabbit 
1/100 
No  
CD11c 
3 
EP1347Y 
Abcam 
Rabbit 
1/500 
Yes 
 
The cut-off of 5% for PD-L1 tumor positivity is in accordance the criteria used in a prior study 
examining the use of this biomarker to predict clinical response in patients treated with a PD-1 
antibody (Topalian SL et al., NEJM, 2012, PMID: 22658127).  
 
The semi-quantitative scoring for this study is in accordance with those published previously 
(Topalian et al., 2012, Chen BJ et al., 2013) and, as described above, will include scores for both 
the neoplastic and non-neoplastic cells within the tumor microenvironment. Data derived from 
pathologist visual scoring (semi-quantitative, but with increased specificity for delineating 
neoplastic and non-neoplastic cells) and pathologist-assisted, automated scoring (quantitative, 
but without accurately delineating neoplastic and non-neoplastic cells) for each marker of 
interest will be assessed for its clinical value. As necessary, the data from combinations of 
makers will also be considered (i.e. combined scores from PD-L1 and PD-L2 expression).  All 
data will be analyzed in conjunction with the biostatistics group.   
 
12.2 
Peripheral blood: 
Serial blood/serum samples will be collected prior to each odd cycle (Cycle 1, Cycle 3, Cycle 5, 
etc.) prior to pembrolizumab administration starting on day 1 (pre-treatment) and at the end of 
the treatment. A panel of cytokines and chemokines will be tested in serum using Luminex 
cytokine assay. Changes in cytokine production in immune cell subsets as a function of treatment 
will be determined by ELISA and intracellular cytokine staining. Absolute lymphocyte count 
(ALC) will be monitored. 
 
Peripheral blood mononuclear cells (PBMCs) will be collected from whole blood to assess 
immune cell populations. Surface staining with a panel of antibodies (CD3, CD4, CD8, CD19, 
CD25, FoxP3, CD11c, CD83, CD86, CD56) and intracytoplasmatic cytokine staining, followed 
by flow cytometry will be performed in order to identify different T cell populations, their 
activation status, myeloid-derived suppressor cells (CD11b, CD14, CD19, CD33, HLA-DR) and 
the production of different cytokines as well as other immune cell population as described in 
table 12.  
 
 
 
 
 
 
 
 
 
 
 

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Table 12. Cytokines and Immune Cells Subsets  
 
Given the results from our study of ipilimumab plus bevacizumab, we will specifically analyze 
changes as a function of treatments for CCR7+/-/CD45RO+ cell populations for both the CD4+ 
and CD8+ compartments. 
 
Serologic changes to antibody responses will be assessed for tumor antigens NY-ESO-1, MART-
1, MUC-1, and MAGE-3 when appropriate. 
 
Table 13. Biomarkers  
 
Biomarker name 
 
Assay 
 
Tissue/Body Fluid Tested 
CD274 (PD-L1) 
Immunohistochemistry 
Tissue 
CD273 (PD-1) 
Immunohistochemistry 
Tissue 
CD279 (PD-1) 
Immunohistochemistry 
Tissue 
ANGPT2 
Immunohistochemistry 
Tissue 
Circulating endothelial cells (CEC) and 
progenitor cells (CPC) 
Surface staining and FACS 
Blood  
Circulating cytokines/Chemokines (as 
indicated in figure 17) 
Luminex assay, ELISA 
Blood 
Circulating angiogenic factors (VEGF, 
Ang-2, PLGF, PDGF, HGF, FGF, BMP-
9, endothelin, endoglin, leptin) 
Luminex assay 
Blood 
Humoral response to angiogenic factors  
ELISA and Western blot 
Blood 
Humoral response to 
ELISA and Western blot 
Blood 

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immunosuppressive molecules  
Expression of angiogenic factors and 
immunosupresive molecules 
IHC 
Tumor tissues 
Circulating Tie-2 expressing Monocytes 
(TEM) 
Surface staining and FACS 
Blood 
Tumor infiltrating TEM 
IHC and/or Surface staining and FACS 
Tumor tissues 
 
Antigen-specific T cell responses are controlled by co-stimulatory and co-inhibitory molecules 
positively and negatively. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and 
programmed cell death 1 (PD-1, CD279) are among the key co-inhibitory molecules, broadly 
categorized as “checkpoint molecules” (Pardoll DM, 2012). CD279 is up-regulated on activated 
T lymphocytes and mediate immunosuppression when binding to its ligands B7-H1 (CD274) and 
B7-DC (CD273).  Blockade of CD279 or CD274 induced durable objective response in patients 
with advanced melanoma, renal cell carcinoma and non-small cell lung cancers in clinical trials 
(Topalian S, 2012; Brahmer J, 2012; Hamid O, 2013). Moreover, immunohistochemical staining 
performed on pretreatment tumor tissues from patients with anti-CD279 treatment showed that 
none of 17 patients with CD274 negative tumors had an objective response whereas 36% (9/25) 
patients with CD274 positive tumors had an objective response (P=0.006). This striking 
difference suggests that CD274 expression on tumor specimen might be a useful biomarker to 
predict response to anti- CD279 treatment.  
 
Anti-vascular endothelial growth factor pathway therapies preferentially target immature tumor 
blood vessels and leave behind normalized and resistant blood vessels.  Angiopoietin-2 
(ANGPT2)/TIE pathway is largely confined to vasculature.  It has two receptors TIE1 and TIE2 
as well as three ligands, angiopoietin-1, angiopoietin-2 (ANGPT2) and angiopoietin-4.  
ANGPT2 plays an important role in vascular remodeling and angiogenesis.  It acts as context-
specific antagonist of angiopoietin-1/TIE2 signaling, destabilizes the quiescent blood vessels as a 
prerequisite to sprouting angiogenesis in the presence of proangiogenic stimulation or vascular 
regression in the absence of such stimuli.  Therapeutics targeting the ANGPT2/TIE pathways 
including selective anti-ANGPT2 antibodies is in development (Gerald D, 2013; Karlan BY, 
2012; Hashizume H, 2010).  Serum ANGPT2 is found to be a biomarker for tumor progression 
and survival in various malignancies (Helfrich I, 2009).    
 
Peripheral Blood Mononuclear Cell isolation and staining procedure for Flow Cytometry 
Peripheral Blood Mononuclear Cells (PBMCs) will be isolated from 25 ml of blood by Ficoll 
centrifugation. Aliquots of 5-10 million cells will be immediately frozen with 500ul of Fetal 
Bovine Serum (FBS) containing 15% Dimethyl Sulfoxide (DMSO). The cryovials containing 
cells will be placed in special freezing containers at -80C overnight. After which, cryovials will 
be transferred to liquid nitrogen. After a minimum of 48 hours in liquid nitrogen storage, cells 
will be thawed in a 37C water bath. A single vial will be resuspended in approximately 10ml of 
warm RPMI with 10% FBS. Cells will be centrifuged at 1800 RPM for 5 minutes, and 
supernatant will be aspirated. The cell pellet will then be resuspended in 2ml of ice cold 
Phosphate Buffered Saline (PBS) containing 2.5% FBS (staining solution) and human anti-
CD16/CD32 blocking antibodies and incubated on ice. After 15 minutes, cells will be aliquoted 

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into a V-bottom 96 well plate (approx. 500,000 cells/100ul/well) and incubated with specific 
antibodies at manufacturer’s recommended concentrations for 45 minutes in the dark. In the case 
of intracellular markers (e.g. FoxP3) plates will be incubated with antibodies targeting membrane 
markers, fixed with 1% Formaldehyde and treated with a cellular permeabilization reagent (e.g., 
saponin) prior to the addition of the intracellular protein targeting antibodies. Cells will be spun 
down at 1800 RPM at 4C for 5 minutes, and washed twice with cold staining solution. After 
washing, plates will be incubated on ice in the dark with 3uM of DAPI for 10 minutes. Cells will 
be washed once more with staining solution and then finally resuspended in 150ul of staining 
solution.  
 
Antibody panels for Flow Cytometry 
The following immune cell populations will be detected in PBMCs using specific marker 
antibodies and flow cytometry gating strategies: Regulatory T cells (CD4+/CD25+/FoxP3+), 
Effector T cells (CD4+/CD69+), Naïve T cells (CD4+/CD69-), Memory T cells 
(CCR7+/CD45RO+), CD8 Cytotoxic cells (CD8+/CD3+), Plasmocytoid Dendritic cells 
(CD123+/CD303+), Myeloid Dendritic cells (CD11c+/CD141+), Natural Killer cells (CD3-
/CD56+), Natural Killer T cells (a/bTCR+/NKG2D+), Classic Monocytes (CD14+), and 
Monocytic Myeloid-Derived Suppressor cells (CD14+/HLADR-).  
 
Detection of soluble biomarkers 
Plasma from heparin treated blood will be collected, aliquoted and stored at -80C. Via 
Cytokine/Chemokine Multiplex assays, concentration levels will be assessed for up to 50 
biomarkers including (but not limited to) the following inflammatory mediators: IL-6, IFNg, 
TNFa, IL-10, IP-10, IL-1b, CXCL16, VEGF, and Ang1. The assays will be performed following 
manufacturer Standard Operating Procedures for each biomarker group panel. 
 
 
12.3 
Integrated Correlative Studies 
 
Immunohistochemical Staining for CD274, CD273, CD279, and ANGP2 
 
We hypothesize that not only CD274 but also CD279 and CD273 protein expression in tumor 
tissues might be associated with favorable clinical response, and might be served as biomarkers 
for patient selection for CD279 blockade in clinical treatment. We also hypothesize that 
ANGPT2 protein expression in tumor tissue might be a biomarker to identify a group of patients 
who might have objective responses with anti-vascular endothelial growth factor therapies.  
 
Assay, patient and specimen information 
 
Immunohistochemical (IHC) staining of CD274, CD273, CD279 and ANGPT2 will be used as 
integrated markers in the clinical trial, which might be used in the future phase II trials to 
identify a group of patients who would have a good response to the treatment as a stratification 
variable. Tumor specimens will be collected from metastatic deposits ovarian cancer, colorectal 
cancer and renal cell carcinoma. Pre-treatment archived specimens will be retrieved if no fresher 
tumor can be obtained prior to treatment initiation on day 1. Post-treatment tissues will be 
collected and fixed by 10% neutral buffered formalin overnight, dehydrated and paraffin 

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embedded.  Four-micrometer-thick sections will be cut.  The paraffin blocks and unstained slides 
will be stored at room temperature.  
 
 
 
 
 
 
Primary antibody characteristics 
 
Mouse monoclonal anti-CD279, anti-CD274 and anti-CD273 antibodies were generated in the 
  The antibodies are human 
gene product and can recognize all isoforms.  The specificity of these antibodies was confirmed 
by western blotting in human cancer cell lines and bands were at expected mass.  The IHC 
staining was abolished in knock-down cancer cells.  CD279 is expressed on the surface of 
activated T cells.  CD274 is present in macrophages, dendritic cells, T cells, B cells and in 
multiple cancers (Sznol M, 2013).  CD273 is expressed on dendritic cells, macrophages and bone 
marrow-derived mast cells whereas its expression on cancers is under exploration (Rozali EN, 
2012).   No cross-reactive proteins that may confound interpretation of IHC staining were 
identified.  The antigens are stable when the period between tissue sectioning and staining is 
more than 30 days. 
 
ANGPT2 antibody will be purchased from Santa Cruz biotechnology company [Ang-2 (F-1): sc-
74403]. It is a mouse monoclonal antibody raised against amino acids of human origin. The 
antibody specificity has been confirmed by western blotting.  ANGPT2 expression is observed 
on endothelial cells and some cancers (Buehler D, 2013; Helfrich I, 2009).  The antigen is stable 
when the period between tissue sectioning and staining is more than 30 days. 
 
Design of immunohistochemical assay 
 
The IHC assay for CD274, CD273 and ANGPT2 is semi-quantitative while CD279 stained slides 
will be scanned by an automated scanning microscope and quantitatively analyzed 
 
 after they are evaluated and positive cells are 
manually counted by a pathologist.   
 
Standard EnVision two-step (indirect) staining method will be utilized. Four-micrometer-thick 
sections will be cut, deparaffinized, rehydrated and participanted to heat mediated antigen 
retrieval in citrate buffer (pH 6) (Invitrogen) by steaming for 30 minutes.  After cooling, tissue 
sections will be incubated with peroxidase block (DAKO, Carpinteria, CA) for five minutes, then 
serum free protein block (DAKO) for 20 minutes.  Slides will be incubated at room temperature 
for one hour with a primary antibody. Antibodies will be diluted in Da Vinci Green Diluent 
(Biocare Medical, Concord, CA).  EnvisionTM anti-mouse HRP-labeled polymer (DAKO) will be 
applied to the sections for 30 minutes, followed by visualization by using the chromogen 3, 3-
diaminobenzidine (DAKO). All the sections will then be counterstained with haematoxylin, 
dehydrated, mounted and coverslipped.   Positive and negative controls shall be included in each 
staining.  Known positive stained Hodgkin lymphoma (CD274), tonsil (CD279 and ANGPT2) 
and melanoma (CD273) slides will be used as external control (separate slides).  Stained slides 

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will be stored at room temperature. 
 
In our pilot study, immunoreactivity for CD274 was 
detected in the cytoplasm and cell membrane while 
CD273 and CD279 expression was observed in the 
cytoplasm.  ANGPT2 expression is present in the 
cytoplasm (Buehler D, 2013).  Scoring for CD274, 
CD273 and ANGPT2 will be semi-
quantitative/ordered categorical.  The percentage of the 
tumor cells staining positive for CD274, CD273 or ANGPT2 and the intensity of the tumor cells 
will be recorded as 0 (no staining), 1 (weak staining), 2 (moderate staining) and 3 (intense 
staining).   Absolute CD279 positive cells will be counted under microscope lens x 20 power 
field.  Representative 5 areas will be chosen to count. The average number from 5 areas will be 
recorded and be compared with data from image analysis.   
 
CD279
CD274
CD273
Assay performance 
 
The results will be obtained on retrospective data sets.  Protocols of these three antibodies have 
been optimized, standardized to minimize staining variance.  Positive control and negative 
controls were used and stained separately with each batch of slides. The IHC staining of three 
markers (CD274, CD273 and CD279) has been performed in two different labs by three different 
technicians on whole tissue sections of Hodgkin lymphomas, melanomas, lung cancers and renal 
cell carcinomas. Three readers were involved, confirming the good reproducibility of the assay. 
 
Tumor will be considered positive if >5% (CD274) (Topalian S, 2012) or 10% (CD273 and 
ANGPT2) of the tumor cell population demonstrates unequivocally staining, respectively.  
CD279 positivity was defined as >3% positive cells/HPF (Bachireddy P, 2013).   
 
 
 
Figure 29 shows the 
immunohistochemical 
staining of CD279, 
CD274 and CD273 in 
advanced melanoma. 

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interpretation. 
 
For CD279 staining, slides will be scanned by an automated scanning microscope and analyzed 
by Aperio image analysis system (Leica Biosystems). Tumor areas will be marked by a 
pathologist to exclude non-neoplastic areas, such as stroma, normal epithelial and necrotic 
regions. The software will be used to count the number of positive cells in each tissue. The 
percentage of CD279 positive cells will be calculated. Data will be compared with that of manual 
counting by a pathologist to exclude tissue artifacts that cannot be recognized by computer image 
software. 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
12.4 
Exploratory/Ancillary Correlative Studies 
 
Monitoring Peripheral Blood for Changes in Immune Function and Angiogeneic Factors 
Correlative sciences will be expanded from the previous determined biology and analyses 
developed through our experience thus far with ipilimumab and ipilimumab-bevacizumab treated 
patients. Subpopulations of PBMCs will be isolated, including but not limited to dendritic cells, 
T cells, and B cells.  Phenotype changes in these cell populations by flow cytometry will be 
determined as a function of treatment. These include regulatory and effector immune panels, 
naïve and memory CD4, CD8 and NK lymphocyte populations.  Given its importance in immune 
regulation and association, we will evaluate Tie-2 expressing monocytes (TEM). Changes in 
antigen specific responses to known tumor associated antigen epitopes (MART-1, NY-ESO-1) 
will be determined utilizing HLA-A20201 peptide system for APC (including DC maturation 
and presentation) and targets.  
Both humoral and cellular immune responses will be investigated by ELISAs, ELISPOTs, and 
cytotoxic T cell chromium release assays.  We will investigate the effects on tumor vasculature 
and vascular active molecules as a function of treatment with the two-drug combination.  We 
have recently reported that pre-treatment serum VEGF levels predict clinical benefit to 
ipilimumab(Yuan, Zhou et al. 2014).  We will therefore investigate angiogenic cytokines 
pretreatment levels as well as changes in levels as a function of treatment.  Studies will include 
monitoring VEGF, bFGF, and HGF levels.  Circulating endothelial cells and progenitors will be 
studied as a function of treatment. 

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For the analysis of cytokines, chemokines, and immune cell populations from serum or blood, 
data will be combined from all four diseases, resulting in longitudinal measurements for 48 
patients.  Serum marker levels will be summarized descriptively and graphically.  The time 
course of expression levels will also be summarized graphically by patient, noting disease group 
and times of disease progression. 
 
12.5 Sites Performing Correlative Study 
 
 
 
 
 
 
 
 
 
13. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting 
 
13.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
 
13.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
 
13.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 

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participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Endpoints 
  
This protocol is a phase Ib trial to assess the safety and tolerability of the combination of 
pembrolizumab with trebananib, determine the recommended dosing, and to obtain preliminary 
estimates of efficacy.  Dose-finding will be based on a standard 3+3, dose escalation design 
conducted in patients with solid tumors (Section 2.1).  After a recommended dose has been 
determined from the dose escalation, a dose expansion study will be conducted in three  cohorts 
of patients: ovarian, renal, or colorectal cancer.  For ovarian cancer 12 patients will be enrolled 
and treated. For CRC patients total of 37 patients will be enrolled on the expansion cohort. For 
the RCC cohort only 4 patients will be enrolled on the expansioncohort . 
 
Safety assessments will include all patients receiving one or more doses of either of the study 
drugs. Secondary and correlative endpoints will be based on the cohorts of patients enrolled in 
the dose expansion portion of the trial, and may include those patients in the dose escalation who 
received the recommended dose and had the same tumor type.  We will summarize secondary 
and correlative endpoints according to disease indication and, in an exploratory fashion, with all 
patients combined. 
 
14.2 
Sample Size, Accrual Rate and Study Duration 
 
Dose Escalation:  The dose escalation portion of the trial will enroll between 6 and 12 patients.  
The minimum would occur if dose cohorts 1 and -1 stop due to excess toxicity after the first three 
patients in each are assessed for DLT.  The maximum is based on two cohorts of 6 patients each.  
Patients in any dose escalation cohort who cease treatment during the DLT assessment window 
due to rapid progression of disease will not be counted as having a DLT, and may be replaced. 
Dose Expansion:  Total sample size will be 53 evaluable patients. The same criteria used to define 
evaluable patients for objective response in section 14.5 should be used here. 
Patients with melanoma, ovarian cancer, colorectal cancer or renal cancer who receive the 
recommended dose in the dose escalation will be included in the dose expansion analyses.    
We will close the melanoma cohort and stop enrolling on the current RCC cohort after 4 patients 
have been enrolled due to low accrual rate. We will continue enrolling ovarian cancer patients on 
the ovarian expansion cohort as planned up to 12 patients. 

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We performed an interim analysis of the 15 CRC patients who received the RP2D (3 in the dose 
escalation and 12 in the dose expansion) and observed a response rate of 7% (1 PR), 4 patients 
(26%) with best RECIST response of stable disease for a median of 10 months, and median OS of 
9 months.  The disease control rate (DCR), defined as best RECIST response of complete or partial 
response or stable disease of at least 6 months duration, was 33%. Since this activity exceeds the 
historical control in patients who were heavily pre-treated with chemotherapy (DCR 15%, median 
OS 5 months) (Grothey, Lancet. 2013 Jan 26;381(9863):303-12) we decided to expand the CRC 
cohort by adding 25 patients. We will expand the CRC cohort with a target sample size of 40 
patients (15 already enrolled plus 25 additional) to assess the DCR in these patients.  This will be 
a single-stage design that will have 85% power to detect a difference in DCR of 15% versus 30% 
with a one-sided alpha=0.1 using a chi-squared test.  The null DCR of 15% will be rejected if there 
are 9 or more patients with disease control out of 40 CRC patients.  For analysis, we will present 
the DCR with a one-sided 90% exact confidence interval. 
14.3 
Patient Characteristics 
Patient characteristics will be summarized by cohort.  Patient demographics and disease 
characteristics will be summarized using descriptive methods such as number and percent for 
factors measured categorically, and median and range for continuous characteristics.   
 
A detailed summary of patient disposition will be provided, which will include the numbers and 
proportions of patients enrolled in the study, treated under the protocol, as well as completing the 
study or discontinuing. 
 
14.4 Treatment Compliance 
The numbers of dose reductions or delays, numbers of cycles of treatment received, and dose 
intensity will be summarized for all treated patients for both study drugs. 
 
14.5 Endpoint Definitions 
Rate of DLT:  The proportion of patients with DLT in each dose escalation cohort. 
Objective response rate (ORR): Objective response will be determined by the best overall 
response designation (per RECIST 1.1) recorded between the date of first dose of trial therapy 
and the date of objectively documented disease progression or cessation of trial therapy, 
whichever occurs first. The objective response rate will be the proportion of patients achieving 
complete or partial response as their best response to therapy.  
 
Progression-free survival (PFS): Time from start of trial treatment until objective disease 
progression (per RECIST 1.1) or death, whichever occurs first. Deaths that occur after 12 weeks 
following the date last known progression-free will not be counted as PFS events.  For patients 
without progression or death within 12 weeks following the date last known progression-free, 
follow-up will be censored at the date of last disease assessment. Overall survival (OS): Time 
from start of trial treatment to death from any cause.  For patients who are lost to follow-up or 
who have no documentation of death at the time of final analysis, follow-up will be censored at 

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the date of last assessment of vital status. 
 
Time-to-progression (TTP): Time interval between the dates of the start of trial treatment and 
first documentation of progressive disease.  In the absence of documented progressive disease, 
follow-up will be censored at date of last disease assessment.  Deaths without prior progression 
will be censored events. 
 
14.6 Efficacy Analysis 
Secondary endpoints will be used to gain preliminary estimates of efficacy.  The analyses of 
secondary endpoints will be based on patients enrolled in the expansion cohorts and will be 
summarized within disease type.  ORR will be estimated for each disease cohort and will be 
summarized with 90% confidence intervals estimated using exact binomial methods.  For 
samples of size 12, the confidence intervals will be no wider than 0.5.   Time-to-event endpoints 
(i.e., PFS, OS, TTP) will be summarized using the product-limit method of Kaplan-Meier; 
confidence intervals will be based on log(-log(survival) methodology.  Six-month PFS, 12-
month OS, and median TTP will be presented, by disease, with 90% confidence intervals.   With 
few patients in each disease, statistical testing will be of low power.  Therefore, the analyses 
within disease will be primarily descriptive and will not rely on p-values.  
 
14.7 Safety Analysis 
Safety data will be presented for all patients who receive at least one dose of either of the study 
drugs.  All adverse events recorded during the trial will be summarized and presented by disease 
cohort or dose level.  The incidence of events that are new or worsening from the time of first 
dose of treatment will be summarized by dose level or disease cohort, system organ class and/or 
preferred term, severity (based on CTCAE V4 grade), type of adverse event, and relation to 
study treatment.  Deaths reportable as SAEs and non-fatal serious adverse events will be listed 
by patient and tabulated by primary system organ class, and type of adverse event. 
 
Safety data from the expansion cohorts will be used to further characterize the safety profile of 
the drug combination and evaluate the toxicity of the MTD from the dose escalation.  We assume 
that toxicities will be similar for each of the expansion cohorts; however, we will summarize 
safety data in both the aggregate and by cohort to allow for different adverse event types. Late 
toxicities observed and assessed as treatment related in the expansion cohort will be monitored. 
If two or more are observed, enrollment in the expansion cohort will be halted for further review 
and changing the RP2D will be considered. Given that trebananib is limited in use during only 
the first 12 weeks (4 cycles), we anticipate there is less chance that the combination of 
trebananib plus pembrolizumab will exhibit late toxicity in comparison to pembrolizumab given 
alone. 
 
The following table summarizes the probability of observing at least one patient with a 
treatment-related toxicity for varying true, but unknown, incidence rates.  Estimates in the table 
are based on individual expansion cohorts of size 12, and also for all 48 patients treated at the 
MTD.  
 

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Underlying incidence rate of 
treatment-related toxicity 
Probability of 1 or more of 12 
with treatment-related toxicity 
Probability of 1 or more of 48 
with treatment-related toxicity 
0.01
0.11
0.38
0.05
0.46
0.91
0.10
0.72
0.99
0.15
0.86
>0.99
0.20
0.93
>0.99
0.25
0.97
>0.99
   
For each expansion cohort of size 12, the probability of observing at least one patient with a 
dose-related toxicity is greater than 0.70 if the incidence rate of that toxicity is 0.10 or higher.  
For the aggregated safety data, there is greater than 0.90 probability of observing a toxicity if the 
incidence rate is 0.05 or higher. 
 
14.8 Proposed analyses of correlative endpoints  
For the analysis of cytokines, chemokines, and immune cell populations from serum or blood, data 
will be combined from all four disease groups according to treatment, resulting in longitudinal 
measurements for approximately 48 patients. Serum marker levels will be summarized 
descriptively and graphically.  The time course of expression levels will also be summarized 
graphically by patient, noting disease group and times of disease progression. Since patients may 
have rapid disease progression and terminate treatment early, the use of linear mixed models 
includes partial data in the analysis allowing characterization of outcome.  Transformations will 
be applied to the outcome measures to stabilize variability and normalize the distributions, when 
appropriate.   
 
In an exploratory analysis, we will summarize changes in biomarker levels in the subsets of 
patients who complete 6 months of treatment, recognizing that this may be a select group of 
participants with less severe disease.  Fold-changes will be calculated comparing 6-month and pre-
treatment levels (6-month/pre) and summarized descriptively.  We estimate that approximately 
40% of patients will complete 24 weeks of treatment, resulting in 19-20 patients.   
 
Biomarkers from tissue will be assessed using IHC.  Analyses relating baseline expression levels 
with response will be based on approximately 48 patient samples from newly obtained excisional 
biopsies or archival tissue.  Paired biopsies will be needed from 20 patients in the dose expansion 
cohort, ideally 5 per disease indication.  An endpoint of interest in the tissue analysis would be the 
proportion of patients with at least a 50% decrease in CD137 M2 macrophages.  We anticipate a 
null proportion of 0.20 with at least a 50% decrease.  The combination of trebananib with 
pembrolizumab would show important biomarker response if the proportion with 50% decrease in 
CD137 M2 macrophages is at least 0.45.  With 20 paired biopsies, an exact binomial test with 
nominal, two-sided, 0.1-significance level will have at least 80% power to detect the difference 
between proportions of 0.20 and 0.47.    
 
15. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 

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are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study.  
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status 
Grade
Description
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.