Clinical trial NCT02489357
Conditions: Stage IV Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2015-12-11; Completion date: 2017-11-30
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial studies the side effects and how well pembrolizumab and cryosurgery work with short term androgen ablation to treat patients with prostate cancer that has traveled from the original tumor, through the body, and formed a small number of new tumors in other parts of the body (oligo-metastatic). Cryosurgery, also known as cryoablation or cryotherapy, kills tumor cells by freezing them. The process also incites an immune response within the ablated tumor. Giving monoclonal antibodies such as pembrolizumab which enhance a systemic anti-cancer immune response, may augment the effects of cryosurgery and increase tumor killing at distant (metastatic) sites.

Detailed description:
PRIMARY OBJECTIVES:

I. Assess feasibility via the proportion of men reaching a low prostate-specific antigen (PSA) nadir (\< 0.6 ng/ml) at 1 year.

II. Evaluate the safety of cryotherapy to the prostate combined with pembrolizumab.

TERTIARY OBJECTIVES:

I. To evaluate the effects of combination cryotherapy / pembrolizumab on programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) expression in the prostate as assessed by biopsy performed 6 months post treatment.

OUTLINE:

Patients receive standard of care androgen ablation with degarelix subcutaneously (SC) once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving the first dose of pembrolizumab, patients undergo whole gland cryoablation of the prostate.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 1 year.

Arms: arm 1: Patients receive standard of care degarelix SC once a month for 8 months. Within 1 month of receiving degarelix, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Within 3 days of receiving pembrolizumab, patients undergo whole gland cryoablation of the prostate.
Interventions: intervention 1: Cryosurgery intervention 2: Degarelix intervention 3: Laboratory Biomarker Analysis intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Undergo whole gland cryoablation intervention 2: Given SC intervention 3: Correlative studies intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE:  A Pilot Study of MK-3475 with Cryotherapy for Men with Newly Diagnosed Oligo-
Metastatic Prostate Cancer  
Johns Hopkins Kimmel Cancer Center 
IRB #: IRB00045444 
SKCCC Protocol #: J1534 
IND number: Exempt 
 
 
Principal Investigator:  
Emmanuel Antonarakis, MD 
Johns Hopkins University School of Medicine 
Department of Oncology 
1550 Orleans Street, CRB1, Room 1M45 
Baltimore, MD 21287 
Office (410) 502-7528 
Email: eantona1@jhmi.edu  
 
Statistician:  Bruce J. Trock MD 
Johns Hopkins Kimmel Cancer Center 
Email: btrock@jhmi.edu 
 
Project Manager 
Ting Wang, MS, MHS 
Johns Hopkins Kimmel Cancer Center 
Email: twang2@jhmi.edu 
Lead Study Coordinator: 
Yelena Milman 
Johns Hopkins Kimmel Cancer Center 
Email: ymilman1@jhmi.edu  
 
 
 
 
Site:  
Johns Hopkins University  (Sidney Kimmel 
Comprehensive Cancer Center at Johns 
Hopkins And The Brady Urological Institute) 
 
Support Provided by: 
Merck & Co., Inc. 
 
Sponsor: 
The Johns Hopkins University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS  
1.0 
TRIAL SUMMARY .................................................................................................. 5 
2.0 
TRIAL DESIGN ....................................................................................................... 5 
2.1 
Trial Design ............................................................................................................. 5 
2.2 
Trial Diagram .......................................................................................................... 6 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) ........................................................................... 6 
3.1 
Primary Objective(s) & Hypothesis (es) ............................................................... 6 
3.2 
Exploratory Objective ............................................................................................ 6 
4.0 
BACKGROUND & RATIONALE ................................................................................ 7 
4.1 
Background ............................................................................................................. 7 
4.1.1 Pharmaceutical and Therapeutic Background ...................................................... 7 
4.1.2 Preclinical and Clinical Trial Data ........................................................................ 8 
4.2 
Rationale .................................................................................................................. 8 
4.2.1 Rationale for the Trial and Selected Subject Population ...................................... 8 
4.2.2 Rationale for Dose Selection/Regimen/Modification ........................................... 8 
4.2.3 Rationale for Endpoints ........................................................................................ 9 
4.2.3.1 Efficacy and Safety Endpoints ....................................................................... 9 
4.2.3.2 Biomarker Research ..................................................................................... 10 
5.0 
METHODOLOGY .................................................................................................. 10 
5.1 
Entry Criteria ........................................................................................................ 10 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 10 
5.1.2 Subject Inclusion Criteria.................................................................................... 10 
5.1.3 Subject Exclusion Criteria .................................................................................. 11 
5.2 
Trial Treatments ................................................................................................... 12 
5.2.1 Dose Selection/Modification .............................................................................. 13 
5.2.1.1 Dose Selection ............................................................................................. 13 
5.2.1.2 Dose Modification ....................................................................................... 13 
5.2.2 Timing of Dose Administration .......................................................................... 14 
5.2.3 Trial Blinding/Masking ....................................................................................... 14 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 14 
5.3.1 Acceptable Concomitant Medications ................................................................ 15 
5.3.2 Prohibited Concomitant Medications.................................................................. 15 
5.4 
Rescue Medications & Supportive Care ............................................................. 16 
5.4.1 Supportive Care Guidelines ................................................................................ 16 


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5.4.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-
related Adverse Events (irAEs) ................................................................... 17 
5.5 
Diet/Activity/Other Considerations ..................................................................... 18 
5.5.1 Diet ...................................................................................................................... 18 
5.5.2 Contraception ...................................................................................................... 18 
5.6 
Subject Withdrawal/Discontinuation Criteria ................................................... 18 
5.7 
Clinical Criteria for Early Trial Termination ................................................... 19 
6.0 
TRIAL FLOW CHART ............................................................................................. 20 
6.1 
Study Flow Chart .................................................................................................. 20 
7.0 
TRIAL PROCEDURES ............................................................................................ 21 
7.1 
Trial Procedures ................................................................................................... 21 
7.1.1 Administrative Procedures .................................................................................. 21 
7.1.1.1 Informed Consent......................................................................................... 21 
7.1.1.2 Inclusion/Exclusion Criteria ........................................................................ 21 
7.1.1.3 Subject Identification Card .......................................................................... 22 
7.1.1.4 Medical History ........................................................................................... 22 
7.1.1.5 Prior and Concomitant Medications Review ............................................... 22 
7.1.1.6 Disease Details and Treatments ................................................................... 22 
7.1.1.7 Assignment of Screening Number ............................................................... 22 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) ................................... 22 
7.1.2 Clinical Procedures/Assessments ........................................................................ 23 
7.1.2.1 Adverse Event (AE) Monitoring .................................................................. 23 
7.1.2.2 Physical Exam .............................................................................................. 23 
7.1.2.3 Vital Signs .................................................................................................... 23 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 23 
7.1.2.5 Tumor Imaging and Assessment of Disease ................................................ 23 
7.1.2.6 Tumor Tissue Collection.............................................................................. 23 
7.1.3 Laboratory Procedures/Assessments .................................................................. 23 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 23 
7.1.3.2 Research blood samples Evaluations ........................................................... 25 
7.1.4 Other Procedures ................................................................................................. 25 
7.1.4.1 Withdrawal/Discontinuation ........................................................................ 25 
7.1.5 Visit Requirements .............................................................................................. 25 
7.1.5.1 Screening...................................................................................................... 25 
7.1.5.2 Treatment Period .......................................................................................... 25 
7.1.5.3 Post-Treatment Visits................................................................................... 26 
7.1.5.4 Follow-up Visits........................................................................................... 26 
7.2 
Assessing and Recording Adverse Events .......................................................... 26 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ......................................................................................... 27 
7.2.2 Reporting of Pregnancy to the Sponsor and to Merck ........................................ 27 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 28 


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7.2.3.1 Serious Adverse Events ............................................................................... 28 
7.2.3.2 Events of Clinical Interest ............................................................................ 29 
7.2.4 Evaluating Adverse Events ................................................................................. 30 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 33 
8.0 
STATISTICAL ANALYSIS PLAN ............................................................................... 33 
8.1 
Statistical Analysis Plan Summary ..................................................................... 33 
8.2 
Statistical Analysis Plan ....................................................................................... 33 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ............... 34 
9.1 
Investigational Product ........................................................................................ 34 
9.2 
Packaging and Labeling Information ................................................................. 34 
9.3 
Clinical Supplies Disclosure ................................................................................. 35 
9.4 
Storage and Handling Requirements .................................................................. 35 
9.5 
Returns and Reconciliation .................................................................................. 35 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ..................................................... 35 
10.1 
Confidentiality ....................................................................................................... 35 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 35 
10.3 
Compliance with Trial Registration and Results Posting Requirements ........ 35 
10.4 
Quality Management System ............................................................................... 36 
10.5 
Data and Safety Monitoring................................................................................. 36 
11.0 
LIST OF REFERENCES ........................................................................................... 36 
12.0 
APPENDICES ....................................................................................................... 39 
12.1 
ECOG Performance Status .................................................................................. 39 
12.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 39 
12.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 39 
 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
MK-3475 and Cryotherapy for treatment of Metastatic 
Prostate Cancer 
Trial Phase 
Pilot 
Clinical Indication 
Metastatic Prostate Cancer 
Trial Type 
Single-arm open-label phase 2 trial 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
N/A 
Treatment Groups  
Single arm (MK-3475 with Cryotherapy and intermittent 
ADT) 
Number of trial subjects 
12 
Estimated duration of trial 2 years (accrual and follow up) 
Duration of Participation 
1 year 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This will be a single-arm open-label phase-2 trial for men with newly diagnosed oligo-
metastatic prostate cancer who are eligible for cryotherapy. 
Current standard of care for men with newly diagnosed metastatic prostate cancer involves 
continual or intermittent androgen deprivation.  These regimens historically result in less than 
25% of men (12% in the most recently reported large study) achieving an undetectable PSA 
(<0.2 ng/ml) at 1 year (Sweeney et al ASCO 2014).  Patients on this study will be treated with 
a single course of intermittent androgen deprivation therapy (ADT) utilizing Degerelix for 8 
months.  One month following initiation of ADT, patients will undergo whole gland 
cryoablation of the prostate.  All patients will receive Pembrolizumab 200mg every 3 weeks, 
starting at the time of cryoablation and continuing for 4 months q 3 weeks (for a total of 6 
doses).  PSA levels will be measured every 3 months with bone scan and CT or MRI scan 
performed at 6 month intervals.  A prostate biopsy will be performed at the 6 month mark.  
Biopsy specimens will be assessed for PD-1 and PD-L1, along with CD8, CD4, FoxP3 and 
Ki67, using standard IHC methods available in the cancer center core.  Staining will be 
compared to the pre-treatment diagnostic biopsies.  The primary efficacy end point will be the 
proportion of men with PSA <0.6ng/ml at one year following initiation of treatment.    
 
 
 
 
 
 
 
 
 
 
 


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2.2 
Trial Diagram 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis (es) 
(1) Objective: Assess feasibility via the proportion of men reaching a low PSA nadir 
(<0.6ng/ml) at 1 year. 
Hypothesis: Cryoablation combined with MK-3475 and intermittent androgen deprivation 
will result in an increased percentage of metastatic patients achieving a PSA nadir of 
<0.6ng/ml at 1 year. 
 (2) Objective: Evaluate the safety of cryotherapy to the prostate combined with 
Pembrolizumab.  
Hypothesis:  The combination of cryoablation of the prostate with MK-3475 
(Pembrolizumab) with standard of care treatment (intermittent androgen blockade) will be 
well tolerated by patients, with minimal Grade 3 or 4 toxicities. 
3.2 
Exploratory Objective 
(1) 
Objective: To evaluate the effects of combination cryotherapy / pembrolizumab on PD-
1 and PD-L1 expression in the prostate as assessed by biopsy performed 6 months post 
treatment. 
 


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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 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) [7; 8].  The structure 
of murine PD-1 has been resolved [9].  PD-1 and its associated 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 [7; 10; 11; 12].  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 [13; 14].  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, Treg and Natural 
Killer cells [15; 16].  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells [17].  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 [18; 19; 20; 13].  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains 
in the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-
L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues [13].  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels 
of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion 
in subjects with melanoma (MEL) [21].  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. 


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MK-3475 (previously known as SCH 900475) 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.   
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
For men with localized prostate cancer, primary treatment with radiation therapy or 
surgery represents standard-of-care therapy with defined efficacy.  For men who present with 
oligo-metastatic disease, the standard treatment is systemic therapy with androgen-ablating 
drugs; a regimen associated with substantial morbidity and mortality, and with only a modest 
benefit in terms of long-term survival.  Indeed the prognosis for men who initially present with 
metastatic disease is not especially favorable; a recent Eastern Cooperative Oncology Group 
(ECOG) study showed that these men have a 3-year overall survival (OS) of only 50%, which 
may be slightly improved by early administration of docetaxel-based chemotherapy.  Indeed, 
an effective treatment for men who present with oligo-metastatic prostate cancer 
represents an unmet medical need. 
One alternative treatment for such men may be a combination of cryotherapy (which 
ablates the prostate in situ, and which is associated with only minimal morbidity) with immune-
modulation.  We (Levy, Drake, Fuchs et al. J Pharmacol Exp Therapeutics 2009) and others 
(Waitz and Allison et al. Cancer Research 2012) showed that cryotherapy has immune-
stimulating properties.  In carefully controlled studies in a prostate cancer model, the Allison 
group showed that combining immune checkpoint blockade with cryotherapy of a single lesion 
could prevent establishment of a second distant metastasis.  Our group has experience in this 
regard, having completed a small proof-of-concept study combining cryotherapy with 
immunomodulatory dosing of cyclophosphamide in men with metastatic prostate cancer 
(Sidana et al Urology 2010).   
While the optimal immunomodulating agent to combine with cryotherapy is the subject 
of ongoing preclinical experimentation, in some respects PD-1 blockade with pembrolizumab 
represents a nearly ideal companion for cryotherapy because of its documented clinical 
efficacy in multiple tumor types, its acceptable toxicity profile, and the notion that prostate 
cancer cells can express PD-L1 upon stimulation with appropriate cytokines in vitro (Drake et. 
al., unpublished).  We thus propose that: cryotherapy for prostate cancer can be 
administered in combination with PD-1 blockade, and that this combination may mediate 
systemic responses in distant lesions.   
Though we feel that the rationale is sound and pre-clinical evidence is promising, the 
informed consent process will specifically inform patients that cryotherapy either alone or in 
combination with MK-3475 and androgen deprivation represents a non-standard approach to 
metastatic disease and that no studies have shown that cryotherapy will be beneficial in this 
setting.  We will also inform patients that cryoablation can be associated with irreversible side 
effects, most notably the inability to maintain erection and in some cases with incontinence.  
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 


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three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date. Recent data from other 
clinical studies within the MK-3475 program have shown that a lower dose of MK-3475 and 
a less frequent schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings and a fixed dose of 200mg every 3 weeks will 
be chosen for this investigation. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy and Safety Endpoints 
Efficacy endpoints include a PSA of <0.6ng/ml at 12 months.  This level of PSA has 
previously been shown to indicate cure in men with localized prostate cancer treated with 
prostate cryoablation (Levy et al J Urol 2009).  The proportion of men with PSA <0.6ng/ml at 
1 year after undergoing cryoablation with MK-3475 and intermittent androgen deprivation will 
be compared to historical controls (12% of men treated with androgen deprivation alone in the 
recently reported CHAARTED trial achieved an undetectable PSA (<0.2ng/ml) at 1 year when 
on androgen deprivation alone) (Sweeney et al ASCO 2014).  Treatment failures will include 
those men with persistently rising PSAs as well as those developing new metastatic disease on 
imaging at the 6 and 12 month assessments.  Men with stable low PSAs but not reaching 
<0.6ng/ml will be considered partial responders.   
A co-primary end point will be safety.  Here, more than 2 clinically significant (i.e. 
non-laboratory) grade IV or any grade V event will prompt ending of the trial and a claim of 
futility. 


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4.2.3.2 Biomarker Research 
We hypothesize that the combination of cryotherapy and pembrolizumab will promote an 
immune infiltrate, enriched in CTLs, into the prostate and that the extent of this infiltrate will 
correlate with clinical response.  PD-1 and PD-L1 levels in the prostate as well as the immune 
infiltration into the prostate will be examined by immuno-histochemistry (IHC).  IHC utilizing 
antibodies directed against PD-1, PD-L1, CD8, CD4, FoxP3 and Ki67 will be used for staining 
on prostate biopsy tissue obtained before treatment and at 6 months following initiation of 
treatment. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Men entering into the trial are required to have oligo-metastatic prostate cancer with 
no prior treatment.  Oligo-metastatic disease will be defined as <5 extra-pelvic metastasis.  The 
metastatic lesions may be lymph nodes, with pathological enlargement considered if greater 
than 10mm in size along the longest axis. 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have histologically or cytologically diagnosed oligo-metastatic prostate cancer.  Oligo-
metastatic disease is defined to reflect men with low volume disease.  Specifically, 
oligo-metastatic disease is defined as less than 5 extra-pelvic metastases.  Metastatic 
lesions may be lymph nodes. 
2. Be willing and able to provide written informed consent/assent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent. 
4. Have available tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
5. ECOG Performance Scale status of 0 or 1. 
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 14 days of 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  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 


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Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
7. Subjects who have been on hormonal therapy up to 30 days prior to enrollment and 
receiving Degarelix are allowed to be on the study. 
8. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has had a prior monoclonal antibody 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.  
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.   
7. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects with 
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 


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8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12. Is expecting to 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. 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways). 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
17. Has severe voiding symptoms (IPSS >20) or urinary retention requiring a catheter 
18. Has contraindications to cryotherapy of the prostate, including:  previous TURP with 
persistent TUR defect, existing peri-anal or recto-urethral fistula, previous external 
beam radiation therapy or brachytherapy, coagulopathy, inability to tolerate anesthesia 
(spinal or general), inability to tolerate transrectal ultrasound (i.e. history of previous 
abdominal perineal resection). 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2.  In regards to cryotherapy, 
whole gland cryoablation will be performed using an argon/helium gas-based system (in this 
study the Endocare cryoablation system will be used).  After the patient is placed under 
anesthesia and into lithotomy position and peri-operative antibiotics are given, a trans-rectal 
ultrasound probe will be entered for volume mapping.  Cryoablation probes and thermocouple 
sensors will then be inserted (with thermocouple probes in the Denovillier’s fascia and at the 
external striated sphincter).  After cystoscopy to demonstrate no probe intrusion into the 
urethra or bladder, a warming catheter will be inserted.  Two cycles of cryoablation will be 
performed under transrectal ultrasound monitoring to documented temperatures below -40 
degrees Celsius.  Following these two freeze / thaw cycles the warming catheter will be left in 
place for an additional 15-20 minutes.  The warming catheter will be replaced by a foley 
catheter.  Catheters will be removed at 10-15 days post treatment and a voiding trial performed.  
Table 2  Trial Treatment 
Drug/ 
Procedure 
Dose/Potency 
Dose 
Frequency 
Route 
of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475 
200mg 
Q3 weeks 
IV infusion 
4 months (starting 1 
month after ADT) 
Experimental 
Degarelix 
240mg 
loading, 80mg 
maintenance  
Q1mo 
SQ injection 
8 months 
Standard 
of 
Care 


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Drug/ 
Procedure 
Dose/Potency 
Dose 
Frequency 
Route 
of 
Administration 
Regimen/Treatment 
Period 
Use 
Cryotherapy 
N/A 
Once 
N/A 
Cryoablation of the 
prostate occurring 1 
month after initiation 
of ADT 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.2.1.2. 
 
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 4.0 – 
Background and Rationale.   
 
5.2.1.2 Dose Modification  
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities, non-hematological 
toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as 
per Table 3 below. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing 
for 
restarting 
treatment 
Dose/Schedule for 
restarting treatment 
Discontinue 
Subject 
(after 
consultation with 
Sponsor) 
Hematological Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding Grade 
3 
neutropenia, 
anemia, 
and 
thrombocytopenia 
Yes 
Toxicity resolves 
to Grade 0-1 or 
baseline 
May increase the 
dosing interval by 1 
week  
Toxicity does not 
resolve within 12 
weeks 
of 
last 
infusion 
Permanent 
discontinuation 
should 
be 
considered 
for 
any 
severe 
or 
life-threatening 
event 
4 
Yes 
Toxicity resolves 
to Grade 0-1 or 
baseline 
May increase the 
dosing interval by 1 
week  
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
Grade 2 alopecia 
Grade 2 fatigue 
 
For 
additional 
information 
regarding Adverse Events with a 
potential 
Immune-Etiology 
reference, please see the separate 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for persistent 
symptoms 
Toxicity resolves 
to Grade 0-1 or 
baseline 
Clinical 
AE 
resolves within 4 
weeks:  Same dose 
and schedule  
 
Clinical AE does 
not resolve within 4 
weeks: 
 
May 
increase the dosing 
interval by  1 week 
for each occurrence 
Toxicity does not 
resolve within 12 
weeks 
of 
last 
infusion 


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Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing 
for 
restarting 
treatment 
Dose/Schedule for 
restarting treatment 
Discontinue 
Subject 
(after 
consultation with 
Sponsor) 
Pembrolizumab Event of Clinical 
Interest Guidance Document. 
3, 4 
 
Yes 
 
Toxicity resolves 
to Grade 0-1 or 
baseline 
 
May increase the 
dosing interval by 1 
week 
for 
each 
occurrence 
 
Toxicity does not 
resolve within 12 
weeks 
of 
last 
infusion 
Permanent 
discontinuation 
should 
be 
considered 
for 
any 
severe 
or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
will be considered for discontinuation. Subjects with a laboratory adverse event still at Grade 
2 after 12 weeks may continue treatment in the trial only if asymptomatic and controlled.  As 
it is unknown whether MK-3475 will increase the local toxicity of cryotherapy, we will 
specifically assess for local toxicity prior to each infusion of drug.  This includes assessment 
of pelvic pain, genital swelling, new incontinence, urinary retention and recto-urethral fistulas.  
If these toxicities are present and worsening with MK-3475 re-challenge the subject will be 
discontinued from trial treatment.   
 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 should be discontinued from trial treatment. 
 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
MK-3475 will be administered as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 5.2.1.2).  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). 
 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 


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vaccination may be required.  The investigator should discuss any questions regarding this 
with the Sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Sponsor, and the subject.  
 
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy beyond that specified in this 
protocol 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than MK-3475 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed..  
• 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.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
• Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).  In symptomatic 
subjects, infectious etiologies should be ruled out, and if symptoms are persistent 
and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), MK-3475 will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated at 
a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), MK-3475 should be withheld 
and anti-diarrheal treatment should be started.  If symptoms are persistent for 
more than one week, systemic corticosteroids should be initiated (e.g., 0.5 
mg/kg/day of prednisone or equivalent).  When symptoms improve to Grade 1 
or less, corticosteroid taper should be started and continued over at least 1 
month.  Regarding guidelines for continuing treatment with MK-3475, see 
Section 5.2. 
o All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard institutional 
practice. 
• Immune-related adverse events: Please see the separate guidance document regarding 
diagnosis and management of adverse experiences of a potential immunologic etiology.   
• Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation 
of tumor pain due to treatment); Urticaria (hives, welts, wheals); Vomiting. 


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Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475. 
 
Table 5 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
MK-3475 with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
trial treatment administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.4.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 


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immune phenomenon.  irAEs may be predicted based on the nature of the MK-3475 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive 
of potential irAEs.  An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Pembrolizumab 
Event of Clinical Interest Guidance Document. 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
5.5.2 Contraception 
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  Men engaging in 
intercourse with a sexual partner able to conceive should use at least 2 methods of birth control.  
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for greater than 1 year will be 
considered postmenopausal), or 3) not heterosexually active for the duration of the study.  The 
two birth control methods can be either two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects should start using birth control from study 
Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
to the Sponsor and to Merck.  If there is any question that a subject will not reliably comply 
with the requirements for contraception, that subject should not be entered into the study. 
 
 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.   
 
A subject must be discontinued from the trial for any of the following reasons: 


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• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Unacceptable adverse experiences  
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow Chart) 
and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue 
for reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each subject will be 
followed by telephone for overall survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
 
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 


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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart  
Trial Period 
Screening 
Phase 
Treatment Cycles MK-3475 
(Treatment cycles are 3 weeks) 
End of MK-
3475  
Post-Treatment 
Treatment Cycle/Title 
Screening  
1 
2 
3 
4 
5 
6 
Discont. 
Safety 
Follow up 
Follow up 
Scheduling Window  
-28 to -1 
+ 3 days for all 
At time of 
Discont. 
30d post 
MK-3475 
Every 
12 
weeks post 
ADT*  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Post-study anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Cryoablation of the Prostate 
 
X 
 
 
 
 
 
 
 
 
Androgen Deprivation 
Therapy (8 months total) 
X 
 
 
Pembrolizumab (MK-3475) 
Administration 
 
X 
X 
X 
X 
X 
X 
 
 
 
Review Adverse Events 
(including local symptoms:  
pelvic pain, swelling, 
incontinence, fistula) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Procedures / Assessments:  analysis performed by LOCAL laboratory 
PT/INR and aPTT 
X** 
 
 
 
 
 
 
 
X 
 
CBC with Differential 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry Panel 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X** 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
X** 
 
X 
 
X 
 
X 
X 
X 
 
Efficacy Measurements 
PSA 
X**** 
 
 
 
X 
 
 
 
X 
X 
Tumor Imaging (BS/CT)  
X**** 
 
 
 
 
 
 
 
X 
X*** 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
Tissue -TRUS guided 
prostate biopsy 
X 
 
 
 
 
 
 
 
 
 
 
TRUS guided prostate biopsy 
Research Biopsy 
 
 
 
 
 
 
 
 
X 
 
Blood for (lymphocytes) and 
serum for immunological 
Studies 
X 
 
X 
 
X 
 
X 
X 
X 
 
*Every 12 weeks post ADT up to 1 year 
**Screening Lab tests for determining eligibility are to be performed within 10 days prior to the first dose of (MK-3475).  
*** Imaging assessment by bone scan and CTor MRI scan will be every 6 months.  
**** Initial scans and PSA should be performed within 60 days of starting MK3475 


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Table 6:  Study flow chart 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.  Importantly, the informed consent will specifically state that 
cryotherapy, either alone or in combination with MK-3475, is not a standard treatment 
approach for metastatic prostate cancer.  No studies have shown that cryotherapy, either 
alone or in combination with MK-3475, is beneficial in this setting and cryotherapy may be 
associated with certain irreversible side effects such as inability to maintain an erection or 
inability to retain urine. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  


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7.1.1.3 Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent. 
 
7.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.  
 
7.1.1.5 Prior and Concomitant Medications Review 
7.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
 
7.1.1.6 Disease Details and Treatments 
7.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
 
7.1.1.7 Assignment of Screening Number 
Subjects will be assigned a screening number at the time of the screening visit. 
  
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Trial compliance will be assessed at treatment and post treatment visits. 


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7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 12.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See the separate Pembrolizumab Event of Clinical Interest Guidance 
Document.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Physical Exam 
The investigator or qualified designee will perform a physical exam during the screening 
period and prior to trial treatment administration. Clinically significant abnormal findings 
during the screening period should be recorded as medical history.   
7.1.2.3 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 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.4) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.  
7.1.2.5 Tumor Imaging and Assessment of Disease 
Tumor imaging by bone scan and CT or MRI scan will begin following discontinuation of 
treatments (6 months after trial initiation).  Bone scan and CT or MRI of the abdomen and 
pelvis will be performed every 6 months; roughly at the 6 month (time of discontinuation) and 
12 month marks.  PSA will also be tested at this time interval. 
 
7.1.2.6 Tumor Tissue Collection  
 Transrectal prostate biopsy will be performed at the 6 month mark to be used for correlative 
studies (immune-histochemistry). 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.   
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.   
 


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Table 7  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
PT (INR) 
Hemoglobin 
Alkaline phosphatase 
Glucose 
aPTT 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Total thriiodothyronine (T3) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Free tyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
PK 
 
  (CO2 or biocarbonate) 
 
Prostate Specific Antigen (PSA) 
 
Uric Acid 
 
 
 
Calcium 
 
Blood for Correlative Studies 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is elevated 
above the upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
‡ If considered standard of care in your region. 
 
 
 


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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
 
7.1.3.2 Research blood samples Evaluations 
7.1.3.2.1 Blood Collection for Peripheral blood lymphocytes 
Peripheral blood lymphocytes (PBLs) will be obtained by collecting 50 mL of blood drawn by 
60cc syringes into a 50 mL heparinized conical tube. PBLs will be prepared by Ficoll-Hypaque 
density gradient centrifugation according to standard protocols, and will be cryopreserved in a 
liquid nitrogen freezer at –140°C for further batched analyses. 
 
The time points for Peripheral blood lymphocytes are described in Section 6 – Trial Flow 
Chart.  
 
7.1.3.2.2 Blood Collection for Sera for Immunoassays  
At each time point (baseline/screening, Cycle 2, Cycle 4, Cycle 6, at time of Discontinuation 
and 30 day post MK-3475), the following research blood samples should be collected and 
processed as outlined below:  
• Draw approximately 10 mL of peripheral blood into 2 plain (red top) or SST (gold top) 
tubes, each containing ≥5 mL of blood per vacutainer.  
• Allow blood to coagulate for 20 minutes, then centrifuge at 25oC, 1500 x g (2700-3000 
rpm), for 15 minutes.  
• Pipette the serum into 10 cryotubes (about 0.5 mL/tube).  
• Store cryotubes frozen, below –20oC (–70oC preferred), until the time of analysis. 
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events. After discontinuing treatment, subjects should return to the site for a Safety 
Follow-up Visit and then proceed to the Follow-Up Period of the study.  
 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 
7.1.5.1 Screening 
Screening will occur after patients are identified via routine clinic visits to Urology, Medical 
Oncology or Radiation Oncology. 
 
7.1.5.2 Treatment Period 
Treatment will consist of androgen deprivation, MK-3475 and cryoablation of the prostate.  -
Degarelixwill begin after the main screening visit.  One month following androgen deprivation, 


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patients will undergo cryoablation of the prostate and additionally begin treatment with MK-
3475.  MK-3475 will continue for 6 treatments. Androgen deprivation will continue until the 
6 month mark. 
 
7.1.5.3 Post-Treatment Visits 
Following treatment, men will be evaluated at 12 week intervals up to the one year mark 
following initiation of treatment.  Evaluation will include following the post-study anticancer 
therapy status and the survival status  as described in the table above.  Following cryoablation 
of the prostate, men will have an indwelling catheter which will be removed 2 weeks later in 
the Urology clinic. 
 
 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.   
 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment will move into the Follow-Up Phase and should be 
assessed every 12 weeks (± 7 days) to follow the post-study anticancer therapy status and the 
survival status. Radiologic imaging assessment will be every 6 months to monitor disease 
status.  Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death or end of the study. 
 
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression (defined as 2 consecutive PSA 
elevations) or starts a new anti-cancer therapy, the subject moves into the survival follow-up 
phase and should be contacted by telephone every 12 weeks to assess for survival status until 
death, withdrawal of consent, or the end of the study, whichever occurs first.  
 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 


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of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose. No specific information is available on 
the treatment of overdose of MK-3475. In the event of overdose, MK-3475 should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
 
7.2.2 Reporting of Pregnancy to the Sponsor and to Merck 
Although pregnancy is not considered adverse events, it is the responsibility of investigators 
or their designees to report pregnancy in a subject’s partner within 120 days of completing the 
trial completing the trial, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier.  All female partners of male subjects who become 
pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 


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outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Refer to Table 8 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
 
JHM IRB reporting: 
Serious adverse events and protocol problems (e.g. protocol deviations, non-adherence) will 
be reported in compliance with JHMI. 
IRB guideline, “Organization Policy on Reports of Unanticipated Problems 
Involving Risks to Participants or Others” [Policy No. 103.6(b)] (most current version).  A 
copy of this document is located at  
http://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/organizatio
n_policies/103_6b.html.   
All deaths on study regardless of attribution must be reported to the JHM IRB. 
 


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All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the Sponsor within 24 hours and to Merck Global Safety within 
2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “Pembrolizumab Event of Clinical 
Interest Guidance Document.”  This document provides guidance regarding identification, 
evaluation and management of ECIs and irAEs.  Additional ECIs are identified in this guidance 
document and also need to be reported to the Sponsor within 24 hours and to Merck Global 
Safety within 2 working days of the event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not 
related to the Merck’s product, must be reported within 24 hours to the Sponsor and to Merck 
Global Safety within 2 working days. 
 


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7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


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Table 8 Evaluating Adverse Events 
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 subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an adverse event 
that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not 
worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not associated with 
an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously 
(designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an investigator who is 
a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and their respective 
elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 
 
 
 
 
 


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Relationship 
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 the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) Merck 
product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY 
THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency with 
Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration 
of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable possibility of 
Merck product relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product is 
reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable possibility 
Merck product relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable OR 
there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


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7.2.5 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.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The co-primary endpoints will be safety, determined as the rate of SAEs, and the 
proportion of patients with PSA (<0.6ng/ml) at 1 year.  Exploratory endpoints include 
correlation of biopsy PD-1 and PD-L1 expression with PSA response and tumor response via 
imaging, as well as evaluating whether expression is associated with other clinical or patient 
characteristics. 
 
8.2 
Statistical Analysis Plan 
Co-primary endpoints.  
Safety:  We will not separately evaluate cryotherapy alone, or ADT alone because they 
have well-established excellent safety profiles in this clinical setting.  Additionally, we will 
not include an arm with Pembrolizumab dose escalation because the approved dose has already 
been established.  We will monitor all patients for AEs, and calculate the proportion of patients 
with AEs by grade.  The trial will be stopped if more than 2 clinically significant (i.e. non-
laboratory) grade IV or any grade V event occurs.  
 
Efficacy:  In this 12 man study, the minimum expectation to continue will be that 30% 
of men reach the primary endpoint (PSA of 0.6ng/ml at 1 year with a detectable testosterone). 
The recently reported results from the CHAARTED study indicate that among men presenting 
with metastatic prostate cancer (without prior local treatment (73% of the cohort)) 11.7% will 
reach a PSA of <0.2ng/ml with continuous androgen deprivation alone at the one year mark.  
No evidence exists regarding the treatment of oligo-metastatic men with cryotherapy of the 
prostate alone - however it can be assumed that none of these men would achieve PSA <0.2 
ng/ml at the one year mark.  Evidence does exist in the primary prostate cancer treatment 
setting for localized disease and suggests that a PSA nadir of <0.6ng/ml after cryo-ablation 
indicates excellent local control (Levy et al J Urol 2009).     
The proportion of men with oligo-metastatic disease undergoing a combination of cryotherapy 
with Pembrolizumab and short term androgen blockade who reach a PSA of <0.6ng/ml at one 
year is unknown, and there is a paucity of PSA response data for other combination treatments 
in this setting. Stereotactic body radiation (SBRT) +/- androgen deprivation has achieved good 
responses with oligo-metastatic disease.  In one study PSA data were available.  Five patients 
had PSA levels recorded at 12 months or greater post-SBRT, and an additional 2 patients had 
PSA increasing within <12 months.  Among these 7 patients 2 (29%) had PSA<0.1 ng/ml at 
>12 months (Ahmed et al 2013).  All 7 patients also received ADT after SBRT.  This provides 
a conservative estimate of the minimum response rate we would like to observe in our trial to 
warrant further development of our proposed treatment regimen (“conservative” because 5 
additional patients achieved PSA <0.1 at last follow-up <12 months and are not included 
among the 7 patients on whom the 29% rate is calculated and because these patients were on 
continual ADT).   
 
 


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% undetectable PSA at 1 
year 
Lower 
95% 
confidence 
bound for n=12 
Lower 
95% 
confidence 
bound for n=14 
30% 
.10 
.11 
35% 
.13 
.15 
40% 
.17 
.18 
 
We will determine the proportion of patients who achieve PSA <0.6ng/ml at 12 months.  
Patients who are unable to complete 12 months of follow-up due to AEs or worsening disease 
will be considered treatment failures and will be included in the intention to treat calculation 
of the proportion with undetectable PSA.  The table shows the lower 95% confidence bound 
for different target proportions of undetectable PSA, including the minimum value of 30% 
derived above.  Confidence interval bounds were calculated using PASS v11 (NCSS Software, 
Inc., Kaysville, UT).  If promising results are seen, it would warrant further investigation in a 
larger, randomized Phase II trial.     
 
Exploratory endpoints  
Biopsy PD-1 and PD-L1:  Expression of each biomarker will be correlated with proportion 
undetectable PSA using logistic regression, and with change in tumor burden using ANOVA 
or Kruskal-Wallis.  Analyses to correlate expression with other binary or continuous clinical 
parameters will be similarly performed. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 10. 
Table 10  Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
Effective January 2017, marketed packs of the Investigational Product will be supplied for 
study use. As such, Merck will not supply any Chemistry, Manufacturing, Control (CMC) 
information. Investigator's regulatory submission should reference the Merck Marketing 
Authorization. If any additional labeling of containers is required, e.g. to add Study Protocol 
number, and it has not been agreed for Merck to perform the additional labeling, it is the 
investigator’s responsibility to arrange for this action to be done in accordance with U.S. 
regulations.  
 


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9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
The investigator agrees to keep all information provided by MERCK in strict confidence 
and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study 
documents provided by MERCK (investigators' brochures and other material) will be stored 
appropriately to ensure their confidentiality. The information provided by MERCK to the 
investigator may not be disclosed to others without direct written authorization from MERCK, 
except to the extent necessary to obtain informed consent from patients who wish to participate 
in the trial. 
 
10.2 Compliance with Financial Disclosure Requirements 
Investigators will provide disclosure of all financial relationships with MERCK or other 
companies to patients enrolling in the trial and additionally on any publications resulting from 
this study. 
 
10.3 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 subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 


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pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.   
   
10.4 Quality Management System 
The quality of data collection will be routinely monitored by the Johns Hopkins Sidney 
Kimmel Comprehensive Cancer Center (SKCCC) Data and Safety Monitoring Committee. 
 
10.5 Data and Safety Monitoring 
This is a DSMP Level II study under the SKCCC Data and Safety Monitoring Plan 
(12/6/2012). Data Monitoring of this protocol will occur on a regular basis with the frequency 
dependent on the rate of subject accrual and the progress of the study.  The protocol will be 
monitored internally at SKCCC by the Principal Investigator and externally by the SKCCC 
CRO in accordance with SKCCC guidelines.  Trial monitoring and reporting will be done 
through the Safety Monitoring Committee (SMC) at SKCCC.  
Additionally, scheduled meetings will take place monthly and will include the protocol 
principal investigator, research nurse, data manager, and, when appropriate, the collaborators, 
subinvestigators, and biostatistician involved with the conduct of the protocol. 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or real 
protocol violations), data completeness, and progress of data for secondary objectives. 
 
 
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S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J.  New response evaluation criteria in solid tumors:  revised RECIST guideline (version 1.1).  
Eur J Cancer 2009; 45:228-247. 
 
Levy DA, Pisters LL, Jones JS.  Primary Cryoablation Nadir Prostate Specific Antigen and 
Biochemical Failure.  J Urol 2009; 182(3):  931-7. 
 
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Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 
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10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. Tumor infiltrating 
lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol 2010;11:19. 
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12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and 
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13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. Int J Clin 
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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival of a patient 
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15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan Pathol 
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17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx V, et al. 
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tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 2008;99(10):1704-11.   
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. Prognostic 
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20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive selection in the 
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21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T cells in 
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22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value of tumour-
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23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell transfer 
therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.   
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic 
melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 2008;358(25):2698-703.   
25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ cell infiltration and 
granzyme B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian 
carcinoma. Cancer Immunol Immunother 2010;59:909-19.   
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-
mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to 
phosphotyrosine. PNAS 2001;98(24):13866-71. 
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 2005;23:515-48.   
28. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma:  prognostic factors. Cancer Control 
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29. Iannone R, Gergich K, Cong C, Kang P, Daud A, Dronca R, et al.  Efficacy and safety of MK-3475 in 
patients with advanced melanoma.  Pigment Cell Melanoma Res 2012;25:836-903. 


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30. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and 
immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med 2012:doi: 10.1056/NEJMoa1200690.   
31. Lyford-Pike S, Peng S, Young GD, et al.  Evidence for a role of the PD-1:PD-L1 pathway in immune 
resistance of HPV-associated head and neck squamous cell carcinoma.  Cancer Res 2013;73(2): Published 
online January 3. 
32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al.  New response evaluation 
criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. 
33. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al.  Guidelines for the evaluation of 
immune therapy activity in solid tumors: immune-related response criteria.  Clin Cancer Res 
2009;15(23):7412-20. 
34. Blum JL, Jones SE, Buzdar AU, LoRusso PM, et al. Multicenter Phase II Study of Capecitabine in 
Paclitaxel-Refractory Metastatic Breast Cancer. J Clin Oncol 17: 485-493, 1999 
35. Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus vinorelbine 
monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: 
final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 
2007;8(3):219. 
36. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, et al.  Phase III Trial of Doxorubicin, Paclitaxel, 
and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast 
Cancer: An Intergroup Trial (E1193).   J Clin Oncol. 2003;21(4):588. 
37. Stewart JSW, Ezra E.W. Cohen EEW, Licitra L, Van Herpen CML, et al.  Phase III Study of Gefitinib 
Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma of the Head and Neck.  
J Clin Oncol. 2009;27(11):1864. 
38. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, et al.  Open-Label, Uncontrolled, Multicenter 
Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent in Patients With 
Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Failed to Respond to 
Platinum-Based Therapy.   J Clin Oncol. 2007;25(16):2171. 
39. Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, et al.  Phase III Trial of Vinflunine Plus 
Best Supportive Care Compared With Best Supportive Care Alone After a Platinum-Containing Regimen 
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40. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, et al.  Phase II Study of Pemetrexed for 
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12.0 APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
* 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert 
Comis M.D., Group Chair. 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment.